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Schizophr Bull. Sep 2007; 33(5): 1100–1119.
Published online Jul 7, 2007. doi:  10.1093/schbul/sbm074
PMCID: PMC2632344

Molecular Targets for Treating Cognitive Dysfunction in Schizophrenia

Abstract

Cognitive impairment is a core feature of schizophrenia as deficits are present in the majority of patients, frequently precede the onset of other positive symptoms, persist even with successful treatment of positive symptoms, and account for a significant portion of functional impairment in schizophrenia. While the atypical antipsychotics have produced incremental improvements in the cognitive function of patients with schizophrenia, overall treatment remains inadequate. In recent years, there has been an increased interest in developing novel strategies for treating the cognitive deficits in schizophrenia, focusing on ameliorating impairments in working memory, attention, and social cognition. Here we review various molecular targets that are actively being explored for potential drug discovery efforts in schizophrenia and cognition. These molecular targets include dopamine receptors in the prefrontal cortex, nicotinic and muscarinic acetylcholine receptors, the glutamatergic excitatory synapse, various serotonin receptors, and the γ-aminobutyric acid (GABA) system.

Keywords: serotonin, dopamine, glutamate, NMDA, acetylcholine, GABA

Introduction

Schizophrenia is characterized by positive symptoms such as delusions and hallucinations, negative symptoms such as avolition and flat affect, and cognitive impairments. Although Kraepelin,1 with his term “dementia praecox,” characterized the relationship between cognitive deficits and schizophrenia nearly a century ago, effective treatments for these deficits have not been developed. Cognitive dysfunction is estimated to occur in 75%–85% of patients with schizophrenia,2 often precedes the onset of other symptoms,2 and persists even after other symptoms have been effectively treated.3 Indeed, a meta-analysis of cognitive deficits suggested that indices of cognitive deficits are much better predictors of functional outcome than indices from any other symptom domain.4 Furthermore, the severity of cognitive deficits is predictive of poorer medication compliance,5 overall treatment adherence,6 and increased tendency for relapse in first-episode patients.7

Until recently, antipsychotic drug development in schizophrenia has focused mainly on developing drugs that reduce the positive symptoms of schizophrenia,8 and indeed, all the current medications appear to be similar in efficacy for reducing positive symptoms in typical patients with schizophrenia.9,10 In a recent meta-analysis, patients treated with typical antipsychotics were actually shown to have small but detectable improvements in several cognitive domains11; however, due to extrapyramidal side effects, many patients are also treated with anticholinergic agents that are well known to impair memory12 and global cognitive ability.13 In addition, there is some evidence for the superiority of atypical antipsychotics, such as olanzapine and risperidone, over typicals in improving cognitive performance,1416 though the benefits are relatively small and have not been consistently reproduced.17 Overall, the widespread use of the atypical antipsychotics has likely offered some cognitive benefit for patients with schizophrenia,18 though significant deficits persist, suggesting a need for directive treatments for enhancing cognition.

Due to the continued need for improved treatment of the cognitive impairments in schizophrenia, Wayne Fenton spearheaded the National Institutes of Mental Health's joint academic and industry initiative termed MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) to facilitate the development of better treatments targeted at cognition.19 An initial MATRICS conference (http://www.matrics.ucla.edu) identified 7 primary cognitive domains that are crucial for developing targets for the treatment of cognition in schizophrenia. These domains included working memory, speed of processing, verbal learning and memory, attention and vigilance, reasoning and problem solving, visual learning and memory, and social cognition.2022 An additional MATRICS conference (http://www.matrics.ucla.edu) identified pharmacologic strategies that hold promise for the treatment of impaired cognition in schizophrenia. The primary molecular targets identified included dopamine receptors in the prefrontal cortex, nicotinic and muscarinic acetylcholine receptors, the glutamatergic excitatory synapse, various serotonin receptors, and the γ-aminobutyric acid (GABA) system. Below, we review many of the molecular targets being studied for potential drug development strategies aimed at enhancing cognition, both generally and specifically in schizophrenia (table 1).

Table 1.
Molecular Targets for Cognitive Enhancement in Schizophrenia

Cholinergic Targets

Acetylcholine is known to play an important role not only in motor function but also in various domains of cognition, particularly attention, learning, and memory.23 Indeed, cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer's disease and has also been postulated to contribute to the cognitive deficits of various neuropsychiatric disorders, including schizophrenia.23 The basal cholinergic complex sends widely diffuse afferents through 2 projections: the septohippocampal and the nucleus basalis of Meynart cortical pathways.24 The septohippocampal pathway is important in working memory processes through hippocampal storage of intermediate-term memory,25,26 whereas the nucleus basalis of Meynart cortical pathway is involved in reference memory through long-term information storage in the neocortex.27,28 Additionally, a role for acetylcholine in the processes of attention has been demonstrated in rats and monkeys.29 Pharmacologically, anticholinergic drugs, like scopolamine, produce learning impairments in healthy subjects similar to those of persons with dementia,30 while cholinomimetic drugs, like physostigmine, can significantly enhance the memory functions of healthy individuals.30,31

Although the degeneration of cholinergic neurons in the basal forebrain and the associated loss of cerebral neurotransmission that is seen in Alzheimer's disease are absent in schizophrenia,32,33 there is evidence of decreased nicotinic34 and muscarinic35 acetylcholine receptors in the cortex and hippocampus of individuals with schizophrenia. Interestingly, in patients with schizophrenia, decreased activity of choline acetyltransferase, a biosynthetic enzyme for acetylcholine production, was correlated with poorer cognitive functioning as measured by the Clinical Dementia Rating.33 In addition, some of the atypical antipsychotics, but not typical antipsychotics, can increase the release of acetylcholine in the prefrontal cortex, possibly contributing to their modest enhancement of cognition in schizophrenia.36 Thus, various targets within the cholinergic system are being investigated as potential enhancers of cognition in schizophrenia.

Cholinesterases

Cholinesterase inhibitors, such as donepezil and rivastigmine, are currently the main pharmacologic approach to the treatment of Alzheimer's disease and have been shown to slow the cognitive decline in this neurodegenerative disease.37 As such, it has been proposed that cholinesterase inhibitors may also be useful in the treatment of the cognitive dysfunction in schizophrenia.38 Acetylcholinesterase and butyrylcholinesterase are present in a wide variety of tissues and are broadly distributed in the brain. Inhibition of cholinesterases increases the synaptic concentration of acetylcholine, thereby enhancing and prolonging the action of acetylcholine on both muscarinic and nicotinic receptors. Therefore, cholinesterase inhibitors act as indirect cholinergic agonists at muscarinic and nicotinic receptors.

Following the administration of atypical antipsychotic treatment, cholinesterase inhibitors can increase the concentration of acetylcholine in the medial prefrontal cortex by 2- to 3-fold36 and have been demonstrated to produce some functional normalization of brain activity during verbal fluency task performance of schizophrenic patients characterized by a significant increase in frontal lobe and cingulate activity on functional magnetic resonance imaging (fMRI).39 As such, in recent years there have been multiple small randomized controlled trials of cholinesterase inhibitors in patients with schizophrenia, though results have been disappointing and inconsistent.40 It has been suggested that the lack of consistent effects of cholinesterase inhibitors may be due to the high rate of cigarette smoking among patients with schizophrenia41 and subsequent desensitization of nicotinic receptors,42 thus rendering increased acetylcholine levels ineffective.43 Indeed, galantamine, an acetylcholinesterase inhibitor that is also an allosteric potentiator of α7 nicotinic receptors,44,45 does not cause α7 receptor desensitization and has been shown to enhance cognitive functioning of schizophrenic patients in a 4-week double-blind placebo controlled trial.46 Interestingly, galantamine produced cognitive enhancement in schizophrenic patients despite the fact that all the patients smoked at least 10 cigarettes per day.46 Unfortunately, despite these initial positive findings, subsequent results with galantamine have been mixed.4749 Thus, while pure cholinesterase inhibitors may be of minimal benefit for enhancing cognition in patients with schizophrenia, possibly due to desensitization of their α7 nicotinic receptors from cigarette smoking, further study may be warranted with combined acetylcholinesterase inhibitors and allosteric potentiators of the nicotinic receptor in schizophrenia. However, it is likely that selective agents at various nicotinic and muscarinic receptors may be a more effective approach to developing drugs for treatment of the cognitive impairment in schizophrenia.

Nicotinic Receptors

It is well known that the smoking rates in individuals with schizophrenia are significantly higher than in the general population, and some have suggested that these individuals may be “self-medicating” with nicotine.50,51 Indeed, nicotine administration has been shown to improve various measures of cognition that may ease some of the side effects of antipsychotic medications.51 For example, in patients with schizophrenia, a nicotine transdermal patch could dose dependently reverse haloperidol-induced impairments in working memory, attention, and reaction time52 and has been shown to reduce haloperidol-induced bradykinesia and rigidity compared with a placebo patch.53 However, other studies have been mixed.54 Interestingly, in one study,55 some of the modest effects of cigarette smoking on clinical and cognitive outcome measures could also be improved by smoking denicotinized cigarettes, suggesting that nonnicotine components of cigarette smoke may also contribute.55 Overall, while research on nicotinic treatment of individuals with schizophrenia has shown that, in single administrations, nicotine improves some aspects of cognition, additional administrations are not effective due to rapid desensitization of nicotinic receptors.42 Thus, considerable research is exploring the potential use of nicotinic agents, particularly partial agonists and allosteric modulators at various nicotinic receptor subunits that would be less likely to cause rapid receptor desensitization.

Nicotinic acetylcholine receptors are ionotropic receptors with a pentameric structure composed of alpha (α2 to α9) and beta (β2 to β4) subunits and are expressed at high levels in the hippocampus, cortex, striatum, and thalamus.34,56 The 2 most prevalent nicotinic receptors are the α4β2, which is a high-affinity receptor, and the α7, which is a low-affinity nicotinic receptor, both of which have been shown to have reduced numbers in patients with schizophrenia.34,56 In addition, functional polymorphisms exist in the promoter region of the α7 receptor that have shown genetic linkage in schizophrenia.57,58

The α7 nicotinic receptor subtype is a highly studied target for the development of drugs for cognitive enhancement. Studies in rodents have shown that antagonists at the α7 nicotinic receptor induce sensory gating deficits similar to those seen in schizophrenia,59 a hippocampal phenomenon manifested as an inability to attend appropriately to sensory stimuli.60 Sensory gating deficits may strongly impact cognitive performance, and it has been shown that smoking transiently normalizes these sensory gating deficits.60 In addition, agonists at α7 receptors such as 3-2,4-dimethoxybenzylidene anabaseine (DMXB-A) can normalize the auditory gating deficits in rodents.61 Moreover, DMXB-A had a positive effect on a cognitive battery in a small proof-of-concept trial in humans,62 and additional clinical trials of α7 receptor agonists are underway. However, there is concern that long-term use of α7 agonists may induce the desensitization of nicotinic receptors, leading to a limited duration of efficacy.63 Thus, further development of α7 receptor partial agonists (eg, GTS-21) and allosteric potentiators (eg, galantamine) that induce minimal receptor desensitization is warranted.

In addition to α7 receptors, it has been suggested that α4β2 nicotinic receptors are involved in cognition.64 Indeed, α4β2 receptors are considered to represent more than 90% of the high-affinity nicotine-binding sites in the rat brain,65 and decreased levels of α4β2 receptor binding have been found in the hippocampus of patients with schizophrenia.56 Furthermore, agonists of α4β2 receptors, such as RJR2403 and SIB-1553A, can produce a significant and long-lasting improvement of memory in rats and monkeys.6668 Additionally, α4β2 agonists have been shown to stimulate the release of dopamine, norepinephrine, and acetylcholine in the hippocampus and frontal cortex in rats.66 Thus, nicotinic α4β2 receptor agonists may be of therapeutic benefit for the treatment of the cognitive deficits in schizophrenia by several mechanisms. In addition to α7 and α4β2 receptors, other nicotinic receptors, such as α3- and α6-containing receptors, may be involved in cognitive performance; however, studies are limited due to the lack of selective agonists and antagonists for these receptors.

Muscarinic Receptors

In addition to the ionotropic nicotinic receptors, numerous studies have implicated metabotropic muscarinic acetylcholine receptors in schizophrenia. Muscarinic receptors are G protein–coupled receptors69 found widely throughout the central nervous system on both cholinergic and noncholinergic cells where they function as both autoreceptors and heteroreceptors.7072 Of the 5 genetically distinct subtypes of muscarinic receptors (M1–M5), the M1 receptor has been most closely linked to cognition and schizophrenia.73 Indeed, the M1 receptor subtype is the most abundant of the muscarinic receptors in forebrain and hippocampus,74,75 brain regions crucial to normal cognitive functions. In addition, decreased M1 receptor binding has been reported in postmortem studies of the prefrontal cortex, hippocampus, and striatum from patients with schizophrenia,7678 that is, importantly, not due to chronic antipsychotic treatment.35,77,79 Interestingly, M1 receptor–deficient mice demonstrate deficits in working memory and remote reference memory indicative of impaired hippocampal-cortical interactions.80 Together, these results suggest that alterations in central M1 receptors may have a role in the pathophysiology of schizophrenia and that M1 receptor agonists may be beneficial in treating schizophrenia, particularly the cognitive impairments.73

Action at M1 receptors has been proposed to be a major contributor to the cognition-enhancing effects of clozapine,81 despite the fact that clozapine is an exceedingly weak partial agonist at M1 and other muscarinic receptors.73,82 Thus, attention has focused on various clozapine metabolites including clozapine-N-oxide and N-desmethylclozapine (NDMC). Clozapine-N-oxide is inactive while NDMC has actions at many receptors (http://pdsp.med.unc.edu/pdsp.php).82 Interestingly, NDMC is the major active metabolic of clozapine and has been reported to be a potent M1 agonist that preferentially binds to M1 receptors vs clozapine,83 although more comprehensive studies fail to demonstrate selectivity of NDMC for M1 receptors.84 In addition, NDMC has high affinities for 5-HT2A and 5-HT2C receptors and is a partial agonist at D2, D3 receptors85,86 and δ-opioid receptors,87 suggesting that this metabolite of clozapine may have antipsychotic and cognition-enhancing properties via a number of mechanisms. Furthermore, NDMC, but not clozapine, increases release of dopamine and acetylcholine in the prefrontal cortex and the hippocampus88 and potentiates NMDA receptor activity in the hippocampus.83 Thus, the cognitive enhancement observed with clozapine could actually be due to its metabolite NDMC via an uncertain mechanism.

Indeed, NDMC (ACP-104) and other M1 receptor agonists are in clinical trials as potential treatments of the cognitive dysfunction in schizophrenia. Xanomeline, a nonselective M1 and M4 muscarinic agonist with potent actions at a variety of additional nonmuscarinic receptors including 5-HT1A and 5-HT2A receptors,89 improved cognition and psychotic-like symptoms in Alzheimer's disease.90 In addition, monotherapy with xanomeline resulted in an improvement of positive symptoms and cognitive function in 20 subjects with schizophrenia91 but was discontinued due to poor tolerability.92 The relatively nonselective actions of xanomeline and NMDC at a number of receptors (http://pdsp.med.unc.edu/pdsp.php) should engender caution among schizophrenia researchers for embracing positive data from xanomeline and NMDC studies as being specifically indicative of a role for M1 receptors in schizophrenia.

Overall, evidence suggests that M1 receptor agonists could be useful in treating various symptom domains in schizophrenia, though the roles of the other muscarinic receptor subtypes are less clear. M5 receptors, for example, may be relevant to schizophrenia as they are located in the brainstem and midbrain, where they have an effect on dopamine release.93 Indeed, xanomeline is also an antagonist at M5 receptors, suggesting that blockade of M5 may be involved in the benefits seen with xanomeline.94 In addition, M4 receptor knockout mice have impairments of cognitive performance and elevated levels of dopamine in the nucleus accumbens, suggesting a potential role for M4 receptor agonists in treating both the positive and cognitive symptoms of schizophrenia.95,96 As selective agonists at muscarinic receptor subtypes have been difficult to develop, positive allosteric modulators are also being explored as potential therapeutic agents.

Glutaminergic Targets

Glutamate is the primary excitatory neurotransmitter for approximately 60% of the neurons in the mammalian brain, including all cortical pyramidal neurons,97 and plays a principal role in modulating long-term potentiation, a likely key cellular mechanism for learning and memory.98,99 Glutamate mediates fast excitatory postsynaptic potentials by acting on 3 ionotropic receptors, which are differentiated based upon sensitivity to the synthetic glutamate derivatives N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate.100 In addition, glutamate exerts slower modulatory effects by acting on various G protein–coupled metabotropic glutamate receptors (mGluRs).101 For example, mGluR2 and mGluR3 receptors modulate the release of glutamate, whereas the mGluR5 receptor potentiates the duration of NMDA receptor–dependent excitatory postsynaptic potentials.102

It has been hypothesized for decades that some deficiency in NMDA function might play a role in the pathophysiology of schizophrenia.103 Since the 1950s, the NMDA receptor antagonists phencyclidine (PCP) and ketamine were known to produce a large range of schizophrenia-like symptoms including psychotic symptoms, negative symptoms, and cognitive dysfunction,103105 and it has been suggested that augmenting NMDA receptor activity may have therapeutic potential in schizophrenia.100 Indeed, some of the atypical antipsychotics, but not typical antipsychotics, have been shown in preclinical models to reverse the effects of ketamine and PCP,106109 presumably through indirect activation of NMDA receptors mediated by other neurotransmitter systems.83 It is also important to note that a competing hypothesis suggests that a hyperactivity of glutamatergic neurotransmission is involved in the psychopathology of schizophrenia, leading to seemingly contradictory pharmacologic approaches being explored.100 Indeed, glutamatergic excitotoxicity is thought to be a factor in the neurodegeneration of Alzheimer's disease110 and a weak NMDA receptor antagonist, memantine, has shown efficacy in slowing cognitive decline in moderate to advanced Alzheimer's disease.111 Thus, the glutamate system, especially its NMDA-dependent components, is complex, and while small increases in NMDA-dependent glutamate neurotransmission might be cognitively enhancing, too much activation may result in neurodegeneration. Fortunately, the glutamatergic excitatory synapse offers multiple targets for drug development to provide the precise level of enhancement to improve cognition without excitotoxicity. Thus, we briefly review below various approaches being explored for modulating NMDA receptor neurotransmission and discuss approaches aimed at other glutamatergic mediators.

NMDA Receptors

NMDA glutamate receptors are ligand-gated ion channels with a primary glutamate-binding site and an allosteric glycine-binding site.100 Interestingly, the opening of the NMDA channel appears to require both glutamate and glycine binding, with glycine binding affecting channel open time and desensitization rate but not inducing channel opening itself.100 In addition, NMDA receptor activity can be allosterically modulated by multiple other substances, including Mg2+, polyamines, and protons.112 Thus, while direct agonists of the glutamate-binding site of the NMDA receptor may not be clinically feasible due to the risk of excess excitation and neurotoxicity, the allosteric sites on the NMDA receptor complex, particularly the glycine-binding site, are promising targets for drug development. Indeed, chronic treatment of rodents with glycine has not been found to induce excitotoxicity.113,114

Compounds that target the glycine site of the NMDA receptor complex have been studied in multiple small clinical trials. These include glycine115 and D-serine,116 which are endogenous agonists at the glycine site of the NMDA receptor complex; D-alanine; and D-cycloserine, an antituberculosis drug that also binds to the glycine modulatory site where it functions as a partial agonist.117 In most of these studies, the test compound was administered along with either a typical or atypical antipsychotic, and there appears to be significant effects at reducing negative symptoms and cognitive impairment in patients with schizophrenia.118 Of the 4 agents, D-cycloserine has been the least efficacious, likely due to it being a partial agonist that acts as an antagonist at high doses. Interestingly, when used concurrently with clozapine, glycine119 and D-serine120 have been reported to be ineffective while D-cycloserine seemed to worsen symptoms,121 possibly because clozapine may already enhance glycine and glutamate neurotransmission. Overall, agonists at the glycine allosteric site of the NMDA glutamate receptor hold promise in the treatment of the negative and cognitive symptoms of schizophrenia, possibly as an augmentation of currently existing antipsychotics. A potential limitation of targeting the glycine modulatory site is that the glycine site is probably half-saturated during physiologic conditions, suggesting that treatments targeting the glycine site would theoretically only be able to effectively double NMDA neurotransmission.118 In addition, both glycine and D-serine must be given at gram-level doses to significantly elevate central nervous system levels, and attempts to modify glycine or D-serine to produce synthetic glycine-site agonists, have, thus far, been unsuccessful. Thus, indirect approaches to activate NMDA receptors are being explored, such as increasing extracellular glycine and glutamate and by modulating AMPA receptors and mGluRs.

Glycine Transporters

An indirect approach being explored to boost NMDA activity via the glycine allosteric site is to increase synaptic glycine by inhibiting the glycine transporter. The glycine transporters, GlyT1 and GlyT2, have been identified on both neuronal and glial cells in the central nervous system, where they are suggested to control the extracellular concentration of glycine.122 Thus, blockade of glycine transporters is predicted to increase extracellular glycine and thus enhance NMDA receptor neurotransmission. Indeed, preclinical data suggest that inhibition of glycine reuptake represents a feasible approach to enhance NMDA receptor activity and possibly be therapeutic in schizophrenia.100 For example, selective, high-affinity inhibitors of the glycine transporter, including Org-24598, N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl] sarcosine, and SSR-504734, have been found to reverse PCP-induced hyperactivity and dopaminergic hyperreactivity in rodents.123,124 Furthermore, the glycine transport inhibitor glycyldodecylamide attenuated PCP-induced hyperactivity more potently than administration of glycine.125,126

Clinical trials to date, however, have only studied the low-potency glycine transport inhibitor sarcosine (N-methyl glycine). In a clinical trial of sarcosine added to the stable antipsychotic regimen of patient with schizophrenia, there was a highly significant reduction in negative symptoms, along with smaller but significant reductions in positive and cognitive symptoms.127 Interestingly, a subsequent study with patients on clozapine found no improvement of symptoms with the addition of sarcosine, a result similar to studies with the NMDA glycine site agonists.128 These results strongly suggest a role of glycine transport inhibitors in the treatment of schizophrenia, though results of trials with selective, high-potency inhibitors are anticipated.

AMPA/Kainate Receptors

Another glutamatergic approach to drug development for cognitive enhancement in schizophrenia has been the development of compounds that stimulate AMPA and kainate glutamate receptors. AMPA and kainate receptors mediate the majority of the fast glutamatergic signaling in the brain, and AMPA receptors work heavily in concert with NMDA receptors.100 AMPA receptors provide the primary depolarization necessary to activate NMDA receptors, while NMDA receptors are required for proper incorporation of AMPA receptors into the postsynaptic membrane, a process involved in synaptic plasticity.129 Thus, activation of AMPA receptors is likely critically important for learning and memory; however, direct AMPA agonists are unlikely to be therapeutically useful as AMPA receptors rapidly desensitize after stimulation.130

In an attempt to avoid desensitization of AMPA receptors, allosteric potentiators of AMPA receptor function, a class of compounds termed ampakines, are being studied as potential treatments for enhancing cognition in schizophrenia.131,132 Indeed, ampakines have been shown to enhance glutamatergic transmission and facilitate long-term potentiation in rodents.133,134 Furthermore, ampakines improve performance in rodents on a variety of memory tasks including spatial mazes135,136 and learned fear137 and have been shown to be effective in reducing age-associated memory deficits in rats.138 In a clinical trial of schizophrenia patients on clozapine, coadministration of the ampakine CX-516 yielded significant improvements in memory and attention;139 however, a trial of CX-516 as monotherapy in schizophrenia showed no clear beneficial effects.140 Importantly, higher potency ampakines are currently under clinical development as both monotherapy for schizophrenia and adjunctive treatment for cognitive dysfunction, though results of trials are not yet available. A higher potency ampakine, farampator, has been tested in healthy elderly volunteers and improved short-term memory but appeared to impair episodic memory,141 and thus, it remains unclear if modulation of AMPA receptors has therapeutic value in the treatment of the cognitive dysfunction in schizophrenia although this is a highly active area of current research.

Metabotropic Glutamate Receptors

Agents acting at mGluRs, which serve to regulate glutamatergic neurotransmission both pre- and postsynaptically, are currently in preclinical development for treatment of the cognitive dysfunction in schizophrenia. There are 8 subtypes of mGluRs (mGluR1–8) which are categorized into 3 groups according to their second messenger-coupling and ligand-binding profiles with group I receptors (mGluR1 and mGluR5) primarily being studied for cognitive enhancement in schizophrenia.102 Group I receptors, particularly mGluR5, function predominantly to potentiate both presynaptic glutamate release and postsynaptic NMDA neurotransmission,142 and mGluR5 receptors show significant colocalization with NMDA receptors in cortical pyramidal neurons.143 Together, these findings suggest that mGluR5 agonism may enhance NMDA activity and improve memory and cognition.142 Indeed, selective mGluR5 agonists were found to inhibit PCP-induced dopamine release in the rodent prefrontal cortex.144 Direct mGluR5 agonists, however, are likely to induce receptor desensitization limiting their therapeutic usefulness. Thus, selective allosteric potentiators of mGluRs have recently been developed and hold promise as therapeutic agents.145,146 Indeed, preliminary positive results with an mGluR2/3 agonist in phase II trials have been reported (http://www.prnewswire.com/cgi-bin/micro_stories.pl?ACCT=916306&TICK=LLY&STORY=/www/story/12-07-2006/0004487009&EDATE=Dec+7,+2006).

Dopaminergic Targets

Dopamine projections to the prefrontal cortex comprising the mesocortical dopamine system are essential for normal cognition.147,148 Thus, it has been hypothesized that decreased dopaminergic neurotransmission in the prefrontal cortex contributes to the cognitive deficits observed in schizophrenia, especially those related to executive functions and working memory.149151 Indeed, postmortem and in vivo imaging studies have linked prefrontal dopamine dysfunction to cognitive impairment,151,152 and various studies have demonstrated that direct and indirect dopamine agonists can improve prefrontal cortex cognitive functions in humans.153,154 However, it seems that precise regulation of prefrontal dopaminergic tone is essential as, in addition to insufficient dopamine, excessive prefrontal dopamine (eg, resulting from acute stress) may be deleterious to cognition.155157 Thus, dopamine function in the prefrontal cortex seems to follow an “inverted-U” dose-response curve whereby increases or decreases from an optimal level result in cognitive impairment.158 Additionally, indirect dopamine agonists could potentially exacerbate psychosis by increasing neurotransmission at mesolimbic dopamine D2 receptors.

D1 Receptors

Dopamine D1 receptors are expressed at high levels on the distal dendrites of pyramidal neurons in the prefrontal cortex that are thought to be involved in working memory processes.158,159 Indeed, evidence suggests an important role of dopamine D1 receptors in the cognitive dysfunction of schizophrenia.138 For example, there is a decreased level of D1 receptor–like binding in the prefrontal cortex of drug-naive patients with schizophrenia as measured with positron emission tomography imaging, and this decrease was found to be correlated with the severity of negative symptoms and cognitive dysfunction but not with the severity of positive symptoms.160 In addition, in nonhuman primates, chronic blockade of D2 receptors results in a downregulation of D1 receptors in the prefrontal cortex and consequently produces severe impairments in working memory.161 This downregulation of D1 receptors may explain why long-term treatment with typical antipsychotics can contribute to the cognitive dysfunction in schizophrenia. Thus, significant efforts are underway to examine the possible role of D1 receptor agonists in treating cognitive dysfunction in schizophrenia. Indeed, low doses of selective D1 agonists, such as dihydrexidine, A77636, and SKF81297, have cognition-enhancing actions in nonhuman primates,162164 and short-term administration of the D1 selective agonist, ABT-431, reversed the cognitive deficits in monkeys treated chronically with a D2 receptor antagonist.161

Although novel compounds that, directly or indirectly, stimulate D1 receptors may be of immense value in treating cognitive deficits in schizophrenia, several potential pitfalls may need to be overcome. First, D1 receptor activity follows the “inverted-U” dose-response curve, where either too little or too much D1 stimulation impairs working memory.158 In addition, chronic treatment with a D1 agonist may actually lead to the downregulation of D1 receptors which could, potentially, worsen cognition in the long term. Thus, an optimized level of D1 receptor activation at the apex of the “inverted-U” may be required to obtain maximal cognitive benefits,157 which may be accomplished by partial agonists or an intermittent pattern of administration.161,165 An additional obstacle is the powerful hypotensive effects of direct-acting D1 agonists on peripheral D1 receptors,166 which may necessitate the use of indirect D1-activating agents such as catechol-O-methyltransferase (COMT) inhibitors (see below).

D4 Receptors

The high affinity of clozapine for dopamine D4 receptors led to speculation that D4 receptors may be clozapine's “magic receptor.”167 Clinical trials of selective D4 antagonists, however, have not demonstrated any appreciable efficacy in the treatment of acute schizophrenia,168170 though it is possible that D4 receptor blockade in collaboration with action at other neurotransmitter receptors may be clinically beneficial. Indeed, studies of the physiological roles for the D4 receptor are finding that D4 receptors may play an important role in impulsivity and working memory.171

The mechanism by which D4 blockade could improve cognition is not fully known,172 though D4 receptors are present on both pyramidal neurons and GABA-producing interneurons in the prefrontal cortex and hippocampus,173 areas important for cognitive function. Studies have demonstrated that activation of D4 receptors decreases NMDA receptor activity in the hippocampus174 and inhibits glutamatergic signaling in the prefrontal cortex.175 Additionally, D4 receptor knockout mice show enhanced activity of cortical pyramidal neurons, an effect mimicked in wild-type mice by administration of the D4 antagonist PNU-101387G.175 Together, these results suggest that D4 antagonism may be a valuable approach to improve cognition in schizophrenia. Indeed, the D4 antagonist NDG96-1 was reported to reverse PCP-induced deficits in object retrieval tasks in monkeys,172 and another D4 antagonist, PNU-101387G, reversed deficits in the delayed response task induced by the pharmacologic stressor FG7142 (a benzodiazepine inverse agonist).176 Interestingly, PCP-induced cognitive deficits are exacerbated by haloperidol, suggesting that strong blockade of other dopamine receptors may counter the beneficial effects of D4 blockade on cognitive functioning.172

Seemingly contradictory evidence also suggests that D4 receptor agonists may improve cognitive function. For example, the selective D4 agonist A-412997 showed dose-dependent improvement in social recognition in rats, a model of short-term memory,177 and the D4 agonist PD168077 was shown to facilitate memory consolidation of an inhibitory avoidance learned response in mice.178 These effects have been hypothesized to be due to D4 receptor modulation of inhibitory GABAergic signaling in the prefrontal cortex.179 Indeed, the D4 agonist PD168077 reduces GABAA inhibitory currents in pyramidal neurons, which could be blocked by the D4 antagonist L-745870 as well as clozapine.179 Thus, in contrast to D4 antagonist–induced enhancement of NMDA currents in the hippocampus, D4 agonists may suppress GABAA inhibitory currents in the prefrontal cortex and thereby indirectly enhance cortical excitability. Taken together, D4 receptor–selective agents may be valuable in the treatment of the cognitive deficits in schizophrenia, though a balance between D4 receptor modulation of prefrontal GABAA and hippocampal NMDA receptors may be necessary.

Catechol-O-methyltransferase

COMT is a postsynaptic enzyme that methylates and thereby deactivates synaptically released catecholamines, particularly dopamine.180 Historically, monoamine oxidase was considered the primary enzyme for the initial deactivation of synaptic dopamine,181 though mounting evidence suggests that COMT may be especially important for the breakdown of dopamine, particularly in the prefrontal cortex.182 For example, COMT knockout mice show increased baseline levels of dopamine, but not other catecholamines such as norepinephrine, specifically in the frontal cortex.183 In addition, the COMT knockout mice also showed enhanced memory performance,183 suggesting a potential role of COMT inhibition in improving cognition. Indeed, a selective, reversible inhibitor of COMT, tolcapone, has been reported to improve working memory in rodents184 and has been shown to improve cognitive dysfunction in patients with advanced Parkinson's disease,185 though use is limited due to a risk of liver failure.186 Other COMT inhibitors are currently being investigated for treatment of the cognitive dysfunction in schizophrenia.

Interestingly, a common single nucleotide polymorphism in the gene encoding COMT, Val158Met, results in the transcription of a variant of the COMT enzyme with approximately 40% less enzymatic activity in humans.187 The reduced COMT enzymatic activity associated with the Met variant presumably results in greater availability of dopamine in the prefrontal cortex and, thus, may improve cognition, hypotheses supported by findings from the COMT knockout mice,183 and an fMRI study in humans.188 Furthermore, the COMT locus at chromosome 22q11 has been identified as a susceptibility locus for schizophrenia in several linkage studies189,190 and 2 meta-analyzes,189,191 though this remains controversial.192194 However, accumulating evidence predicts that patients with schizophrenia who have the Met allele may have improved cognitive response to clozapine.195 Interestingly, a recent proof-of-concept experiment in normal human subjects treated with tolcapone demonstrated significant improvements on measures of executive function and verbal episodic memory in individuals with a Val/Val genotype but a diminished performance of individuals with the Met/Met genotype.196 Thus, overall, the potential of pharmacologic inhibition of COMT in the long-term treatment of the cognitive dysfunction in schizophrenia remains to be determined.

Serotonergic Targets

5-HT2A Receptors

5-HT2A receptors are particularly abundant in the pyramidal neurons from cortical layer V,197 where they have been described to colocalize with NMDA glutamate receptors,198,199 suggesting a role in modulating cognitive functions. Indeed, studies have demonstrated that 5-HT2A receptors interact with postsynaptic density protein 95, a protein involved in anchoring NMDA receptors to postsynaptic densities,200 and it has been suggested that activation of 5-HT2A receptors increases the release of glutamate onto pyramidal cells.201 Interestingly, the selective 5-HT2A receptor antagonist M100907 blocked the cognition-impairing effects of MK-801, an NMDA receptor antagonist.202,203 Similar findings have been reported for another 5-HT2A antagonist AC-90179.204 Taken together, these studies suggest an intimate association between NMDA and 5-HT2A receptors and imply that drugs with potent 5-HT2A antagonistic actions may prove beneficial at improving cognition in schizophrenia, perhaps by normalizing NMDA receptor functioning.203

In addition, 5-HT2A receptors are located on dopaminergic neurons in the ventral tegmental area,205 where they may modulate dopamine neuronal activity.206 Indeed, it is likely that a predominant role of 5-HT2A receptors in antipsychotic action is to modulate dopaminergic tone, particularly along the mesocortical pathway.206208 For example, clozapine, olanzapine, and ziprasidone, but not haloperidol or risperidone, can preferentially augment dopamine and norepinephrine release in the prefrontal cortex relative to the subcortical areas.209 In rats, however, repeated administration of the selective 5-HT2A antagonist M100907 can alter the activity of midbrain dopamine neurons in rats, though there is disagreement as to whether cortical dopamine levels are potentiated210 or inhibited.211 Thus, it has been hypothesized that the ultimate effect of 5-HT2A antagonists on dopaminergic neurotransmission might be to stabilize it.208,212

Clinical studies with selective 5-HT2A receptor compounds have also demonstrated a role of 5-HT2A receptors in cognitive functioning in schizophrenia. For example, in a study of 30 hospitalized patients with schizophrenia, administration of mianserin, a 5-HT2A/2C and α2-adrenergic antagonist, improved scores on the Automated Neuropsychological Assessment Metrics at 4 weeks, though no significant improvement was found on the Wisconsin Card Sorting Test.213 These results suggest that 5-HT2A receptor antagonism may improve cognitive function in schizophrenia,214,215 though additional clinical studies are needed. However, because nearly all approved atypical antipsychotic drugs have potent 5-HT2A antagonist actions, it is unlikely that adding on a drug with potent 5-HT2A antagonism will provide any significant boosting of cognition in treated patients.212 The potential cognition-enhancing effects resulting from 5-HT2A receptor antagonism with the currently available atypical antipsychotics may be masked by other drug actions, such as anticholinergic effects, known to cause cognitive impairment.216

5-HT1A Receptors

5-HT1A receptors are densely concentrated in the hippocampus, lateral septum, amygdala, and cortical limbic areas, as well as both the dorsal and median raphe nuclei.217,218 On raphe neurons, 5-HT1A receptors function as somatic autoreceptors providing inhibitory feedback control of 5-HT release.219 However, the highest concentrations of 5-HT1A receptors are on cortical and hippocampal pyramidal neurons220 suggesting a role of 5-HT1A receptors in mediating cognitive functions. 5-HT1A receptors on cortical pyramidal neurons are colocalized with 5-HT2A receptors,221 though while 5-HT2A receptor activation is excitatory, 5-HT1A receptor activation inhibits pyramidal neurons.222

Because they act on different locations of the receptors, both 5-HT1A partial agonists and full antagonists have shown a positive effect on cognitive activity in animals.223 Thus, 5-HT1A partial agonists, presumably acting on pyramidal neurons, improve cognition in animals, while 5-HT1A antagonists also improve cognition, probably by acting at the raphe autoreceptors.208,223 Indeed, atypical antipsychotic drugs modestly enhance cognition, and several atypical antipsychotic drugs have 5-HT1A partial agonist actions (eg, aripiprazole, clozapine, olanzapine, ziprasidone, quetiapine),224,225 while others are 5-HT1A antagonists (eg, risperidone and sertindole).224 Preclinical experiments also show that both 5-HT1A partial agonists and antagonists can improve cognition. For example, intraprefrontal infusion of 8-OH-DPAT, a nonselective 5-HT1A agonist, improved visual-spatial attention and decreased impulsivity in rats,226 while WAY100635, a 5-HT1A antagonist, blocked the deleterious effects of MK-801 and NMDA antagonist in rats.227 Thus, the preclinical literature is mixed regarding whether 5-HT1A agonists or antagonists enhance cognition.

Clinical data in humans are equally mixed. For example, activating 5-HT1A receptors with a single dose of tandospirone, a 5-HT1A partial agonist, diminished explicit memory function228 in demented patients, though chronic administration of tandospirone enhanced verbal memory in patients with schizophrenia.229,230 Interestingly, the 5-HT1A agonist NAE-086 actually induced hallucinations and nightmares in normal individuals after repeated doses,231 suggesting that 5-HT1A agonists may not be tolerated well in schizophrenic individuals. Taken together, these results demonstrate that additional clinical studies are needed but suggest that 5-HT1A receptors may need to be differently modulated to optimally enhance cognition in various pathologic conditions (ie, dementia vs schizophrenia) and that 5-HT1A partial agonists with a high level of efficacy may present a significant risk of exacerbating positive symptoms in schizophrenia.231

5-HT4 Receptors

Serotonin 5-HT4 receptors are found at high densities in the hippocampus, frontal cortex, and amygdala, suggesting a role of these receptors in cognitive functions.232,233 Indeed, 5-HT4 receptors have been shown to be markedly decreased in patients with Alzheimer's disease.234 In addition, 5-HT4 receptor agonists have shown promise in the treatment of cognitive impairment by enhancing cholinergic transmission in the hippocampus.212,235 For example, a 5-HT4 receptor partial agonist, SL65.0155, improved learning and memory performance in chemically induced rat model of amnesia,236 and this improvement may be due in part to lengthening of the excitatory postsynaptic potential in hippocampal CA1 pyramidal neurons.237 Interestingly, a recent study also showed that the activation of 5-HT4 receptors in a neuronal culture inhibited the secretion of β-amyloid peptide and enhanced neuronal survival.238 Thus, while 5-HT4 receptor–selective agonists are mostly being studied for their role in the treatment of Alzheimer's disease, they may also be of benefit in the treatment of the cognitive dysfunction in schizophrenia.

5-HT6 Receptors

Several atypical antipsychotics, including clozapine and olanzapine, and some tricyclic antidepressants, such as amoxapine, amitriptyline, and clomipramine, were found to have high affinity for 5-HT6 receptors239241 prompting significant efforts to understand its possible role in schizophrenia and other neuropsychiatric disorders. When antisense oligonucleotides were used to decrease the level of 5-HT6 receptor expression in rats, the rats exhibited an increased number of yawns and stretches that could be blocked by atropine, suggesting a role of the 5-HT6 receptor in the control of cholinergic neurotransmission.242,243 In addition, the selective 5-HT6 receptor antagonist SB-271046 has been shown to improve memory retention in the water maze test of spatial learning and memory.244,245 Thus, it appears likely that 5-HT6 receptors may have an important future role in the treatment of cognitive deficits in neuropsychiatric illnesses such as Alzheimer's disease and schizophrenia.212

5-HT7 Receptors

The 5-HT7 receptor exhibits a distinct distribution in the central nervous system with relatively high levels in the thalamus, hypothalamus, and hippocampus and lower levels in the cortex and amygdala.246248 In addition to possible roles in regulating circadian rhythms and sleep,249251 5-HT7 receptors may also have an important role in hippocampus-dependent functions such as learning and memory.252 For example, 5-HT7 receptor knockout mice have been found to exhibit a specific impairment in contextual fear conditioning in which the animal learns to associate the environment with an aversive stimulus, a process generally believed to require the hippocampus.253 Electrophysiological studies have also shown that 5-HT7 receptor activation modulates the excitability and intracellular signaling of pyramidal neurons in the CA1 region of the hippocampus.254,255 Additionally, in 5-HT7 receptor knockout mice, there is a reduced ability to induce long-term potentiation in the CA1 region of the hippocampus.253 Together, these findings suggest an important role for the 5-HT7 receptor in hippocampus-dependent functions, including learning and memory.252 Thus, selective 5-HT7 receptor activators might prove therapeutically useful for the treatment of the cognitive dysfunction of schizophrenia.212

Other Neurotransmitter Targets

α2-Adrenergic Receptors

The central noradrenergic system projects from the locus ceruleus to the prefrontal cortex where α2-adrenergic receptors appear to play an important role in cognitive functioning.256 Indeed, treatment with the α2-adrenergic receptor agonists, clonidine and guanfacine, has been shown to improve cognitive performance without exacerbating positive symptoms in small trials of patients with schizophrenia.257,258 In addition, patients randomized to risperidone plus guanfacine showed significant improvement on tasks of working memory and attention compared with patients receiving typical antipsychotics plus guanfacine.258 However, clozapine and other atypicals have potent antagonist properties at α2-adrenergic receptors,259 which may contribute to the atypicality of atypicals by preferentially enhancing dopaminergic transmission in the frontal cortex over subcortical dopaminergic pathways.260 Indeed, combined treatment of a typical antipsychotic with the highly selective α2-adrenergic receptor antagonist, idazoxan, has been reported to produce a profile of antipsychotic activity similar to clozapine.261 Thus, as α2-adrenergic receptor activity may be important in developing new drugs for schizophrenia that can improve cognition, balancing α2-adrenergic receptor activity to achieve both antipsychotic and procognitive efficacy may be challenging.

GABAA Receptors

Appropriately synchronized GABA neurotransmission in the dorsolateral prefrontal cortex is required for adequate working memory,262 suggesting that impairments in GABA-mediated inhibition could contribute to the cognitive impairments in schizophrenia. Indeed, postmortem studies have shown reduced GABAergic transmission in schizophrenia.263265 In addition, recent observations266,267 have noted decreases in messenger RNA levels for glutamic acid decarboxylase 67, the synthetic enzyme for GABA, selectively in the prefrontal cortex of patients with schizophrenia. Interestingly, a recent study revealed that GABA alterations in the dorsolateral prefrontal cortex of schizophrenic patients may be restricted to certain cell classes, such as the chandelier cells, which synchronize the activation of pyramidal neurons via GABAA receptor subtypes.268 Thus, the use of new benzodiazepine-like agents—selective for the α2 subunit of the GABAA receptor—in cognitive disorders could be both interesting and revealing. Indeed, there is evidence that reduced GABA neurotransmission in chandelier cells may be secondary to altered NMDA receptor function and could represent a “final common pathway” of prefrontal dysfunction in schizophrenia.269 Thus, drugs targeted to mitigate the disturbances in inhibition might be particularly effective in improving cognitive performance in schizophrenia. For example, positive allosteric modulators selective for GABAA receptors containing α2 subunits (eg, a GABAA α2-selective benzodiazepine) may improve working memory function in schizophrenia.270 However, drugs that directly activate α2-containing GABAA receptors independent of the presence of GABA may disrupt the critical synchronization of this circuit and impair working memory.269 In addition, activation of GABAA receptors containing other subunits (eg, α1 or α5), such as by currently available benzodiazepines, may impair cognitive function. Indeed, a recent study in healthy volunteers showed that, contrary to lorazepam, a GABAA α23 subtype–selective partial agonist, TPA023, caused no detectable memory impairment.271

As activation of GABAA receptors containing α5 subunits, such as by currently available benzodiazepines, may impair cognitive function and cause sedation, inhibitors of these receptors have been hypothesized to enhance cognition. Indeed, functionally selective inverse agonists at α5-containing GABAA receptors have been demonstrated to enhance performance in animal models of cognition,272274 apparently without lowering the seizure threshold as seen with nonselective GABAA inverse agonists.274,275 In addition, α5 subunit knockout mice demonstrate increased hippocampal activity due to the release of tonic GABAergic inhibition.276 Thus, antagonists or inverse agonists at α5-containing GABAA receptors may hold promise in the treatment of the cognitive dysfunction in schizophrenia.

Neurosteroids and Sigma Receptors

The sigma (σ) receptor was initially designated as a subtype of opioid receptors277 but was later found to be a distinct pharmacological entity due to lack of binding of the classical opiate receptor antagonists naloxone and naltrexone.278 Indeed, when the σ1 receptor was isolated and cloned, it was found to have no structural similarity to the opioid receptors.279 The functions of these receptors are poorly understood and endogenous ligands have yet to be identified, though it has been proposed that steroid hormones (eg, progesterone and testosterone), drugs of abuse (eg, cocaine, heroin, PCP), and psychiatric drugs (haloperidol, imipramine, and sertraline) may interact with σ receptors.280,281 In addition, it is well documented that σ1 receptor ligands increase the NMDA receptor response in the hippocampus,282284 suggesting a role in enhancing cognition. Indeed, σ1 receptor agonists can reverse the memory impairments induced by the NMDA antagonists MK-801 in rodents.285

Neurosteroids, such as dehydroepiandrosterone (DHEA) and allopregnanolone, have been implicated in neuroprotection286288 and enhancement of NMDA receptor neurotransmission,287,289,290 possibly through interaction with σ1 receptors,290 suggesting therapeutic potential for enhancing cognition in schizophrenia. Consistent with the enhancement of NMDA neurotransmission, DHEA can enhance memory in rodents.291294 In humans, a double-blind study of DHEA as an adjunct to antipsychotic treatment in chronic schizophrenic patients with prominent negative symptoms suggests some efficacy at improving negative symptoms, especially in women,295 though further studies are needed. Thus, neurosteroids may have therapeutic potential for improving the cognitive deficits observed in schizophrenia, though long-term treatment with steroids is problematic. In addition, while the contribution of σ receptor agonism to the actions of neurosteroids is not entirely known, highly selective σ receptor agonists are needed and hold therapeutic promise.

Potential Future Targets

There are a number of additional largely theoretical pharmacotherapeutic approaches for the treatment of cognition and schizophrenia. For example, significant progress has been made in recent years on elucidating various susceptibility genes in schizophrenia, including dysbindin, neuregulin 1, COMT, DISC1, and others.296 Interestingly, many of these genes appear to be related to the control of synaptic plasticity and glutamate transmission (particularly NMDA receptor function) and thus may allow for hypothesis-driven approaches for developing of actual disease-modifying drugs for schizophrenia and cognitive disorders.297 Another strategy involves the role of neurotrophic factors in the pathophysiology of schizophrenia and the theory that schizophrenia may involve a neurodegenerative process.298 Neurotrophic factors, such as brain-derived neurotrophic factor, may play a role in neuronal and glial differentiation, proliferation, and regeneration and influence synaptic organization, neurotransmitter synthesis, and the maintenance of synaptic plasticity.299,300 Thus, strategies to enhance neurotrophic factor action may be able to prevent progression of schizophrenia.

Altering neurotransmitter signaling by targeting intracellular signaling cascades has long been suggested to be a future approach to novel therapeutic agents.301 Though there has been concern about the feasibility of this approach, lithium is a signal transduction modifier that has been used safely for decades. Some targets being investigated include protein kinase C isoforms and glycogen synthase kinase 3.302 In addition, subtype-selective phosphodiesterase (PDE) inhibitors, particularly at PDE10A, are actively being explored for the treatment of various symptom domains in schizophrenia.303 Another interesting approach at the receptor level would be developing ligands that differentially activate the various signaling pathways mediated by a single receptor, a process termed “functional selectivity”.304 Indeed, functional selectivity has been described in serotonin, opioid, dopamine, vasopressin, and adrenergic receptor systems304 and may be initiated by different ligand-induced conformational states, as shown for the β2-adrenergic receptor.305 Thus, the possibility of selecting or designing novel ligands that differentially activate only a subset of receptor functions is intriguing as an approach to drug discovery that may optimize therapeutic action.

Conclusions

Cognitive dysfunction is a major feature of schizophrenia that contributes significantly to the long-term functional impairment that patients experience. While the past half-century of antipsychotic development has had a profound effect on the treatment of schizophrenia, the cognitive deficits in schizophrenia have been insufficiently addressed. Therefore, it is critical to continue the pursuit of diverse molecular targets for discovering new pharmacotherapeutic agents for the treatment of schizophrenia. For the past 20 years, psychopharmacologic research in schizophrenia has aimed for the development of new antipsychotic drugs with a more rapid onset of action, lower risk of side effects, and improved efficacy in the domains of negative and cognitive symptoms from a single compound. Currently, however, it seems unlikely that a single drug will have the desired effect across all these domains, and thus, optimal treatment of schizophrenia will likely rely on individualized polypharmacy and augmentation strategies. The ultimate goal, of course, will be the development of “cure therapeutics”297 which will require significant advances in our understanding of the underlying pathophysiology of schizophrenia, highlighting the need for continued basic research efforts at identifying and validating diverse and novel molecular targets.

Funding

National Institutes of Health (RO1MH61887 to B.R., RO1MH57635 to B.R.); National Institute of Mental Health (NO1MH32004 to B.R.).

References

1. Kraepelin E. Dementia Praecox and Paraphrenia [1919] New York, NY: Robert E. Krieger; 1971.
2. Reichenberg A, et al. Premorbid intellectual functioning and risk of schizophrenia and spectrum disorders. J Clin Exp Neuropsychol. 2006;28:193–207. [PubMed]
3. Heinrichs RW. The primacy of cognition in schizophrenia. Am Psychol. 2005;60:229–242. [PubMed]
4. Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry. 1996;153:321–330. [PubMed]
5. Burton SC. Strategies for improving adherence to second-generation antipsychotics in patients with schizophrenia by increasing ease of use. J Psychiatr Pract. 2005;11:369–378. [PubMed]
6. Prouteau A, et al. Cognitive predictors of psychosocial functioning outcome in schizophrenia: a follow-up study of subjects participating in a rehabilitation program. Schizophr Res. 2005;77:343–353. [PubMed]
7. Chen EY, et al. A prospective 3-year longitudinal study of cognitive predictors of relapse in first-episode schizophrenic patients. Schizophr Res. 2005;77:99–104. [PubMed]
8. Miyamoto S. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry. 2005;10:79–104. [PubMed]
9. Lieberman JA, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209–1223. [PubMed]
10. Leucht S. New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet. 2003;361:1581–1589. [PubMed]
11. Mishara AL. A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book. Biol Psychiatry. 2004;55:1013–1022. [PubMed]
12. Strauss ME. Effects of anticholinergic medication on memory in schizophrenia. Schizophr Res. 1990;3:127–129. [PubMed]
13. Davidson M, et al. Severity of symptoms in chronically institutionalized geriatric schizophrenic patients. Am J Psychiatry. 1995;152:197–207. [PubMed]
14. Bilder RM, et al. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry. 2002;159:1018–1028. [PubMed]
15. Harvey PD. Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry. 2001;158:176–184. [PubMed]
16. Purdon SE, et al. Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia. Arch Gen Psychiatry. 2000;57:249–258. [PubMed]
17. Keefe RS. The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr Bull. 1999;25:201–222. [PubMed]
18. Woodward ND. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol. 2005;8:457–472. [PubMed]
19. Marder SR. Measurement and Treatment Research to Improve Cognition in Schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophr Res. 2004;72:5–9. [PubMed]
20. Nuechterlein KH. Identification of separable cognitive factors in schizophrenia. Schizophr Res. 2004;72:29–39. [PubMed]
21. Keefe RS, et al. Baseline neurocognitive deficits in the CATIE schizophrenia trial. Neuropsychopharmacology. 2006;31:2033–2046. [PubMed]
22. Bowie CR. Cognition in schizophrenia: impairments, determinants, and functional importance. Psychiatr Clin North Am. 2005;28:613–633. 626. [PubMed]
23. Friedman JI. Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists. Psychopharmacology (Berl). 2004;174:45–53. [PubMed]
24. Woolf NJ. Cholinergic systems in the rat brain: IV. Descending projections of the pontomesencephalic tegmentum. Brain Res Bull. 1989;23:519–540. [PubMed]
25. Brito GN. Memory and the septo-hippocampal cholinergic system in the rat. Psychopharmacology (Berl). 1983;81:315–320. [PubMed]
26. Fadda F. Increased hippocampal acetylcholine release during a working memory task. Eur J Pharmacol. 1996;307:R1–R2. [PubMed]
27. Dunnett SB. Comparative effects of cholinergic drugs and lesions of nucleus basalis or fimbria-fornix on delayed matching in rats. Psychopharmacology (Berl). 1985;87:357–363. [PubMed]
28. Meck WH. Nucleus basalis magnocellularis and medial septal area lesions differentially impair temporal memory. J Neurosci. 1987;7:3505–3511. [PubMed]
29. Robbins TW. Comparative effects of ibotenic acid- and quisqualic acid-induced lesions of the substantia innominata on attentional function in the rat: further implications for the role of the cholinergic neurons of the nucleus basalis in cognitive processes. Behav Brain Res. 1989;35:221–240. [PubMed]
30. Sitaram N. Human serial learning: enhancement with arecholine and choline impairment with scopolamine. Science. 1978;201:274–276. [PubMed]
31. Davis KL. Physostigmine: improvement of long-term memory processes in normal humans. Science. 1978;201:272–274. [PubMed]
32. el-Mallakh RS, et al. The nucleus basalis of Meynert, senile plaques, and intellectual impairment in schizophrenia. J Neuropsychiatry Clin Neurosci. 1991;3:383–386. [PubMed]
33. Powchik P, et al. Postmortem studies in schizophrenia. Schizophr Bull. 1998;24:325–341. [PubMed]
34. Freedman R. Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry. 1995;38:22–33. [PubMed]
35. Dean B. Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry. 2002;7:1083–1091. [PubMed]
36. Ichikawa J. Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum. Neuropsychopharmacology. 2002;26:325–339. [PubMed]
37. Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2006 1:CD005593. [PubMed]
38. Friedman JI. Pharmacologic strategies for augmenting cognitive performance in schizophrenia. Biol Psychiatry. 1999;45:1–16. [PubMed]
39. Nahas Z, et al. Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study. Neurocase. 2003;9:274–282. [PubMed]
40. Ferreri F. Cognitive dysfunctions in schizophrenia: potential benefits of cholinesterase inhibitor adjunctive therapy. J Psychiatry Neurosci. 2006;31:369–376. [PMC free article] [PubMed]
41. Hughes JR. Prevalence of smoking among psychiatric outpatients. Am J Psychiatry. 1986;143:993–997. [PubMed]
42. Benwell ME. Desensitization of the nicotine-induced mesolimbic dopamine responses during constant infusion with nicotine. Br J Pharmacol. 1995;114:454–460. [PMC free article] [PubMed]
43. Friedman JI, et al. A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia. Biol Psychiatry. 2002;51:349–357. [PubMed]
44. Maelicke A, et al. Noncompetitive agonism at nicotinic acetylcholine receptors; functional significance for CNS signal transduction. J Recept Signal Transduct Res. 1995;15:333–353. [PubMed]
45. Schrattenholz A. Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands. Mol Pharmacol. 1996;49:1–6. [PubMed]
46. Allen T. Galantamine as an adjunctive therapy in the treatment of schizophrenia
47. Bora E. The effect of galantamine added to clozapine on cognition of five patients with schizophrenia. Clin Neuropharmacol. 2005;28:139–141. [PubMed]
48. Lee SW. A 12-week, double-blind, placebo-controlled trial of galantamine adjunctive treatment to conventional antipsychotics for the cognitive impairments in chronic schizophrenia. Int Clin Psychopharmacol. 2007;22:63–68. [PubMed]
49. Schubert MH. Galantamine improves cognition in schizophrenic patients stabilized on risperidone. Biol Psychiatry. 2006;60:530–533. [PubMed]
50. Dalack GW. Nicotine dependence in schizophrenia: clinical phenomena and laboratory findings. Am J Psychiatry. 1998;155:1490–1501. [PubMed]
51. Kumari V. Nicotine use in schizophrenia: the self medication hypotheses. Neurosci Biobehav Rev. 2005;29:1021–1034. [PubMed]
52. Levin ED. Nicotine-haloperidol interactions and cognitive performance in schizophrenics. Neuropsychopharmacology. 1996;15:429–436. [PubMed]
53. Yang YK. Nicotine decreases bradykinesia-rigidity in haloperidol-treated patients with schizophrenia. Neuropsychopharmacology. 2002;27:684–686. [PubMed]
54. Sacco KA, et al. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Arch Gen Psychiatry. 2005;62:649–659. [PubMed]
55. Smith RC. Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia. Neuropsychopharmacology. 2002;27:479–497. [PubMed]
56. Breese CR, et al. Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology. 2000;23:351–364. [PubMed]
57. Freedman R, et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA. 1997;94:587–592. [PMC free article] [PubMed]
58. Riley BP, et al. Haplotype transmission disequilibrium and evidence for linkage of the CHRNA7 gene region to schizophrenia in Southern African Bantu families. Am J Med Genet. 2000;96:196–201. [PubMed]
59. Luntz-Leybman V. Cholinergic gating of response to auditory stimuli in rat hippocampus. Brain Res. 1992;587:130–136. [PubMed]
60. Adler LE. Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry. 1993;150:1856–1861. [PubMed]
61. Simosky JK. Intragastric DMXB-A, an alpha7 nicotinic agonist, improves deficient sensory inhibition in DBA/2 mice. Biol Psychiatry. 2001;50:493–500. [PubMed]
62. Olincy A, et al. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry. 2006;63:630–638. [PubMed]
63. Simosky JK. Nicotinic agonists and psychosis. Curr Drug Targets CNS Neurol Disord. 2002;1:149–162. [PubMed]
64. Schreiber R. Effects of alpha 4/beta 2- and alpha 7-nicotine acetylcholine receptor agonists on prepulse inhibition of the acoustic startle response in rats and mice. Psychopharmacology (Berl). 2002;159:248–257. [PubMed]
65. Flores CM. A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is up-regulated by chronic nicotine treatment. Mol Pharmacol. 1992;41:31–37. [PubMed]
66. Bontempi B, et al. SIB-1553A, (+/-)-4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol hydrochloride, a subtype-selective ligand for nicotinic acetylcholine receptors with putative cognitive-enhancing properties: effects on working and reference memory performances in aged rodents and nonhuman primates. J Pharmacol Exp Ther. 2001;299:297–306. [PubMed]
67. Levin ED. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl). 2006;184:523–539. [PubMed]
68. Lloyd GK, et al. The potential of subtype-selective neuronal nicotinic acetylcholine receptor agonists as therapeutic agents. Life Sci. 1998;62:1601–1606. [PubMed]
69. Felder CC. Muscarinic acetylcholine receptors: signal transduction through multiple effectors. FASEB J. 1995;9:619–625. [PubMed]
70. Raiteri M. Heterogeneity of presynaptic muscarinic receptors regulating neurotransmitter release in the rat brain. J Pharmacol Exp Ther. 1984;228:209–214. [PubMed]
71. Wamsley JK. Distribution of muscarinic cholinergic high and low affinity agonist binding sites: a light microscopic autoradiographic study. Brain Res Bull. 1984;12:233–243. [PubMed]
72. Vizi ES, et al. Heterogeneity of presynaptic muscarinic receptors involved in modulation of transmitter release. Neuroscience. 1989;31:259–267. [PubMed]
73. Raedler TJ. Towards a muscarinic hypothesis of schizophrenia. Mol Psychiatry. 2007;12:232–246. [PubMed]
74. Levey AI. Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. J Neurosci. 1991;11:3218–3226. [PubMed]
75. Wei J. m1-m5 muscarinic receptor distribution in rat CNS by RT-PCR and HPLC. J Neurochem. 1994;63:815–821. [PubMed]
76. Crook JM. Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation. Biol Psychiatry. 2000;48:381–388. [PubMed]
77. Crook JM. Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of Brodmann's areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment. Am J Psychiatry. 2001;158:918–925. [PubMed]
78. Dean B. The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia. Mol Psychiatry. 1996;1:54–58. [PubMed]
79. Watanabe S. Increased muscarinic cholinergic receptors in prefrontal cortices of medicated schizophrenics. Life Sci. 1983;33:2187–2196. [PubMed]
80. Anagnostaras SG, et al. Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat Neurosci. 2003;6:51–58. [PubMed]
81. Bymaster FP. Muscarinic receptors as a target for drugs treating schizophrenia. Curr Drug Targets CNS Neurol Disord. 2002;1:163–181. [PubMed]
82. Armbruster BN. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci USA. 2007;104:5163–5168. [PMC free article] [PubMed]
83. Sur C, et al. N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. Proc Natl Acad Sci USA. 2003;100:13674–13679. [PMC free article] [PubMed]
84. Davies MA. The highly efficacious actions of N-desmethylclozapine at muscarinic receptors are unique and not a common property of either typical or atypical antipsychotic drugs: is M1 agonism a pre-requisite for mimicking clozapine's actions? Psychopharmacology (Berl). 2005;178:451–460. [PubMed]
85. Burstein ES, et al. Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist. J Pharmacol Exp Ther. 2005;315:1278–1287. [PubMed]
86. Weiner DM, et al. The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine. Psychopharmacology (Berl). 2004;177:207–216. [PubMed]
87. Onali P. N-Desmethylclozapine, a major clozapine metabolite, acts as a selective and efficacious [delta]-opioid agonist at recombinant and native receptors. Neuropsychopharmacology. 2006;32:773–785. [PubMed]
88. Li Z. N-desmethylclozapine, a major metabolite of clozapine, increases cortical acetylcholine and dopamine release in vivo via stimulation of M1 muscarinic receptors. Neuropsychopharmacology. 2005;30:1986–1995. [PubMed]
89. Watson J, et al. Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors. Br J Pharmacol. 1998;125:1413–1420. [PMC free article] [PubMed]
90. Bodick NC, et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol. 1997;54:465–473. [PubMed]
91. Shekhar A, et al. Efficacy of xanomeline, a selective muscarinic agonist, in treating schizophrenia: a double-blind, placebo controlled study
92. Mirza NR. Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists. CNS Drug Rev. 2003;9:159–186. [PubMed]
93. Miller AD. Midbrain muscarinic receptor mechanisms underlying regulation of mesoaccumbens and nigrostriatal dopaminergic transmission in the rat. Eur J Neurosci. 2005;21:1837–1846. [PubMed]
94. Grant MK. Persistent binding and functional antagonism by xanomeline at the muscarinic M5 receptor. J Pharmacol Exp Ther. 2005;315:313–319. [PubMed]
95. Tzavara ET, et al. M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related CNS pathologies. FASEB J. 2004;18:1410–1412. [PubMed]
96. Tzavara ET, et al. Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice. Mol Psychiatry. 2003;8:673–679. [PubMed]
97. Nieuwenhuys R. The neocortex. An overview of its evolutionary development, structural organization and synaptology. Anat Embryol (Berl). 1994;190:307–337. [PubMed]
98. Bliss TV. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol. 1973;232:331–356. [PMC free article] [PubMed]
99. Malenka RC. LTP and LTD: an embarrassment of riches. Neuron. 2004;44:5–21. [PubMed]
100. Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry. 2004;9:984–997. 979. [PubMed]
101. Nicoletti F. Coupling of inositol phospholipid metabolism with excitatory amino acid recognition sites in rat hippocampus. J Neurochem. 1986;46:40–46. [PubMed]
102. Moghaddam B. Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia. Psychopharmacology (Berl). 2004;174:39–44. [PubMed]
103. Domino EF. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965;6:279–291. [PubMed]
104. Javitt DC. Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia. Hillside J Clin Psychiatry. 1987;9:12–35. [PubMed]
105. Olney JW. NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res. 1999;33:523–533. [PubMed]
106. Bakshi VP. Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine. Psychopharmacology (Berl). 1995;122:198–201. [PubMed]
107. Corbett R, et al. Antipsychotic agents antagonize non-competitive N-methyl-D-aspartate antagonist-induced behaviors. Psychopharmacology (Berl). 1995;120:67–74. [PubMed]
108. Duncan GE. Comparison of the effects of clozapine, risperidone, and olanzapine on ketamine-induced alterations in regional brain metabolism. J Pharmacol Exp Ther. 2000;293:8–14. [PubMed]
109. Wang RY. M100907 and clozapine, but not haloperidol or raclopride, prevent phencyclidine-induced blockade of NMDA responses in pyramidal neurons of the rat medial prefrontal cortical slice. Neuropsychopharmacology. 1998;19:74–85. [PubMed]
110. Chohan MO. From tau to toxicity: emerging roles of NMDA receptor in Alzheimer's disease. J Alzheimers Dis. 2006;10:81–87. [PubMed]
111. Reisberg B. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348:1333–1341. [PubMed]
112. Yamakura T. Subunit- and site-specific pharmacology of the NMDA receptor channel. Prog Neurobiol. 1999;59:279–298. [PubMed]
113. Shoham S. High dose glycine nutrition affects glial cell morphology in rat hippocampus and cerebellum. Int J Neuropsychopharmacol. 1999;2:35–40. [PubMed]
114. Shoham S. Chronic high-dose glycine nutrition: effects on rat brain cell morphology. Biol Psychiatry. 2001;49:876–885. [PubMed]
115. Johnson JW. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature. 1987;325:529–531. [PubMed]
116. Mothet JP, et al. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci USA. 2000;97:4926–4931. [PMC free article] [PubMed]
117. Hood WF. D-cycloserine: a ligand for the N-methyl-D-aspartate coupled glycine receptor has partial agonist characteristics. Neurosci Lett. 1989;98:91–95. [PubMed]
118. Javitt DC. Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients. Curr Opin Psychiatry. 2006;19:151–157. [PubMed]
119. Evins AE. Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry. 2000;157:826–828. [PubMed]
120. Tsai GE. D-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry. 1999;156:1822–1825. [PubMed]
121. Goff DC. D-cycloserine added to clozapine for patients with schizophrenia. Am J Psychiatry. 1996;153:1628–1630. [PubMed]
122. Bergeron R. Modulation of N-methyl-D-aspartate receptor function by glycine transport. Proc Natl Acad Sci USA. 1998;95:15730–15734. [PMC free article] [PubMed]
123. Aubrey KR. N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine (NFPS) is a selective persistent inhibitor of glycine transport. Br J Pharmacol. 2001;134:1429–1436. [PMC free article] [PubMed]
124. Brown A, et al. Discovery and SAR of org 24598-a selective glycine uptake inhibitor. Bioorg Med Chem Lett. 2001;11:2007–2009. [PubMed]
125. Javitt DC. Reversal of phencyclidine-induced hyperactivity by glycine and the glycine uptake inhibitor glycyldodecylamide. Neuropsychopharmacology. 1997;17:202–204. [PubMed]
126. Javitt DC. Glycyldodecylamide, a phencyclidine behavioral antagonist, blocks cortical glycine uptake: implications for schizophrenia and substance abuse. Psychopharmacology (Berl). 1997;129:96–98. [PubMed]
127. Tsai G. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 2004;55:452–456. [PubMed]
128. Lane HY, et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol Psychiatry. 2006;60:645–649. [PubMed]
129. Black MD. Therapeutic potential of positive AMPA modulators and their relationship to AMPA receptor subunits. A review of preclinical data. Psychopharmacology (Berl). 2005;179:154–163. [PubMed]
130. Suppiramaniam V, et al. Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors. Synapse. 2001;40:154–158. [PubMed]
131. Yamada KA. Modulating excitatory synaptic neurotransmission: potential treatment for neurological disease? Neurobiol Dis. 1998;5:67–80. [PubMed]
132. Arai A. A centrally active drug that modulates AMPA receptor gated currents. Brain Res. 1994;638:343–346. [PubMed]
133. Hampson RE. Facilitative effects of the ampakine CX516 on short-term memory in rats: enhancement of delayed-nonmatch-to-sample performance. J Neurosci. 1998;18:2740–2747. [PubMed]
134. Hampson RE. Facilitative effects of the ampakine CX516 on short-term memory in rats: correlations with hippocampal neuronal activity. J Neurosci. 1998;18:2748–2763. [PubMed]
135. Granger R, et al. A drug that facilitates glutamatergic transmission reduces exploratory activity and improves performance in a learning-dependent task. Synapse. 1993;15:326–329. [PubMed]
136. Staubli U, et al. Centrally active modulators of glutamate receptors facilitate the induction of long-term potentiation in vivo. Proc Natl Acad Sci USA. 1994;91:11158–11162. [PMC free article] [PubMed]
137. Lebrun C. Effects of S 18986-1, a novel cognitive enhancer, on memory performances in an object recognition task in rats. Eur J Pharmacol. 2000;401:205–212. [PubMed]
138. Granger R, et al. Facilitation of glutamate receptors reverses an age-associated memory impairment in rats. Synapse. 1996;22:332–337. [PubMed]
139. Goff DC, et al. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol. 2001;21:484–487. [PubMed]
140. Marenco S, et al. Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series. Schizophr Res. 2002;57:221–226. [PubMed]
141. Wezenberg E. Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers. Neuropsychopharmacology. 2007;32:1272–1283. [PubMed]
142. Chavez-Noriega LE. Metabotropic glutamate receptors: potential drug targets for the treatment of schizophrenia. Curr Drug Targets CNS Neurol Disord. 2002;1:261–281. [PubMed]
143. Alagarsamy S, et al. NMDA-induced phosphorylation and regulation of mGluR5. Pharmacol Biochem Behav. 2002;73:299–306. [PubMed]
144. Maeda J. Different roles of group I and group II metabotropic glutamate receptors on phencyclidine-induced dopamine release in the rat prefrontal cortex. Neurosci Lett. 2003;336:171–174. [PubMed]
145. Marino MJ. Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors. Curr Opin Pharmacol. 2006;6:98–102. [PubMed]
146. Govek SP, et al. Benzazoles as allosteric potentiators of metabotropic glutamate receptor 2 (mGluR2): efficacy in an animal model for schizophrenia. Bioorg Med Chem Lett. 2005;15:4068–4072. [PubMed]
147. Aalto S. Frontal and temporal dopamine release during working memory and attention tasks in healthy humans: a positron emission tomography study using the high-affinity dopamine D2 receptor ligand [11C]FLB 457. J Neurosci. 2005;25:2471–2477. [PubMed]
148. Brozoski TJ. Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science. 1979;205:929–932. [PubMed]
149. Davis KL. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991;148:1474–1486. [PubMed]
150. Doran AR. Structural brain pathology in schizophrenia revisited. Prefrontal cortex pathology is inversely correlated with cerebrospinal fluid levels of homovanillic acid. Neuropsychopharmacology. 1987;1:25–32. [PubMed]
151. Weinberger DR. Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. III. A new cohort and evidence for a monoaminergic mechanism. Arch Gen Psychiatry. 1988;45:609–615. [PubMed]
152. Abi-Dargham A, et al. Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci. 2002;22:3708–3719. [PubMed]
153. Barch DM. Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers. Schizophr Res. 2005;77:43–58. [PubMed]
154. Dolan RJ. Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia. Nature. 1995;378:180–182. [PubMed]
155. Granon S. Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J Neurosci. 2000;20:1208–1215. [PubMed]
156. Mattay VS, et al. Effects of dextroamphetamine on cognitive performance and cortical activation. Neuroimage. 2000;12:268–275. [PubMed]
157. Williams GV. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature. 1995;376:572–575. [PubMed]
158. Goldman-Rakic PS. D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev. 2000;31:295–301. [PubMed]
159. Fremeau RT, Jr, et al. Localization of D1 dopamine receptor mRNA in brain supports a role in cognitive, affective, and neuroendocrine aspects of dopaminergic neurotransmission. Proc Natl Acad Sci USA. 1991;88:3772–3776. [PMC free article] [PubMed]
160. Okubo Y, et al. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature. 1997;385:634–636. [PubMed]
161. Castner SA. Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science. 2000;287:2020–2022. [PubMed]
162. Arnsten AF. Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl). 1994;116:143–151. [PubMed]
163. Cai JX. Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys. J Pharmacol Exp Ther. 1997;283:183–189. [PubMed]
164. Schneider JS. Effects of dihydrexidine, a full dopamine D-1 receptor agonist, on delayed response performance in chronic low dose MPTP-treated monkeys. Brain Res. 1994;663:140–144. [PubMed]
165. Castner SA. Enhancement of working memory in aged monkeys by a sensitizing regimen of dopamine D1 receptor stimulation. J Neurosci. 2004;24:1446–1450. [PubMed]
166. Pellissier G. Hypotensive and bradycardic effects elicited by spinal dopamine receptor stimulation: effects of D1 and D2 receptor agonists and antagonists. J Cardiovasc Pharmacol. 1991;18:548–555. [PubMed]
167. Van Tol HH, et al. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature. 1991;350:610–614. [PubMed]
168. Corrigan MH. Effectiveness of the selective D4 antagonist sonepiprazole in schizophrenia: a placebo-controlled trial. Biol Psychiatry. 2004;55:445–451. [PubMed]
169. Kramer MS. The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group. Arch Gen Psychiatry. 1997;54:567–572. [PubMed]
170. Truffinet P. Placebo-controlled study of the D4/5-HT2A antagonist fananserin in the treatment of schizophrenia. Am J Psychiatry. 1999;156:419–425. [PubMed]
171. Tarazi FI. Dopamine D4 receptors: beyond schizophrenia. J Recept Signal Transduct Res. 2004;24:131–147. [PubMed]
172. Jentsch JD. Dopamine D4 receptor antagonist reversal of subchronic phencyclidine-induced object retrieval/detour deficits in monkeys. Psychopharmacology (Berl). 1999;142:78–84. [PubMed]
173. Mrzljak L. Localization of dopamine D4 receptors in GABAergic neurons of the primate brain. Nature. 1996;381:245–248. [PubMed]
174. Kotecha SA, et al. A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission. Neuron. 2002;35:1111–1122. [PubMed]
175. Rubinstein M, et al. Dopamine D4 receptor-deficient mice display cortical hyperexcitability. J Neurosci. 2001;21:3756–3763. [PubMed]
176. Arnsten AF. The selective dopamine D4 receptor antagonist, PNU-101387G, prevents stress-induced cognitive deficits in monkeys. Neuropsychopharmacology. 2000;23:405–410. [PubMed]
177. Browman KE, et al. A-412997, a selective dopamine D4 agonist, improves cognitive performance in rats. Pharmacol Biochem Behav. 2005;82:148–155. [PubMed]
178. Bernaerts P. Facilitatory effect of the dopamine D4 receptor agonist PD168,077 on memory consolidation of an inhibitory avoidance learned response in C57BL/6J mice. Behav Brain Res. 2003;142:41–52. [PubMed]
179. Wang X. Dopamine D4 receptors modulate GABAergic signaling in pyramidal neurons of prefrontal cortex. J Neurosci. 2002;22:9185–9193. [PubMed]
180. Tunbridge EM. Catechol-O-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry. 2006;60:141–151. [PubMed]
181. Kopin IJ. Catecholamine metabolism: basic aspects and clinical significance. Pharmacol Rev. 1985;37:333–364. [PubMed]
182. Karoum F. 3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model. J Neurochem. 1994;63:972–979. [PubMed]
183. Gogos JA, et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA. 1998;95:9991–9996. [PMC free article] [PubMed]
184. Liljequist R. Catechol O-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats. Behav Brain Res. 1997;82:195–202. [PubMed]
185. Gasparini M. Cognitive improvement during Tolcapone treatment in Parkinson's disease. J Neural Transm. 1997;104:887–894. [PubMed]
186. Watkins P. COMT inhibitors and liver toxicity. Neurology. 2000;55:S51–S52. discussion S53–S56. [PubMed]
187. Chen J, et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet. 2004;75:807–821. [PMC free article] [PubMed]
188. Meyer-Lindenberg A, et al. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci. 2005;8:594–596. [PubMed]
189. Badner JA. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry. 2002;7:405–411. [PubMed]
190. Coon H, et al. Genomic scan for genes predisposing to schizophrenia. Am J Med Genet. 1994;54:59–71. [PubMed]
191. Lewis CM, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am J Hum Genet. 2003;73:34–48. [PMC free article] [PubMed]
192. Fan JB, et al. Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry. 2005;57:139–144. [PubMed]
193. Glatt SJ. Association between a functional catechol-O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. Am J Psychiatry. 2003;160:469–476. [PubMed]
194. Munafo MR. Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry. 2005;10:765–770. [PubMed]
195. Woodward ND. COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia. Schizophr Res. 2007;90:86–96. [PubMed]
196. Apud JA, et al. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology. 2007;32:1011–1020. [PubMed]
197. Willins DL. Serotonin 5-HT2A receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse. 1997;27:79–82. [PubMed]
198. Rodriguez JJ. Subcellular distribution of 5-hydroxytryptamine2A and N-methyl-D-aspartate receptors within single neurons in rat motor and limbic striatum. J Comp Neurol. 1999;413:219–231. [PubMed]
199. Rodriguez JJ. N-methyl-D-aspartate (NMDA) receptors in the ventral tegmental area: subcellular distribution and colocalization with 5-hydroxytryptamine(2A) receptors. J Neurosci Res. 2000;60:202–211. [PubMed]
200. Xia Z. A direct interaction of PSD-95 with 5-HT2A serotonin receptors regulates receptor trafficking and signal transduction. J Biol Chem. 2003;278:21901–21908. [PubMed]
201. Aghajanian GK. Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Brain Res Rev. 2000;31:302–312. [PubMed]
202. Carlsson ML, et al. The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice. J Neural Transm. 1999;106:123–129. [PubMed]
203. Varty GB. M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats. Neuropsychopharmacology. 1999;20:311–321. [PubMed]
204. Weiner DM, et al. 5-hydroxytryptamine2A receptor inverse agonists as antipsychotics. J Pharmacol Exp Ther. 2001;299:268–276. [PubMed]
205. Doherty MD. Ultrastructural localization of the serotonin 2A receptor in dopaminergic neurons in the ventral tegmental area. Brain Res. 2000;864:176–185. [PubMed]
206. Nocjar C. Localization of 5-HT(2A) receptors on dopamine cells in subnuclei of the midbrain A10 cell group. Neuroscience. 2002;111:163–176. [PubMed]
207. Alex KD. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther. 2007;113:296–320. [PMC free article] [PubMed]
208. Roth BL. Atypical antipsychotic drug actions: unitary or multiple mechanisms for ‘atypicality’? Clin Neurosci Res. 2003;3:108–117.
209. Li XM. Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum. Psychopharmacology (Berl). 1998;136:153–161. [PubMed]
210. Minabe Y. Acute and repeated administration of the selective 5-HT(2A) receptor antagonist M100907 significantly alters the activity of midbrain dopamine neurons: an in vivo electrophysiological study. Synapse. 2001;40:102–112. [PubMed]
211. Pehek EA. M100,907, a selective 5-HT(2A) antagonist, attenuates dopamine release in the rat medial prefrontal cortex. Brain Res. 2001;888:51–59. [PubMed]
212. Roth BL. Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology (Berl). 2004;174:17–24. [PubMed]
213. Poyurovsky M, et al. Effect of the 5-HT2 antagonist mianserin on cognitive dysfunction in chronic schizophrenia patients: an add-on, double-blind placebo-controlled study. Eur Neuropsychopharmacol. 2003;13:123–128. [PubMed]
214. Roth BL. Activation is hallucinogenic and antagonism is therapeutic: role of 5-HT2A receptors in atypical antipsychotic drug actions. Neuroscientist. 1999;5:254–262.
215. Williams GV. The physiological role of 5-HT2A receptors in working memory. J Neurosci. 2002;22:2843–2854. [PubMed]
216. Tune LE. Serum levels of anticholinergic drugs and impaired recent memory in chronic schizophrenic patients. Am J Psychiatry. 1982;139:1460–1462. [PubMed]
217. Pazos A. Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res. 1985;346:205–230. [PubMed]
218. Hamon M. The main features of the central 5-HT1A receptors. In: Baumgarten HG, editor. Serotoninergic Neurons and 5-HT Receptors in the CNS. Berlin, Germany: Springer; 1997. pp. 238–268.
219. Barnes NM. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38:1083–1152. [PubMed]
220. Azmitia EC. Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells. Neuropsychopharmacology. 1996;14:35–46. [PubMed]
221. Martin-Ruiz R, et al. Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism. J Neurosci. 2001;21:9856–9866. [PubMed]
222. Araneda R. 5-Hydroxytryptamine2 and 5-hydroxytryptamine 1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience. 1991;40:399–412. [PubMed]
223. Schechter LE. The potential utility of 5-HT1A receptor antagonists in the treatment of cognitive dysfunction associated with Alzheimer s disease. Curr Pharm Des. 2002;8:139–145. [PubMed]
224. Newman-Tancredi A, et al. Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study. Eur J Pharmacol. 1998;355:245–256. [PubMed]
225. Shapiro DA, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003;28:1400–1411. [PubMed]
226. Winstanley CA. Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats. Psychopharmacology (Berl). 2003;167:304–314. [PubMed]
227. Boast C. 5HT antagonists attenuate MK801-impaired radial arm maze performance in rats. Neurobiol Learn Mem. 1999;71:259–271. [PubMed]
228. Yasuno F, et al. Inhibitory effect of hippocampal 5-HT1A receptors on human explicit memory. Am J Psychiatry. 2003;160:334–340. [PubMed]
229. Sumiyoshi T, et al. Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment. Am J Psychiatry. 2001;158:1722–1725. [PubMed]
230. Sumiyoshi T, et al. The effect of tandospirone, a serotonin(1A) agonist, on memory function in schizophrenia. Biol Psychiatry. 2001;49:861–868. [PubMed]
231. Renyi L, et al. The pharmacological profile of (R)-3,4-dihydro-N-isopropyl-3-(N-isopropyl-N-propylamino)-2H-1-benzopyran- 5-carboxamide, a selective 5-hydroxytryptamine(1A) receptor agonist. J Pharmacol Exp Ther. 2001;299:883–893. [PubMed]
232. Craig DA. Pharmacological characterization of a neuronal receptor for 5-hydroxytryptamine in guinea pig ileum with properties similar to the 5-hydroxytryptamine receptor. J Pharmacol Exp Ther. 1990;252:1378–1386. [PubMed]
233. Patel S. Localization of serotonin-4 receptors in the striatonigral pathway in rat brain. Neuroscience. 1995;69:1159–1167. [PubMed]
234. Reynolds GP, et al. 5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases. Br J Pharmacol. 1995;114:993–998. [PMC free article] [PubMed]
235. Meneses A. Effects of 5-HT4 receptor agonists and antagonists in learning. Pharmacol Biochem Behav. 1997;56:347–351. [PubMed]
236. Micale V. Cognitive effects of SL65.0155, a serotonin 5-HT4 receptor partial agonist, in animal models of amnesia. Brain Res. 2006;1121:207–215. [PubMed]
237. Mlinar B. 5-HT4 receptor activation induces long-lasting EPSP-spike potentiation in CA1 pyramidal neurons. Eur J Neurosci. 2006;24:719–731. [PubMed]
238. Cho S. Activation of 5-HT4 receptors inhibits secretion of beta-amyloid peptides and increases neuronal survival. Exp Neurol. 2007;203:274–278. [PubMed]
239. Boess FG, et al. Functional and radioligand binding characterization of rat 5-HT6 receptors stably expressed in HEK293 cells. Neuropharmacology. 1997;36:713–720. [PubMed]
240. Monsma FJ., Jr Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol. 1993;43:320–327. [PubMed]
241. Roth BL, et al. Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors. J Pharmacol Exp Ther. 1994;268:1403–1410. [PubMed]
242. Bourson A. Determination of the role of the 5-ht6 receptor in the rat brain: a study using antisense oligonucleotides. J Pharmacol Exp Ther. 1995;274:173–180. [PubMed]
243. Bourson A. Involvement of 5-HT6 receptors in nigro-striatal function in rodents. Br J Pharmacol. 1998;125:1562–1566. [PMC free article] [PubMed]
244. Rogers DC. Cognitive enhancement effects of the selective 5-HT6 antagonist SB-271046. Br J Pharmacol. suppl. 1999;127:22.
245. Routledge C. Characterisation of SB-271046: a potent and selective 5-HT6 receptor antagonist. Br J Pharmacol. suppl. 1999;127:21.
246. Gustafson EL. A receptor autoradiographic and in situ hybridization analysis of the distribution of the 5-ht7 receptor in rat brain. Br J Pharmacol. 1996;117:657–666. [PMC free article] [PubMed]
247. Mengod G. 5-HT receptors in mammalian brain: receptor autoradiography and in situ hybridization studies of new ligands and newly identified receptors. Histochem J. 1996;28:747–758. [PubMed]
248. Neumaier JF. Localization of 5-HT(7) receptors in rat brain by immunocytochemistry, in situ hybridization, and agonist stimulated cFos expression. J Chem Neuroanat. 2001;21:63–73. [PubMed]
249. Ehlen JC. In vivo resetting of the hamster circadian clock by 5-HT7 receptors in the suprachiasmatic nucleus. J Neurosci. 2001;21:5351–5357. [PubMed]
250. Lovenberg TW, et al. A novel adenylyl cyclase-activating serotonin receptor (5-HT7) implicated in the regulation of mammalian circadian rhythms. Neuron. 1993;11:449–458. [PubMed]
251. Thomas DR, et al. SB-656104-A, a novel selective 5-HT7 receptor antagonist, modulates REM sleep in rats. Br J Pharmacol. 2003;139:705–714. [PMC free article] [PubMed]
252. Manuel-Apolinar L. 8-OH-DPAT facilitated memory consolidation and increased hippocampal and cortical cAMP production. Behav Brain Res. 2004;148:179–184. [PubMed]
253. Roberts AJ. Mice lacking 5-HT receptors show specific impairments in contextual learning. Eur J Neurosci. 2004;19:1913–1922. [PubMed]
254. Bickmeyer U. Differential modulation of I(h) by 5-HT receptors in mouse CA1 hippocampal neurons. Eur J Neurosci. 2002;16:209–218. [PubMed]
255. Tokarski K. 5-HT7 receptors increase the excitability of rat hippocampal CA1 pyramidal neurons. Brain Res. 2003;993:230–234. [PubMed]
256. Arnsten AF. Adrenergic targets for the treatment of cognitive deficits in schizophrenia. Psychopharmacology (Berl). 2004;174:25–31. [PubMed]
257. Fields RB, et al. Clonidine improves memory function in schizophrenia independently from change in psychosis. Preliminary findings. Schizophr Res. 1988;1:417–423. [PubMed]
258. Friedman JI, et al. Guanfacine treatment of cognitive impairment in schizophrenia. Neuropsychopharmacology. 2001;25:402–409. [PubMed]
259. Millan MJ, et al. S18327 (1-[2-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)piperid-1-yl]ethyl]3-phenyl imidazolin-2-one), a novel, potential antipsychotic displaying marked antagonist properties at alpha(1)- and alpha(2)-adrenergic receptors: I. Receptorial, neurochemical, and electrophysiological profile. J Pharmacol Exp Ther. 2000;292:38–53. [PubMed]
260. Gobert A. Simultaneous quantification of serotonin, dopamine and noradrenaline levels in single frontal cortex dialysates of freely-moving rats reveals a complex pattern of reciprocal auto- and heteroreceptor-mediated control of release. Neuroscience. 1998;84:413–429. [PubMed]
261. Litman RE. Idazoxan and response to typical neuroleptics in treatment-resistant schizophrenia. Comparison with the atypical neuroleptic, clozapine. Br J Psychiatry. 1996;168:571–579. [PubMed]
262. Rao SG. Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory. J Neurosci. 2000;20:485–494. [PubMed]
263. Benes FM. Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects. Neuroscience. 1996;75:1021–1031. [PubMed]
264. Blum BP. The GABAergic system in schizophrenia. Int J Neuropsychopharmacol. 2002;5:159–179. [PubMed]
265. Lewis DA. Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia. Biol Psychiatry. 1999;46:616–626. [PubMed]
266. De Luca V. Polymorphisms in glutamate decarboxylase genes: analysis in schizophrenia. Psychiatr Genet. 2004;14:39–42. [PubMed]
267. Hashimoto T, et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci. 2003;23:6315–6326. [PubMed]
268. Lewis DA. Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction. Psychopharmacology (Berl). 2004;174:143–150. [PubMed]
269. Lewis DA. Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol. 2006;63:1372–1376. [PubMed]
270. Lewis DA. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005;6:312–324. [PubMed]
271. de Haas SL, et al. Pharmacodynamic and pharmacokinetic effects of TPA023, a GABAA α2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers. J Psychopharmacol. 2006 doi:10.1177/0269881106072343. [PubMed]
272. Dawson GR, et al. An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition. J Pharmacol Exp Ther. 2006;316:1335–1345. [PubMed]
273. Collinson N. An inverse agonist selective for alpha5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze. Psychopharmacology (Berl). 2006;188:619–628. [PubMed]
274. Atack JR. L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors. Neuropharmacology. 2006;51:1023–1029. [PubMed]
275. Chambers MS, et al. An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties. J Med Chem. 2004;47:5829–5832. [PubMed]
276. Glykys J. Hippocampal network hyperactivity after selective reduction of tonic inhibition in GABA A receptor alpha5 subunit-deficient mice. J Neurophysiol. 2006;95:2796–2807. [PubMed]
277. Martin WR. The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976;197:517–532. [PubMed]
278. Su TP. Evidence for sigma opioid receptor: binding of [3H]SKF-10047 to etorphine-inaccessible sites in guinea-pig brain. J Pharmacol Exp Ther. 1982;223:284–290. [PubMed]
279. Hanner M, et al. Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci USA. 1996;93:8072–8077. [PMC free article] [PubMed]
280. Su TP. Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science. 1988;240:219–221. [PubMed]
281. Su TP. Delineating biochemical and functional properties of sigma receptors: emerging concepts. Crit Rev Neurobiol. 1993;7:187–203. [PubMed]
282. Monnet FP. N-methyl-D-aspartate-induced neuronal activation is selectively modulated by sigma receptors. Eur J Pharmacol. 1990;179:441–445. [PubMed]
283. Ishihara K. [Modulation of neuronal activities in the central nervous system via sigma receptors] Nihon Shinkei Seishin Yakurigaku Zasshi. 2002;22:23–30. [PubMed]
284. Hayashi T. Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. CNS Drugs. 2004;18:269–284. [PubMed]
285. Zou LB. Sigma receptor ligands (+)-SKF10,047 and SA4503 improve dizocilpine-induced spatial memory deficits in rats. Eur J Pharmacol. 1998;355:1–10. [PubMed]
286. Bologa L. Dehydroepiandrosterone and its sulfated derivative reduce neuronal death and enhance astrocytic differentiation in brain cell cultures. J Neurosci Res. 1987;17:225–234. [PubMed]
287. Compagnone NA. Dehydroepiandrosterone: a potential signalling molecule for neocortical organization during development. Proc Natl Acad Sci USA. 1998;95:4678–4683. [PMC free article] [PubMed]
288. Roberts E. Effects of dehydroepiandrosterone and its sulfate on brain tissue in culture and on memory in mice. Brain Res. 1987;406:357–362. [PubMed]
289. Bergeron R. Potentiation of neuronal NMDA response induced by dehydroepiandrosterone and its suppression by progesterone: effects mediated via sigma receptors. J Neurosci. 1996;16:1193–1202. [PubMed]
290. Debonnel G. Potentiation by dehydroepiandrosterone of the neuronal response to N-methyl-D-aspartate in the CA3 region of the rat dorsal hippocampus: an effect mediated via sigma receptors. J Endocrinol. suppl. 1996;150:S33–S42. [PubMed]
291. Flood JF. Dehydroepiandrosterone and its sulfate enhance memory retention in mice. Brain Res. 1988;447:269–278. [PubMed]
292. Flood JF. Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc Natl Acad Sci USA. 1992;89:1567–1571. [PMC free article] [PubMed]
293. Maurice T. Dehydroepiandrosterone sulfate attenuates dizocilpine-induced learning impairment in mice via sigma 1-receptors. Behav Brain Res. 1997;83:159–164. [PubMed]
294. Reddy DS. The effects of neurosteroids on acquisition and retention of a modified passive-avoidance learning task in mice. Brain Res. 1998;791:108–116. [PubMed]
295. Strous RD, et al. Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry. 2003;60:133–141. [PubMed]
296. Ross CA. Neurobiology of schizophrenia. Neuron. 2006;52:139–153. [PubMed]
297. Insel TR. Cure therapeutics and strategic prevention: raising the bar for mental health research. Mol Psychiatry. 2006;11:11–17. [PMC free article] [PubMed]
298. Lieberman JA. Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective. Biol Psychiatry. 1999;46:729–739. [PubMed]
299. Thome J. Neurotrophic factors and the maldevelopmental hypothesis of schizophrenic psychoses. Review article. J Neural Transm. 1998;105:85–100. [PubMed]
300. Stahl SM. When neurotrophic factors get on your nerves: therapy for neurodegenerative disorders. J Clin Psychiatry. 1998;59:277–278. [PubMed]
301. Zarate J. Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry. 2006;59:1006–1020. [PubMed]
302. Jope RS. Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. Curr Drug Targets. 2006;7:1421–1434. [PMC free article] [PubMed]
303. Menniti FS. Phosphodiesterase 10A inhibitors: a novel approach to the treatment of the symptoms of schizophrenia. Curr Opin Investig Drugs. 2007;8:54–59. [PubMed]
304. Urban JD, et al. Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther. 2007;320:1–13. [PubMed]
305. Ghanouni P, et al. Functionally different agonists induce distinct conformations in the G protein coupling domain of the beta 2 adrenergic receptor. J Biol Chem. 2001;276:24433–24436. [PubMed]

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