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Chattopadhyay A, editor. Serotonin Receptors in Neurobiology. Boca Raton (FL): CRC Press/Taylor & Francis; 2007.

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Chapter 7The 5-HT1A Receptor: A Signaling Hub Linked to Emotional Balance

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Abstract

Serotonin or 5-hydroxytryptamine (5-HT) is an ancient chemical that is synthesized in the brain and also in the peripheral system. It binds to 14 or more receptor proteins, all but one of which are G protein-coupled receptors. Pharmacological, behavioral, and clinical studies have placed one of these receptors, the serotonin 1A (5-HT1A) receptor, in the forefront as a protein that binds to 5-HT with high affinity to exert subtle control over emotion and behavior. This review will compare and contrast existing data on expression and signaling activity of the brain 5-HT1A receptor. Our purpose is to critically assess the current understanding of those 5-HT1AR-mediated signaling cascades that are physiologically important and also to unravel the poorly understood processes that have yet to be delineated through further experiments.

INTRODUCTION

Signal transduction through several classes of receptors brings about quick as well as slow effects that regulate neuronal activity, cellular organization, and functional development of the brain. The quick effects are, for example, neuronal excitation and inhibition, which are downstream of the ion channel receptors. In contrast, some of the slow effects are growth cone guidance and cell survival, which are caused by the activation of ephrin/semaphorin receptors and G protein-coupled receptors, respectively. Each of these receptor-mediated effects contributes toward the birth of new neurons as well as formation and maintenance of their connections with targets. Based on their function, the receptors have been classified into two groups: (1) effectors, which produce the final change in neuronal signals, and (2) modulators, which regulate the efficacy of the effectors to produce a timely change that enables the organism to steer itself into an altered state of homeostasis.

The slow-acting receptors regulate phosphorylation of functional proteins, expression of specific genes, and protein–protein interactions. By bringing about growth cone guidance, neurogenesis, and cell survival, these concerted processes play an important role in sculpturing and maintenance of brain compartments. Therefore, it is not surprising that the aberrant function of many G protein-coupled receptors, such as dopamine receptors, noradrenergic receptors, and serotonin receptors, is associated with emotional and cognitive disorders. This article will review the current literature on one serotonin receptor subtype, the serotonin 1A receptor (5-HT1A-R), and lay out its known signaling cascades that function independently or through interactions with signaling cascades initiated by other receptors.

A few seminal studies have established the pivotal role of the 5-HT1A-R in brain development. First, aberrant expression of this receptor and any disturbance in its signaling activity are concurrent with depression and suicidal tendencies (1–5), which often surface after the infantile and early juvenile stages of brain development. Furthermore, either complete deletion of this receptor or its tissue-specific elimination in the frontal cortex during neonatal development causes elevated anxiety levels in mice (6–9). Finally, many therapeutic agents that are used to ameliorate emotional disorders function through the 5-HT1A receptor (10–13). Despite such observations, there is only limited information available to clearly link the 5-HT1AR to early brain development through well-defined biochemical cascades. With this in mind, we will extensively review the existing literature on 5-HT1A-R mediated signaling in brain cells.

Although the expression and role of the 5-HT1A receptor in the brain is of prime importance, there is a significant body of literature on the expression of this receptor in T and B cells (14,15). Consequently, these studies link the 5-HT1A receptor also to the functional state of the immune system and, as expected, the schizophrenia drug clozapine, which is a partial agonist at the 5-HT1A-R, occasionally causes a dangerous side effect, agranulocytosis (16–18). Therefore, our discussion will also include reports on the functional activity of this receptor in the blood cells and the immune system.

DISTRIBUTION AND ONTOGENY OF THE 5-HT1A-R

Ligand binding, immunohistochemistry, and in situ hybridization in rats, mice, cats, tree shrews, and humans have revealed the presence of significant levels of 5-HT1A-R in almost all parts of the brain, including the cerebellum (19–26). Positron emission tomography (PET) studies using the 5-HT1A-R ligand [18F]MPPF in combination with in vitro autoradiography with [3H]MPPF, [3H]8-OH-DPAT, and [3H]paroxetine have revealed the highest level of expression in the hippocampus, cingulate, septum, and intralimbic cortex and the lowest in the cerebellum (23).

[3H]8-OH-DPAT binding studies have revealed a similar distribution profile for the 5-HT1A-R, although the overall level of receptor expression determined from binding assays were lower than those obtained from the more sensitive technique, autoradiography. From PET studies using [11C]WAY-100635, Parsey and coworkers have reported regional heterogeneity of 5-HT1AR in human cerebellum (25). Lack of 5-HT1A-R expression was observed in the cerebellar white matter, whereas the other regions displayed detectable levels of the receptor.

Cellular distribution of this receptor and its mRNA has also been analyzed. Santana and coworkers report that ~60% of glutamatergic cells express the 5-HT1A-R transcript and ~25% of GAD-expressing cells contain the 5-HT1A-R mRNA (27). Similarly, using immunohistochemistry with multiple antibodies, in vitro autoradiography with [3H]8-OH-DPAT, and also in situ hybridization. Palchauchuri and Függe report 5-HT1A-R mRNA expression in pyramidal neurons of layer 2 within the pre-frontal, insular, and occipital cortex (21). In contrast, [3H]8-OH-DPAT labeling occurred in layers 1 and 2, generating a columnar pattern in the prefrontal and occipital cortex. Pyramidal neurons in the claustrum and anterior olfactory nucleus expressed the receptor. Neurons in the hippocampal CA1 region expressed 5-HT1A-R mRNA and [3H]8-OH-DPAT labeling was observed in stratum oriens and stratum radiatum. Low receptor expression was observed in CA3 pyramidal neurons, but the granule neurons in the dentate gyrus contained moderate concentrations of the receptor.

Only a few studies describe the ontogeny of this receptor. Using immunohistochemistry, Patel and Zhou have demonstrated that almost all hippocampal neurons begin expressing the 5-HT1A-R upon completion of their terminal mitosis (28). At postnatal day 5 (P5) the receptor is expressed mainly on the cell bodies, but at P10 the receptor appears on both cell bodies as well as proximal apical dendrites. Finally, following neuronal maturation (at P21), a relatively sparse distribution is observed on the dendrites of stratum radiatum and stratum oriens of the hippocampus. Curiously, S100 and GFAP-positive glial cells transiently express the 5-HT1A-R during early postnatal development of the hippocampus. More than 90% of the S100-positive astrocytes in CA1, CA3, and dentate gyrus also show moderate 5-HT1A-R immunoreactivity at P7, which decreases in a dramatic manner by P16. Although tissue-specific distribution of the 5-HT1A-R has been studied earlier, this does not ensure that the signaling activity of the receptor will always be proportional to the expression levels of the receptor. Therefore, the regional and temporal profile of 5-HT1A-R signaling in the neuronal cells is an important determinant in the functional effect of this receptor. Such signaling effects are regulated by the second messenger coupling of the receptor.

PRESYNAPTIC AND POSTSYNAPTIC 5-HT1A-R AND THEIR SIGNALING EFFECTS

The major electrical effect mediated by the 5-HT1A receptor in neurons involves Go-mediated activation of hyperpolarizing K+ channels (29–32), which in turn causes attenuated firing of action potentials, thus resulting in decreasing firing of neurotransmitters from the synaptic ends of these neurons. Although the hyperpolarizing effect of the 5-HT1A-R is observed in both pre- and postsynaptic environments, the profiles of 5-HT1A-R desensitization seem to be widely different for the pre- and postsynaptic 5-HT1A-R molecules. Sustained administration of a 5-HT1A-R agonist or the serotonin reuptake inhibitor (SSRI) causes internalization of the 5-HT1A auto receptors in the raphé neurons but not the postsynaptic 5-HT1A receptors in the hippocampus (33–38). This is also believed to be the basis of action of the SSRIs. Initially, serotonin reuptake inhibition caused by the SSRIs in the presynaptic neurons results in increased serotonin release from these neurons (Figure 7.1). The discharged serotonin molecules bind to the 5-HT1A autoreceptors present on the soma of the raphé neurons, thus causing inhibition of firing from these neurons. Subsequently, the ligand-bound autoreceptors are internalized, thus causing termination of 5-HT1A-R signaling in the presnaptic neurons and resumption of serotonin release from the raphé neurons at the synapse with the dendritic terminals of the postsynaptic neurons. In the absence of the 5-HT1A autoreceptors, the released serotonin binds only to the postsynaptic 5-HT1A receptors, thereby eliciting the anxiolytic effect of the SSRIs (Figure 7.1) (36).

FIGURE 7.1. Increased postsynaptic activity after long-term administration of SSRIs or 5-HT1A-R agonists.

FIGURE 7.1

Increased postsynaptic activity after long-term administration of SSRIs or 5-HT1A-R agonists. The SERT molecules are not expressed at the synapses, but they are found on apposed neurons or on the same neurons but away from the synapse (102). (a) The SSRIs (more...)

Similarly, the antidepressant effects of the 5-HT1A agonists like buspirone or flesinoxan are also caused by the desensitization of only the 5-HT1A autoreceptors (35,37). Thus, after acute treatment, the agonist binds to the autoreceptors on the soma of the raphé neurons. The hyperopolarizing effect of 5-HT1A autoreceptors causes inhibition of serotonin release from the presynaptic terminal (Figure 7.1). Under this condition, the excess agonist acts on the postsynaptic (dendritic) 5-HT1A receptors, thereby causing inhibition of the postsynaptic neurons. Persistent action of the agonist causes internalization and desensitization of the 5-HT1A receptors on the raphé neurons but not the postsynaptic neurons. In the absence of the inhibitory 5-HT1A autoreceptors, the presynaptic raphé neurons elicit uninhibited firing of serotonin, which binds to the 5-HT1A-R molecules on the postsynaptic neurons to bring forth the characteristic anxiolytic effect of these agonists (Figure 7.1).

Signaling effects of the pre- and postsynaptic 5-HT1A receptors also appear to be different for at least one biochemical pathway. In hippocampal neuron-derived HN2-5 cells as well as in organotypic cultures of hippocampal slices, agonist activation of the 5-HT1A-R causes stimulation of the mitogen-activated protein kinase (MAPK) pathway (39–41). In contrast, Kushwaha and Albert observed that agonist activation of the 5-HT1A-R in the raphé-derived cell line RN46A causes a dramatic inhibition of the basal MAPK activity (42). Nonetheless, in both pre- and postsynaptic neurons, agonist activation of the 5-HT1A-R causes the customary inhibition of intracellular cAMP (32,42,43). The 5-HT1A-R also mediates stimulation of phospholipase C (PLC) in a postsynaptic neuron-derived cell line and in nonneural cells, but this signaling activity has yet to be studied in presynaptic (serotonergic) or raphé-derived neurons (32,39,40).

ABERRANT 5-HT1A-R EXPRESSION AND DISEASES

Expression and signaling activity of the 5-HT1A-R play a major role in multiple affective disorders. In schizophrenia (which often appears during adolescence), the majority of postmortem studies have reported increases in 5-HT1A-R density in the prefrontal cortex in the approximate range of 15–80% (10). Burnet and coworkers have gone further to show that whereas the 5-HT1A-R binding sites are significantly increased (+23%) in the dorsolateral prefrontal cortex, the 5-HT2A binding sites are decreased (27%) in the same region in the postmortem brain of schizophrenics (44). Recent studies in Alzheimer’s disease have shown that reduced 5-HT1A-R binding in the temporal cortex correlates with aggressive behavior in Alzheimer’s disease (45). Thus, altered 5-HT1A-R expression is observed in emotional and behavioral disorders.

Sheline and coworkers have reported that subjects with a history of major depression have smaller left and right hippocampal volumes (46). Following this, Pantel and coworkers reported the presence of brain atrophy using 3-D MRI in primary degenerative dementia (47). Drevets and coworkers have shown that the mean gray matter volume in prefrontal cortex, ventral to the genu of the corpus callosum, is reduced by 39% and 48% in bipolar and unipolar samples, respectively (48). A study carried out by Ashtari and coworkers builds a potentially important correlation between hippocampal structure and the expression of major depression in the elderly (49). It is noteworthy that all these morphological changes involve regions that show high expression and activity of the 5-HT1A receptor. In addition to 5-HT1A-R expression, its signaling activity is also altered in multiple disorders that affect the brain, such as alcoholism, cocaine abuse, and schizophrenia (10,44,45,50–53).

Genetic analysis performed by Lemonade and coworkers have shown that a C(−1019)G polymorphism in the 5-HT1A-R promoter leads to uncontrolled expression of the 5-HT1A receptor. Overexpression of this receptor in the presynaptic raphé neurons results in reduced serotonin firing at the synapse, thus causing decreased postsynaptic 5-HT1A-R activity, which in turn is closely associated with major depression and suicide (1). Finally, disruption of the 5-HT1A-R gene has been shown to cause elevated anxiety disorder in mice. Furthermore, temporal silencing of this gene up to postnatal day 21 in mouse front brain causes permanent occurrence of elevated anxiety (6–9). Intriguingly, silencing of this gene at a later stage of development does not have any phenotypic consequence. Collectively, such observations establish the profound importance of 5-HT1A-R signaling in a number of emotional disorders.

THERAPEUTIC AGENTS THAT FUNCTION BY REGULATING 5-HT1A-R SIGNALING

Over the last decade it has been suggested that 5-HT1A antagonists may have therapeutic utility in such diseases as depression, anxiety, drug- and nicotine-withdrawal. Recently, a compelling rationale has been developed for the therapeutic potential of 5-HT1A receptor antagonists also in Alzheimer’s disease and, potentially, other diseases with associated cognitive dysfunction (54). Involvement of the 5-HT1A-R in the effects of alcohol intake has been demonstrated by prenatal ethanol treatment of rats, which causes an increase in 5-HT1A-R-mediated wet-dog shakes (53). The 5-HT1A-R antagonist p-MPPI causes a decrease in ethanol-induced hypothermia and sleep (55). Furthermore, 5-HT1A agonists and antagonists have shown considerable promise in the treatment of depression, cocaine seeking, schizophrenia, and Alzheimer’s disease (10,44,54,56,57). Similarly, cocaine treatment of rats has been shown to cause increased serotonergic activity in the hippocampus and nucleus accumbens, which is blocked by a 5-HT1A-R antagonist (58). Likewise, the 5-HT1A-R antagonist WAY 100635 has been shown to block the locomotor stimulant effect of cocaine (57).

Serotonin 1A receptor-mediated signaling is involved in the therapeutic action of several formulations used for schizophrenia. Thus, the atypical antipsychotics, such as clozapine, olanzapine, risperidone, and perhaps other atypical antipsychotics, function through the 5-HT1A receptor (11,59,60). Pharmacological studies have shown that the atypical antipsychotics function as partial agonists at the 5-HT1A-R and as antagonists at 5-HT2A and D2 receptors. The atypical antipsychotics cause increased dopamine release in the brain, which is mediated by simultaneous activation of the 5-HT1A-R and blockage of 5-HT2A-R and D2 receptors (59,61,62). Additionally, the antipsychotics regulate serotonin release in the brain, and it is believed that their ability to modulate serotonin as well as dopaminergic function is crucial for their therapeutic activity as well as side effects (63). In fact, it is currently believed that the partial 5-HT1A agonist activity of the atypical antipsychotics contribute toward their efficacy to block psychosis without eliciting the extrapyramidal side effects of the typical (or earlier generation) antipsychotics such as haloperidol (60).

Based on such compelling data, it can argued that, in order to understand the etiology of many developmental disorders of the brain and also to make a headway into development of 5-HT1A-R-targeted drugs, it is essential to study the profile of signaling activity of this receptor in the developing brain.

RECENT ADVANCEMENT THROUGH THE USE OF THE SNRIs

Although the SSRIs have been the therapeutic agents of choice for a number of years, increasing lines of evidence suggest that the serotonin and nor-adrenalin reuptake blockers (SNRIs) are sometimes more useful in treating various affective disorders (64). The most widely used SNRI venlafaxine, commercially known as Effexor (Wyeth Chemicals, Inc.), functions as a 5-HT reuptake blocker at lower doses (75 mg/d) and as a 5-HT and nor-adrenalin reuptake inhibitor at higher concentrations (225–375 mg/d) (65). Multiple structural derivatives of venlafaxine and other SNRIs have shown similar efficacy as venlafaxine in treating a spectrum of affective disorders, including obsessive compulsive disorder (OCD) and depression (66,67). Additionally, application of a 5-HT1A receptor blocker WAY100635 would mask the inhibitory 5-HT1A autoreceptors and thereby bolster release of 5-HT from these neurons, thus augmenting the anxiolytic effect of the SNRI (66). However, other studies have also shown that the SNRIs produce some nor-adrenergically mediated side effects, such as increase in blood pressure, dry mouth, and constipation, which can be avoided by using an SSRI such as sertraline (68,69).

ROLE OF 5-HT1A-R IN THE IMMUNE SYSTEM AND CANCER

Expression of the 5-HT1A receptor in the immune system has been the central topic of many articles. Initial studies have shown that 5-HT1A-R-mediated signaling is responsible for mitogen-stimulated lymphocyte proliferation in mouse, rat, and fish (70,71). Subsequent experiments demonstrated that treatment of spleen-derived B and T lymphocytes with mitogens, such as lipopolysaccharide or phorbol 12-myristate 13-acetate plus ionomycin, causes induced expression of the 5-HT1A-R in these cells. Agonist activation of the newly expressed 5-HT1A receptors triggers proliferation of these cells (14). Finally, 5-HT1A-R-mediated promotion of mitogen-activated T and B cell survival and proliferation is associated with activation of NF-kappa B (15). Signaling via 5-HT1A signaling also plays an important role in the mononuclear cells, because agonist activation of this receptor causes activation of MAPK in these cells (72).

Based on such reports on the role of 5-HT1A-R in the cells of the immune system, it is expected that this receptor would play an important role in cancer, which is often caused by a malfunction of the immune system. Notwithstanding the limited number of publications observed so far on this topic, a few reports have implicated this receptor in the function of cancer cells. Thus, 5-HT1A-R mediated signaling exerts mitogenic effect on human small cell lung carcinoma cells (73). Dizeyi and coworkers have shown that high-grade prostate cancer cell lines express the 5-HT1A-R, and signaling via this receptor causes proliferation of the cancer cells (74). Intriguingly, Rizk and Hesketh report a 5-HT1A-R agonist with pronounced antiemetic effect, which could be used to prevent vomiting induced by cancer chemotherapy (75). Collectively, data from multiple laboratories suggest that signaling cascades mediated by the 5-HT1A-R cause increased proliferation of cancer cells (76).

Literature reviewed in the preceding sections also indicates that the 5-HT1A-R mediates positive regulation toward the immune system, which could be beneficial for health. Thus, the anxiolytic agents described earlier may in fact help stimulate our immune system. However, the effect of such therapeutic agents may also produce adverse effects in cancer patients by causing unwanted proliferation of the transformed cells.

REQUIRED FUTURE STUDIES TO UNRAVEL MECHANISMS OF 5-HT1A-R SIGNALING

This review has so far discussed mechanisms of action of 5-HT1A ligands and 5-HT reuptake inhibitors that eventually cause increased signaling through the 5-HT1A-R. But the mechanism of action of most of these therapeutic agents has been defined only up to a limited extent. A thorough analysis of the complete pathway of action of a therapeutic agent, from the action of the drug up to the exact ion channel or set of proteins that are involved in causing anxiolysis, has not been elucidated. Such detailed knowledge is expected to yield improved therapeutic agents and strategies to treat affective disorders with minimum side effects. Therefore, it is imperative to delineate the mechanism of action of each therapeutic agent that is currently used to treat depression, anxiety, OCD, schizophrenia, and other related disorders. This section will summarize some of the mechanisms known so far and also point out the large gap in information that still plagues the field of research on affective disorders.

SSRIs

These compounds block the 5-HT transporter (SERT) molecules on the soma of the dorsal raphé neurons (DRN). Normally, 5-HT taken up by the serotonergic neurons (DRN) somehow causes an inhibition of tryptophan hydroxylase (TPH), which is the rate limiting enzyme in the conversion of tryptophan to serotonin. This inhibition is eliminated in the presence of the 5-HT uptake blockers, such as the SSRIs. It has been shown that SSRIs, such as fluoxetine (Prozac) and sertraline, cause an activation of TPH (77,78). It is known that the TPH promoter harbors a cAMP response element (79) and a cAMP-protein kinase A (PKA)-mediated process is responsible for the SSRI-evoked transcriptional activation of the TPH gene (78). The inverse relationship between SERT and serotonin synthesis is further corroborated by the observation that 5-HT synthesis is increased 25–79% in the brain of SERT(−/−) mice (80).

Although such findings strongly suggest that intracellular 5-HT somehow inhibits the activity or expression of TPH, molecular mechanisms of this process have not been elucidated yet. The possibility that the end product, 5-HT, would cause a feed-back inhibition of TPH by binding to its catalytic pocket is not applicable here because physiological concentrations of 5-HT (in the micromolar range) do not inhibit TPH (81). Finally, as mentioned earlier, it is not clear how exactly postsynaptic 5-HT1A-R signaling functions to keep a check on depression and anxiety.

SNRIs

In addition to blocking the SERT molecules, the SNRIs also inhibit adrenalin/nor-adrenalin reuptake into the adrenergic neurons, which are regulated in the same way as the serotoninergic neurons. The monoaminergic hypothesis posits that a general decrease of monoamine neurotransmission occurs in the CNS during depression, whereas excessive monoamine neurotransmission occurs during the manic phase (82). Although it has been claimed in some studies that the SNRIs are more effective in ameliorating symptoms of depression, how the nor-adrenergic neurons regulate depression is far from clear. Furthermore, nonmonoaminergic systems are also involved because only 50% of subjects with depression experience full remission of symptoms with therapeutic agents targeted at the monoaminergic systems (83,84).

5-HT1A Agonists and 5-HT1A-R-Mediated Signaling

Antidepressant activity of several 5-HT1A-R agonists has been reported (85). The 5-HT1A agonists bind to the cognate receptors at both presynaptic, raphé neuron soma as well as the dendrites of the postsynaptic neurons. As discussed earlier, 5-HT1A-R signaling in the presynaptic neurons causes inhibition of 5-HT firing and reduced availability of 5-HT at the dendritic terminals of the synapses (Figure 7.1). In the postsynaptic neurons, the elicited 5-HT1A-R signaling causes hyperpolarization and inhibition of action potential, but it also results in other signaling effects that could be crucial for the anxiolytic properties of 5-HT1A signaling. The major observation that the therapeutic effect of 5-HT1A agonists was observed only after prolonged treatment for 2 weeks suggested that the mechanism of the action of antidepressants involved desensitization of the presynaptic 5-HT1A receptors (the postsynaptic 5-HT1A-R molecules are not downregulated under this condition; see earlier discussion) and subsequent excitation (lack of hyperpolarization) of the 5-HT-firing raphé neurons (Figure 7.1). However, such prolonged stimulation of the postsynaptic 5-HT1A-R molecules could also have other effects, such as increased cell division, which may be crucial for the anxiolytic activity of all agents that function by stimulating postsynaptic 5-HT1A-R signaling. Corroborating studies by Mehta and coworkers demonstrate that agonist activation of the hippocampal (postsynaptic) 5-HT1A receptors causes increased neurogenesis through a MAPK-mediated pathway (41). Furthermore, Santarelli and coworkers report that the antidepressant effect of Prozac can be eliminated by blocking Prozac-induced neurogenesis in the hippocampus of mice (13). Thus, the pathway, from the stimulation of postsynaptic 5-HT1A-R to the anxiolytic effect of the therapeutic agents, still remains to be elucidated.

Antipsychotics

Conventionally, antipsychotics have been placed into two categories: the typical (or earlier generation) antipsychotics such as haloperidol, and the atypical or newer antipsychotics, for example, clozapine. Most of these antipsychotics have been used to treat schizophrenia and, in some cases, depression. The earlier generation antipsychotics yielded the debilitating side effect of dykinesia or Parkinsonian-type muscle rigidity and movement disorder, which was eliminated when atypical antipsychotics were used. Some mechanistic studies on the atypical antipsychotics have been described earlier. According to the most popular hypothesis, schizophrenia is a result of disturbed dopamine release from the dopamine neurons in the brain (84). Experimental findings in support of this hypothesis show that treatment with antipsychotics causes an increase in dopamine release from the dopaminergic neurons (11,59,60,62). So, is schizophrenia caused by low dopaminergic neurotransmission? This possibility is negated by the observation that schizophrenic patients, when psychotic, show increased dopamine synthesis (86–88) and elevated dopaminergic neurotransmission (89–91). Moreover, other theories also implicate molecules such as calcineurin, neuregulin, and NMDA receptors in the incidence of schizophrenia-associated psychosis (92–95). In fact, the recent understanding is that perturbation of dopamine levels is only an associated effect but not the cause of schizophrenia (84). In view of such observations and also based on 5-HT1A agonist activity of the atypical antipsychotics, it can expected that the 5-HT1A-R may play an important role in the etiology of schizophrenia. Thus, further mechanistic studies are required to delineate the role of 5-HT1A-R-mediated signaling in schizophrenia.

EXAMPLES OF SOME STUDIES AND POSSIBLE STRATEGIES

In this section, we will present some mechanistic studies that elucidate the role of the 5-HT1A-R in mouse brain development and also shed light on the mechanism of action of the antipsychotic agent clozapine. The main purpose of presenting these results is to add the practical flavor of a multifarious approach, which is required in studying mechanisms underlying brain development and mode of action of antipsychotic drugs.

Early Mouse Brain Development and the 5-HT1A-R

Impairment of 5-HT1A-R signaling during this stage leads to emotional disorders, such as heightened anxiety, which indicates that 5-HT1A-R signaling is crucial for brain development. Yet, how this receptor is linked to brain development is far from clear. Our studies have shown that 5-HT1A-R signaling stimulates division of pre-neuronal cells in neonatal mouse brain (41). Data presented here show that agonist stimulation of the 5-HT1A-R causes such widespread activation of MAP kinase in the hippocampus that its averaged effect can be measured by Western blotting (Figure 7.2a,b). Also, this MAPK activation finally results in induced expression of cyclin D1, which is crucial for cell division.

FIGURE 7.2. Stimulation of 5-HT1A-R mediated MAPK activation in mouse hippocampus at P6.

FIGURE 7.2

Stimulation of 5-HT1A-R mediated MAPK activation in mouse hippocampus at P6. Cultured hippocampal slices were placed in serum-free medium and then treated with 8-OHDPAT (D) in the absence and presence of 4 μM WAY100635. (a) For Western blotting, (more...)

The mechanism of MAPK-mediated activation of cyclin D1 has been already established (Figure 7.3a). In this pathway, activated Erk1/2 causes phosphorylation-mediated stimulation of the transcription factor Elk-1, which boosts expression of c-Fos. Once induced, c-Fos combines with existing c-Jun molecules to yield elevated levels of the dimeric transcription factor AP-1 (96), which then induces cyclin D1 expression (97,98). Intriguingly, the 5-HT1A-R mediated induction of cyclin D1 also requires protein kinase C (PKC), because, in addition to WAY100635 (5-HT1A antagonist) and PD98059 (blocks phosphorylation-mediated activation of Erk1/2 by MEK), the PKC inhibitor GFX causes reversal of this 5-HT1A-R-mediated induction of cyclin D1 (Figure 7.3b).

FIGURE 7.3. Serotonin 1A receptor-mediated stimulation of cyclin D1 in P6 hippocampal slices.

FIGURE 7.3

Serotonin 1A receptor-mediated stimulation of cyclin D1 in P6 hippocampal slices. (a) Reported pathway for MAPK-mediated induction of cyclin D1. (b) Cultured, hippocampal slices from P6 mouse brain were placed in serum-free medium and then treated for (more...)

Involvement of 5-HT1A-R in Clozapine-Evoked Neuronal Activity

Even though it is known that dopaminergic disturbance may not be the cause of schizophrenia, most mechanistic studies of antipsychotic drugs have focused mainly on dopamine release from neurons. Some parts of the brain, like the striatum and ventral tegmental area (VTA), have a high density of dopaminergic neurons, but behavioral abnormalities observed in schizophrenia and other studies on brain activity implicate abnormal function of the prefrontal cortex (PFC) in schizophrenia. Therefore, in our study, we have asked the fundamental question, “Does clozapine cause a change in excitability of neurons in the PFC?” Our studies have revealed the interesting finding that clozapine causes a dramatic increase in activity of the PFC neurons as measured by population spikes (Figure 7.4). Intriguingly, this activity was reversed in the presence of the 5-HT1A-R antagonist, WAY100635, thus confirming the involvement of the 5-HT1A-R in the clozapine-evoked increase in neuronal activity in the PFC (Figure 2.4). Further analysis of this pathway may help elucidate the mechanism of antipsychotic effects of clozapine.

FIGURE 7.4. Clozapine-evoked increase in population spike is blocked by the 5-HT1A-R antagonist WAY100635.

FIGURE 7.4

Clozapine-evoked increase in population spike is blocked by the 5-HT1A-R antagonist WAY100635. Prefrontal cortex (PFC) slices from P20–30 mice were stimulated as described in the methods. After obtaining a stable baseline of population spike (a), (more...)

CONCLUDING REMARKS

Involvement of the 5-HT1A receptor in crucial physiological processes linked to emotional balance is a well-accepted concept in the current scientific culture. Many scientists still share the notion that the physiologically relevant signaling activity of the 5-HT1A-R is limited to the inhibition of adenylyl cyclase. Notwithstanding such dogma, several important studies in cell lines have demonstrated that this receptor is linked to multiple, discreet, yet physiologically important pathways that are not always linked to the inhibition of cAMP (32). Led by such in vitro studies, other research teams have conducted similar analysis of signal transduction in mice, rats, and other animals. Due to the complexity of such model systems, results thus obtained have yielded relatively limited mechanistic insight. Nonetheless, they have confirmed the existence of new signaling pathways linked to the 5-HT1A-R. Further-more, importance of this receptor in neonatal brain development has been established by using mutant mice in which receptor expression can be turned on only in the front brain. Despite such findings, it is not clear how this receptor actually helps in brain development.

Similarly, multiple antidepression and antipsychotic drugs are known to function through the 5-HT1A receptor. Yet the mechanisms of action of these therapeutic agents have not been elucidated. Therefore, it is of utmost importance to perform further mechanistic studies to understand how the 5-HT1A-R functions in the brain. In addition to the in vivo animal models used in some studies, our group has observed that cultured brain slices are more useful in creating a functionally active system that can be placed in a defined medium for appropriate drug treatment (41). By coupling tools like electrophysiology and immunohistochemistry with rigorous biochemical analysis while also using micro-dialysis and genetic manipulation of both animals as well as brain slices, it will now be possible to perform more elaborate studies to unravel the mechanism of involvement of the 5-HT1A-R in brain development.

EXPERIMENTAL PROCEDURES

Materials

Antibodies to P-Erk and cyclin D1 were obtained from Cell Signaling (Beverly, MA). The horse radish peroxidase-labeled secondary antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). The anti-ß-actin antibody, 8-OH-DPAT, WAY100635, wortmannin, and PD98059 were obtained from Sigma Chemicals (St. Louis, MO). Bis-indolylmaleimide or GF109203X (GFX) was purchased from Calbiochem (La Jolla, CA). The Alexafluor-labeled fluorescent secondary antibodies and the fluorescent Nissl stain were obtained from Molecular Probes (Eugene, OR).

Organotypic culture of hippocampal slices

The procedure of isolation of mouse brain slices for culture was adapted from publications by Stoppini and coworkers, Xiang and coworkers, and Grimpe and coworkers (99–101). Briefly, mouse pups of specific ages were anaesthetized with ketamine (100 mg/kg) and decapitated. Under sterile conditions, the brains were isolated and then cut at 60° from the longitudinal fissure at the top using a hippocampus dissecting tool to expose the hippocampus. The hemispheres containing the hippocampi were then placed for 30–40 min in modified Gey’s balanced salt solution (mGBSS) (prechilled to 4°C) while bubbling a mixture of 95% O2 and 5% CO2. Individual hippocampi were isolated using dissection tools and then 400-μm thick transverse slices were prepared using a tissue chopper (Stoelting, IL). The slices were placed in ice-cold mGBSS and inspected using a dissection microscope for the presence of uninterrupted bright transparent neuronal layers characteristic of the hippocampal structure. Only such slices were placed on Millicell CM filters (Millipore, Bedford, MA). Up to 3 slices were placed on each filter and the filters were placed in a 6-well dish with 1 ml of medium. The slices were thus kept at the air-medium interphase on high potassium culture medium (25% horse serum, 50% Basal Essential Media-Eagles, 25% Earle’s balanced salt solution (EBSS), 25 mM Na-HEPES, 1 mM glutamine, 28 mM glucose, pH 7.2) for the first 2 d. After incubation at 32°C in a 5% CO2 atmosphere, the culture medium was changed to physiological potassium slice culture medium (20% dialyzed fetal bovine serum, 5% Basal Essential Media-Eagles, and EBSS modified to adjust the potassium concentration to 2.66 mM). After 20% dialyzed serum treatment for two days, and before drug treatment, the slices were placed on serum-free medium (the same medium as above, but without serum) for one hour. This was followed by treatment with the inhibitors and antagonists for 30 min, followed by treatment with the agonist for the specified time periods. After drug treatment, the slices were either fixed in 4% paraformaldehyde or lysed as discussed in the following sections. mGBSS composition (in mM): CaCl2 (1.5), KCl (4.9), KH2PO4 (0.2), MgCl2 (11.0), MgSO4 (0.3), NaCl (138), NaHCO3 (2.7), Na2HPO4 (0.8), NaHEPES (25), glucose 6% (w/v), pH 7.2.

Drug treatment of slices

The slices were routinely treated with drugs on the fourth day of culture. The inhibitors were added 30 min before the agonist (100 nM 8-OH-DPAT). The concentrations of antagonists and inhibitors were as follows: WAY100635 (4 μM), PD98059 (25 μM), and GFX (2 μM).

Western blotting

The drug-treated slices were lysed in 1 ml RIPA buffer (PBS containing 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS, 0.5 mM Na3VO4 plus freshly added protease inhibitor cocktail; Boeringer), the lysate (10 μg protein) was resolved using a 716% gradient acrylamide gel, protein bands transferred to a nitrocellulose membrane, in a blocking solution containing 5% solution of defatted milk in 0.1% TWEEN 20 in TBS (20 mM Tris-HCl, pH 7.4, 0.8% NaCl) (t-TBS) and then the membrane probed with an ERK1/2 antibody (1: 500) followed by treatment with HRP-linked goat antirabbit IgG (1:50,000). Both antibodies were dissolved in the blocking solution. After probing with the Erk1/2 antibody, the blot was stripped by incubating for 1 h at room temperature in 0.2 M glycine (pH 2.5), and then blocked in 5% defatted milk solution and reprobed using a monoclonal, phospho-Erk specific (antiactive) antibody at 1:1000 dilution and then with horseradish peroxidase (HRP)-labeled antimouse IgG (1:5000). The immunoreactive bands were visualized using the Supersignal luminol kit (Pierce). The ERK1/2 bands were used to confirm that the observed increase in P-Erk bands is not due to an increase in the amount of ERK1/2 proteins. As the P-Erk antibody could not be stripped off in successive stripping/reprobing, it was always used in the final probing.

While monitoring cyclin D1 levels, a similar procedure was followed. The cyclin D1 antibody was used at 1:1000 dilution and the ß-actin antibody was diluted to 1:10,000 in 5% defatted milk solution.

Immunostaining of slices

The cultured and drug-treated slices were washed quickly with chilled 10 mM phosphate buffer (PB) and then fixed overnight at 4°C in 4% paraformaldehyde. The sections were then removed from the membrane with a brush and placed in a 48-well plate in TBS. This was followed by 2–3 washes (15 each) with TBS. For immunofluorescence staining, free-floating sections were first incubated for 30 min in 2N HCl at 37°C, and then rinsed 3X (15 each) with TBS. Sections were then blocked in TBS-X (TBS-0.1% Triton X-1003% serum from the animal used to raise the 2° antibody that was going to be used later) for 1 h at room temperature. This was followed by treatment with primary (1°) antibody in TBS for 48 h at 4°C with gentle rocking. Antibody concentration used: P-Erk (1:400). The sections were next washed 3 × 15′ at room temperature with TBS and then treated with fluorescent, 2° antibodies covalently linked to AlexaFluor488 (green) (1:200). After 48 h of 2° antibody treatment at 4°C, the sections were washed in TBS and then treated with Nissl stain. Slices were incubated in NeuroTrace red fluorescent Nissl stain (Molecular Probes) (1:200) in blocking solution without Triton-X-100 at room temperature for 20–30′. Following this, the slices were mounted on slides with ProLong Gold antifade reagent (Molecular Probes, Eugene, CA) for visualization and photography using a Laser confocal microscope.

Confocal microscopy of the immunstained slices, cell counting, and statistical analysis

Using a Nikon C1-LU3 laser scanning confocal system and 488 nm exciting wavelength for P-Erk (green) and 568 nm for Nissl-labeled (red) cells, the slices were viewed at 4× and 20×. The EZC1-system software was used to determine the total thickness of each slice after adjusting channels to obtain pictures from each exciting wavelength separately while blocking the laser beam of the other, exciting wavelength.

Recording neuronal activity from acutely isolated prefrontal cortex slices

Prefrontal cortex slices from postnatal day 20 to day 30 Swiss–Web-ster mice. Thick coronal sections (300-μm thick) from Prefrontal cortex were used for the electrical recording the stimulating electrode was placed on Layer VI and population spike was measured from Layer IV. Low frequency (0.03 Hz) repeated stimulation was applied at every 30-sec time interval. Once a steady basal level of population spike was obtained for about 10 min, clozapine (15 μM) was added to the bath (Ringer buffer, containing, in mM: NaCl 124, KCl 3.1, KH2PO4 1.3, MgSO4 1.3, CaCl2 3.1, NaHCO3 25.5, glucose 10.0) and the recording was continued until a plateau was reached (60 min). The same experiment was repeated four times (n = 4). In all experiments clozapine resulted in a significant increase in the population spike. The average value of the clozapine-boosted population spike obtained from 4 sets of experiments was compared with the average of population spike observed before drug treatment, and also in the presence of WAY100635 (4 μM) plus clozapine (Figure 7.4).

Acknowledgments

We thank Dr. G. Merz (Digital Microscopy Lab, IBR, NY) for expert advice and help in performing confocal microscopy. Fellowship supports were provided by the NYNYS–OMRDD (Mukti Mehta) and Macromolecular Assembly Institute (CUNY) (Baishali Kanjilal). Part support obtained from NIH grant MH071376.

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