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Van Dongen AM, editor. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press/Taylor & Francis; 2009.

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Chapter 3NMDA and Dopamine: Diverse Mechanisms Applied to Interacting Receptor Systems

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3.1. INTRODUCTION

N-methyl-D-aspartate (NMDA) and dopamine (DA) receptors and their interactions control an incredible variety of functions in the intact brain and, when abnormal, these interactions underlie and contribute to numerous disease states. These receptor interactions are relevant in such diverse functions as motor control, cognition and memory, neurodegenerative disorders, schizophrenia, and addiction. It is thus not surprising that a wealth of information has been generated by the neuroscience community interested in the coordinated functions of NMDA and DA receptors. This chapter will describe the numerous mechanisms underlying DA–NMDA receptor interactions, particularly in the striatum, the main focus of our investigations.

DA modulation of spontaneous or glutamate-induced action potentials in the caudate nucleus has been known for some time [1–3]. Since the discoveries of different subtypes of glutamate and DA receptors, the number of potential interactions and their mechanisms has multiplied because the functions of glutamate and DA receptor subtypes are governed by multiple factors that tap into different types of signaling systems. Thus, the outcomes of interactions of these receptor families can be very diverse.

It has been 10 years since we published our first review summarizing known DA–NMDA receptor interactions and their mechanisms [4]. Since then, exciting findings have added new levels of complexity. For example, in addition to intracellular interactions via second messenger pathways, recent studies revealed the presence of physical interactions between NMDA and DA receptors at the membrane and cytoplasm levels. Furthermore, the generation of mice deficient of specific DA receptors or NMDAR subunits and mice expressing enhanced green fluorescent protein (EGFP) under the control of specific DA receptor subtype promoters has provided new tools for studying relationships of DA and NMDA receptors.

3.2. CLASSIFICATION AND MORPHOLOGICAL BASIS FOR INTERACTIONS AMONG GLUTAMATE AND DA RECEPTOR SUBTYPES

Glutamate receptors have been classified as ionotropic and metabotropic. Ionotropic glutamate [α-amino-3-hydroxy-5-methyl-4-propionate (AMPA), kainate (KA), and NMDA] receptors are ligand-gated cation channels, whereas metabotropic glutamate receptors are coupled to various signal transduction systems [5–7]. NMDARs are unique in that their activation is governed by a strong voltage dependence due to receptor channel blockade by Mg2+ at hyperpolarized membrane potentials [8]. Mg2+ blockade gives NMDARs their characteristic negative slope conductance.

DA receptors also exhibit diversity. Five receptor subtypes have been cloned. They are classified into two main families: the D1 (D1 and D5 receptor subtypes) and the D2 families (D2, D3, and D4 receptor subtypes) [9,10]. All DA receptors are G protein-coupled and primarily alter the production of cAMP in cells when activated but also can affect other transduction systems. In this chapter, subscripted notations indicate DA receptor subtypes and nonsubscripted notations indicate the two DA receptor families.

The striatum is the main input structure of the basal ganglia. It is a central region where afferents from the cerebral cortex, thalamus, and substantia nigra converge and interact. Glutamate is released from cortical and, to a lesser extent, thalamic terminals [11,12]. DA is released from nigrostriatal terminals [13]. Because glutamate and DA inputs terminate on the same spines of striatal medium-sized spiny neurons (MSSNs), these sites offer the potential for physiological interactions between the glutamate and DA transmitter systems [14]. Morphological evidence demonstrates the presence of synaptic complexes formed by axospinous contacts in which the dendritic spine is the target of both an asymmetric (glutamatergic) bouton and a DA-positive symmetric synapse in striatal MSSNs [15]. This arrangement is also found in cortical pyramidal neurons [16] and provides a morphological basis for DA–glutamate receptor interactions at synapses. These interactions in the striatum support major sensory, motor, cognitive, and motivational functions [17–21]. In the cortex, they affect learning and memory [22] as well as normal and abnormal thought processes [23].

DA receptors are also found presynaptically, where they can modulate neurotransmitter release. In the dorsal striatum, D2 receptors are present on corticostriatal inputs and function to decrease glutamate release by presynaptic mechanisms [24–27]. Conversely, DA release can also be modulated by activation of glutamate receptors located on DA terminals [28,29]. Glutamate and DA receptor interactions are complex and their outcomes depend on a number of factors including receptor subtype, site of action (i.e., pre- or postsynaptic), timing of inputs, and concentration of neurotransmitter, to name only a few. For more exhaustive reviews see Cepeda and Levine [4] and Seamans and Yang [30].

3.3. DA AND D1 RECEPTOR ENHANCEMENT OF NMDA RECEPTOR-MEDIATED RESPONSES

DA and D1 receptor-mediated potentiation of NMDA responses was first described in human cortex and rodent striatum in the early 1990s [31,32]. Since then, with only a few notable exceptions [33,34], this enhancement has been verified in these and other brain structures [35–38]. D1 receptor potentiation of NMDA responses can lead to significant functional consequences. For example, potentiation of NMDAR-mediated responses can emphasize the most important input signals, but can also enhance glutamate activity, predisposing the system to excitotoxicity. In the striatum, activation of D1 receptors is required for the induction of long-term potentiation (LTP) [39,40], suggesting further that activation of D1 receptors effectively amplifies cortical signals to the striatum [41].

Although NMDA and D1 receptor interactions are clearly important, the nature and consequences of these interactions are complex and in some cases controversial or not fully elucidated. Multiple mechanisms underlie the interactions of D1 and NMDARs and fall into two main categories: interactions through signal transduction systems and direct physical interactions (Table 3.1).

TABLE 3.1

TABLE 3.1

NMDA–D1 and NMDA–D2 Receptor Interactions

3.3.1. Interactions through Second Messengers

D1 receptor enhancement of NMDA responses can be mediated by a number of redundant and cooperative signaling cascades in the striatum [4,30]. The most prominent involve protein kinase A (PKA) and dopamine- and adenosine-3′,5′-monophosphate (cAMP)-regulated phosphoprotein of 32 kDa (DARPP-32) [37,42,43], phosphorylation of NMDAR NR1 subunits [44], and activation of voltage-gated Ca2+ channels, particularly L-type channels [45,46].

In other cerebral regions, different mechanisms may occur. For example, in the nucleus accumbens, NMDAR potentiation by phospholipase C-coupled D1-like receptors occurs via protein kinase C (PKC) activation.35 Similarly, in cortical pyramidal neurons, intracellular application of the calmodulin Ca2+ chelator or inhibition of PKC activity significantly reduces the potentiation of NMDA currents, indicating that this interaction may be independent of PKA [38].

3.3.2. Physical DA–NMDA Receptor Interactions

In addition to modulation of NMDAR function through activation of signal transduction cascades [47,48], recent studies have shown that physical interactions between these receptors allow cross-talk via receptor linkages. Direct physical interactions between the C-terminal tails of D1 receptors and either the NR1 or NR2A NMDAR subunit have been demonstrated [49]. These protein–protein interactions are functionally relevant because D1 receptor activation decreases NMDA currents when PKA and PKC activation are blocked.

Evidence indicates that the D1 interaction with the NR2A subunit is involved in the inhibition of NMDAR-gated currents. The reduction of NMDA currents occurs via a decrease in the number of cell surface receptors [49]. The D1 interaction with the NR1 subunit has been implicated in the attenuation of NMDAR-mediated excitotoxicity through a phosphatidylinositol 3-kinase (PI-3 kinase)-dependent pathway. The D1–NR1 interaction also enables NMDAR activation to increase membrane insertions of D1 receptors [50].

The observation that physical receptor–receptor interactions reduce NMDA currents when second messenger pathways are blocked has been complicated by the demonstration that other mechanisms independent of D1 receptor activation may produce similar effects. A recent study revealed that one mechanism underlying reduction of NMDA currents is direct channel pore block of NMDARs by DA and several D1 receptor ligands [51]. Thus, without excluding the possibility that receptor–receptor interactions may lead to functional modulation, the inhibitory effects of DA or its agonists and antagonists require further examination since they may also occlude the channel.

3.4. RECIPROCAL D1–NMDA RECEPTOR INTERACTIONS

Activation of one type of receptor may alter the distribution of other types. In primary cultures of striatal neurons, activation of NMDARs increased the recruitment of D1 but not D2 receptors into the plasma membrane [52]. This translocation is abolished in the presence of an NMDAR antagonist or by removing Ca2+. After NMDA treatment, a dramatic increase in the number of D1 receptor-containing spines occurs.

The translocation of D1 receptors to the plasma membrane was confirmed in subcellular fractionation experiments using slices of adult rat striatum. Furthermore, in striatal organotypic cultures from rat, application of NMDA caused an increase in D1 receptor-positive spines [53].

Surprisingly, under these conditions, this effect is independent of Ca2+ and also occurs in the presence of Mg2+. Thus, in addition to the Ca2+-dependent recruitment of D1 receptors by activation of NMDARs seen in primary cultures, other NMDAR-dependent mechanisms may cause redistribution of D1 receptors to spines. This is achieved by a diffusion trap mechanism in which subsets of D1 receptors that typically move by lateral diffusion in the plasma membrane are trapped in the spines when NMDA binds to its receptor. Exposure to NMDA reduces the diffusion rate of D1 receptors and allows the formation of D1–NMDA heteroreceptor complexes.

This process may be explained by the allosteric theory of receptor activation [54]. After ligand binding, one conformation of the receptor is stabilized, shifting the equilibrium toward this state so that occupation of the binding site of the NMDAR favors a conformation that will bind to D1 receptors and thus stabilize them in spines. This mechanism is highly energy-efficient because it depends on D1 receptor diffusion and NMDAR allosterism—not on activation of transduction systems and intra-cellular signaling [53]. One interesting caveat to these studies is that glutamate is the endogenous agonist for NMDARs and these experiments did not examine all the outcomes in the presence of glutamate rather than NMDA, bringing into question the natural relevance of some of these findings.

While activation of NMDARs induces changes in the distribution of D1 receptors, the converse is also true. D1 receptor activation produces an increase in NR1, NR2A, and NR2B proteins in the synaptosomal membrane fraction [55] that is dependent on Fyn protein tyrosine kinase but not DARPP-32 [56]. Based on the partial overlap of NMDA and D1 receptors in dendritic spines, protein–protein interactions may direct the trafficking of D1 and NMDARs to the same subcellular domain.

The mechanism by which D1 receptors are delivered to different spine domains was examined in co-immunoprecipitation studies [57]. In the striatal postsynaptic density (PSD), the D1 receptor selectively complexes with the NR1 subunit of the NMDA channel through its C-terminal tail. The physical proximity between D1 receptors and NR1 subunits can best be explained by the formation of constitutive protein dimers. Oligomerization with the NMDAR thus regulates D1 receptor targeting to the plasma membrane. When the D1 receptor and the NR1 subunit are coexpressed in HEK293 cells, the D1 receptor is only partially targeted to the cell membrane, with most of the D1 receptor staining retained in cytoplasmic structures where it is colocalized with NR1.

Coexpression of the D1 receptor with both the NR1 and NR2B subunits relieves the cytoplasmic retention of the complex, allowing insertion of both the NR1 subunit and the D1 receptor at the plasma membrane, where they are completely colocalized. These data suggest that D1 and NMDARs are assembled as oligomeric units in the endoplasmic reticulum and transported to the cell surface as a preformed complex [57]. This implies that a direct protein–protein interaction with the NMDAR is one of the mechanisms directing the trafficking of D1 receptors to specific subcellular compartments. This direct interaction may be crucial to recruit the D1 receptor to the place where synaptic activity occurs and to keep it in close proximity to the NMDAR to allow rapid cAMP-PKA-DARPP-32-mediated potentiation of NMDA transmission [57].

It is interesting that the current evidence indicates that most physical hetero-receptor interactions lead to mutual inhibitory effects. This idea seems to contrast with the well-known observation that D1–NMDAR complexes play a role in enhancing synaptic plasticity and potentiating NMDA responses.

3.5. TOPOGRAPHIC AND TEMPORAL ASPECTS OF D1–NMDA OCCURS RECEPTOR INTERACTIONS

The ultimate outcome of D1–NMDAR interactions depends on a number of factors including temporal and topographic aspects (i.e., when and where the receptors are activated) [4,30]. The outcome of activation of interacting receptors in the brain may depend on the temporal sequence of neurotransmitter release. For example, activation of D1 receptors due to DA release caused by unexpected reward can prime particular corticostriatal synapses (including synapses in the nucleus accumbens) and recruit D1–NMDAR complexes in a regulated manner.57

Reynolds et al. [58] measured responses to cortical afferents before and after intracranial self-stimulation of the substantia nigra that would release DA. Such stimulation of DA cells with behaviorally reinforcing parameters induces potentiation of glutamatergic corticostriatal synapses that is blocked by administration of a D1 receptor antagonist. Timing is an important requirement for this type of synaptic plasticity because DA release should occur before excitatory afferents are activated in order to induce potentiation [59]. It is tempting to speculate that if D1 receptors are activated first, G protein- and Ca2+-dependent oligomerization of D1–NMDARs occurs, providing a regulated delivery of these complexes to plasma membranes, dendritic spines, or both. Massive DA release due to unexpected reward enhances the relevance of the stimulus by potentiating NMDA responses. This process is particularly important in MSSNs enriched with D1 receptors.

DA concentration and the mode of release are also important. Phasic release may produce different effects from tonic release. MSSNs are constantly bombarded by cortical and thalamic inputs and tonic release of DA filters a sizable percentage of these glutamatergic inputs through D2 receptors located on presynaptic terminals [60]. Higher local concentrations of DA occurring when it is phasically released are likely to activate D1 receptors and enhance selected corticostriatal synapses. For synaptic responses, studies in cortical pyramidal neurons revealed that the enhancement of NMDAR-mediated responses by DA follows an inverted U-shaped dose-response curve [30] in agreement with the idea that optimal levels of D1 receptor activation are required for efficient working memory formation [61]. Too much DA and hence too much activation of D1 receptors, as during stress, may be deleterious for cortical function.

3.6. REDUCTION OF NMDA RECEPTOR-MEDIATED RESPONSES BY DA OCCURS VIA D2 RECEPTORS

In contrast to the enhancing effects of D1 receptors on NMDAR-mediated responses, D2 receptor activation leads to inhibitory effects [32]. This may be relevant to preventing excessive activation of NMDARs and its consequent Ca2+ accumulation that may be deleterious to neurons. For example, DA and the D1 receptor agonist SKF 38393 increased the magnitude of NMDA-induced cell swelling, an index of excitotoxicity [62,63]. This effect was reduced in the presence of SCH 23390 (a D1 receptor antagonist), demonstrating specificity. In contrast, activation of D2 family receptors with quinpirole (a D2 receptor agonist) resulted in decreased cell swelling [64]. These results provided evidence that DA receptors have the potential to modulate excitotoxicity in the striatum, a process suggested to be responsible for cell dysfunction and ultimately cell death as in Huntington’s disease (HD).

Compared to D1–NMDAR interactions, much less is known about the mechanisms by which D2 receptor activation leads to reduction of NMDA currents. Decreased cAMP production and PKA activity are certainly potential mechanisms. D2 receptors also can modulate neuronal excitability by activating the PLC–IP3–Ca2+ cascade [65]. However, at least in cortical pyramidal neurons, D2 attenuation of NMDA responses does not require intracellular Ca2+ or PKA inhibition but requires activation of GABAA receptors, suggesting that this effect is mediated through excitation of GABA interneurons [46].

D4 receptors are abundant in the prefrontal cortex [66] and may play an important role in schizophrenia and other psychiatric disorders [67]. Mice lacking D4 receptors show signs of hyperexcitability [68]. Application of a D4 receptor agonist produces a decrease of NMDA currents via inhibition of PKA, activation of PP1 and the consequent inhibition of Ca2+ calmodulin-dependent kinase II [69]. In CA1 pyramidal neurons, quinpirole depresses excitatory transmission mediated by NMDARs by increasing release of intracellular Ca2+. This depression is dependent on transactivation of platelet-derived growth factor β by D4 receptors [70]. Similar effects were found in prefrontal cortical neurons but they were mediated by D2/3 receptors [71]. Physical coupling between D2 receptors and NR2B subunits can also reduce NMDA currents [72]. The mechanism underlying this effect involves disruption of the association between NR2B and CaMKII, thereby reducing subunit phosphorylation. It is believed that the D2–NR2B interaction plays a critical role in the stimulative effect of cocaine [72].

3.7. GENETIC MANIPULATIONS OF DA–NMDA RECEPTOR INTERACTIONS

The generation of mice lacking specific receptors or receptor subunits via genetic engineering approaches marked a new era in the study of receptor function. These techniques permit the generation of mice deficient in selective DA receptors or NMDAR subunits. Our previous studies demonstrated that in D1 receptor-deficient mice, DA potentiation of striatal NMDA responses was greatly reduced [73]. Similarly, presynaptic modulation of glutamate release along the corticostriatal pathway was enhanced in D2 receptor knock-out animals [27].

Our laboratory recently examined the enhancement of NMDA currents in mice lacking NR2A subunits [74]. Preliminary observations indicate that D1 modulation of these currents is similar in MSSNs from wild type and NR2A knock-out cohorts. We also examined D2 attenuation of NMDA responses in these mice and again found no statistically significant differences in modulation levels. These results suggest that the presence or absence of the NR2A subunit does not affect D1 or D2 modulation of NMDAR-mediated currents. These studies are relevant to DA–NMDA interactions as modulation of NMDA currents by DA receptors may be mediated by phosphorylation of specific receptor subunits or by physical coupling. Further, recent evidence indicates specific NMDAR subunits may play different roles in synaptic plasticity and excitotoxicity [75–77].

Mice that express EGFP reporter genes in a variety of cells have been generated [78]. Mice that express specific DA receptor subtypes represent important tools to differentiate neuronal populations within the striatum. DA or its agonists almost always modulate responses induced by NMDAR activation in MSSNs. However, the magnitude of this modulation varies from cell to cell possibly because D1 and D2 receptors are largely segregated in different populations of MSSNs.

Although all MSSNs are GABAergic, they differ in expression of DA receptor subtypes, peptide contents, and projection targets [79]. Two major neuronal subpopulations of MSSNs have been described. One projects primarily to the substantia nigra pars reticulata and the internal segment of the globus pallidus (direct pathway). The other subpopulation projects primarily to the external segment of the globus pallidus (indirect pathway) [80]. MSSNs originating the direct pathway mainly express D1 receptors and colocalize substance P. MSSNs originating the indirect pathway mainly express D2 receptors and colocalize enkephalin although some overlap exists [81–83].

We are currently examining DA–NMDAR interactions in acutely dissociated D1 and D2 EGFP-positive MSSNs. Application of SKF 812907 (a D1 agonist) dose-dependently and reversibly increased NMDA currents in D1 but not in D2 cells. NMDA current enhancement was prevented by SCH 23390 (a D1 antagonist) [84]. In contrast, quinpirole, (a D2 agonist), dose-dependently and reversibly decreased NMDA currents in D2 but not in D1 cells. The effect was blocked by remoxipride, a D2 antagonist. At the highest concentration, quinpirole induced decreases of NMDA currents in some D1 cells as well.

3.8. FUNCTIONAL RELEVANCE OF DA–NMDA RECEPTOR INTERACTIONS

The function of DA–NMDAR interactions may vary according to the area in which they occur. In the dorsal striatum, these interactions are important in motor control. In the ventral striatum, they provide mechanisms that may underlie addiction. In the frontal cortex, these interactions are implicated in working memory and cognition. In other areas such as the amygdala, their role is less clear. Overall, the D1–NMDAR interaction, when mediated by second messenger cascades, appears synergistic. The membrane-delimited physical interactions appear antagonistic and have more relevance to neuroprotection, with the caveat that DA agonists and antagonists can also directly modulate the NMDAR channel pore.

In the striatum, electrophysiological studies have shown that high-frequency stimulation of corticostriatal inputs induces LTP in normal physiological conditions or after Mg2+ removal [85–89]. Activation of D1 family receptors is required for LTP induction [40], whereas coactivation of D1 and D2 receptors is required for LTD [90]. The mechanisms by which D1 receptors are permissive to LTP induction are unclear but may involve enhancement of Ca2+ influx through L-type channels [45]. In certain conditions, cortical pyramidal neurons and striatal MSSNs oscillate between two preferred (up and down) states [91]. The D1–NMDAR interaction favors the transition to and maintenance of the up state [92], and thus is more permissive toward synaptic plasticity involving potentiation.

Assuming there is segregation of D1 (direct pathway) and D2 (indirect pathway) receptors in striatal MSSNs, plasticity that depends on DA–NMDAR interactions is likely to go in different directions (produce different outcomes). Thus, the D1–NMDAR interaction, by strengthening synapses in the direct pathway (LTP), may function to reinforce a motor program, for example. The D2–NMDAR interaction, by weakening synaptic strength (LTD) along the indirect pathway, may serve to extinguish competitive motor programs.

In the cerebral cortex, D1 receptors and D1–NMDAR interactions play a very important role in working memory and cognitive function. In particular, accumulating evidence indicates that induction and maintenance of persistent activity in prefrontal cortex and related networks is dependent on D1–NMDAR interactions [23]. Alterations of these receptors and their interactions occur in schizophrenia. One important aspect of these interactions is the existence of an optimal level of D1 receptor activation below or above which DA’s effects on working memory are deleterious [93].

D1–NMDAR interactions facilitate the transition and maintenance of the up states in the cerebral cortex and may also initiate these state transitions [92]. One caveat of up and down states in the striatum or cortex is that they are best observed in anesthetized animals or during slow-wave sleep and their relevance or even evidence of their occurrence in the awake state is indirect or unknown. Recent studies of the striatum indicate that these membrane transitions in waking animals do not occur and cell firing is more random than in anesthetized animal preparations [94].

Synchronous activity (gamma oscillations) may occur in awake animals and this activity may play an important role in cognition [95]. Alterations in gamma oscillations, particularly in the frontal cortex, have been observed in schizophrenia [96–99]. In humans DA D4 receptor and DA transporter-1 polymorphisms have been shown to modulate gamma activity [100].

Another form of synchronous activity called neuronal “avalanche” has been demonstrated to occur spontaneously in mature cortical organotypic cultures and in slices after bath application of D1 agonists and NMDA [101,102]. These avalanches may play a role in optimizing information flow across cortical networks. Interestingly, D1 NMDA-induced avalanches displayed a U-shaped pharmacological profile in which moderate DA concentrations maximize spatial correlations in the cortical network; lower or higher concentrations reduce spatial correlations [103]. One speculation is that phasic release of DA as during unexpected reward [104] produces exactly the correct concentration to enhance NMDAR activation and produce an avalanche capable of sustaining working memory. This avalanche may propagate or be replicated in striatal D1 MSSNs to reinforce specific motor sets conducive to reward.

DA–NMDA interactions also play an important role in neurodegenerative diseases because unregulated enhancement of excitation, particularly excitation mediated by NMDARs, will cause neuronal dysfunction and disturb structural neuronal integrity. For example, the excitotoxicity hypothesis of HD posits that excessive glutamate release at the corticostriatal terminal or altered sensitivity of postsynaptic NMDARs and their signaling systems may induce cell death [105]. Studies in genetic mouse models of HD confirmed increased sensitivity of NMDARs in MSSNs [106–108]. However, the precise location of NMDARs in synaptic or extrasynaptic compartments determines the outcome of receptor activation. In hippocampal neurons, activation of synaptic NMDARs triggers an anti-apoptotic pathway, whereas activation of extrasynaptic NMDARs may cause cell death [109].

Assuming that activation of NMDARs recruits more functional D1 receptors in plasma membranes [50,52,53] and that these D1 receptors in turn recruit more NMDARs [55], a positive feedback mechanism may be created and the outcome of these interactions can be deleterious for the neuron if the mechanism is not stopped [110].

Both D1 and NMDARs independently exert toxic effects on striatal neurons. In addition, D1 receptor activation also potentiates NMDA toxicity [64]. A number of protective mechanisms must be in place to prevent the deleterious effect of excessive D1–NMDAR stimulation. Activation of D2 receptors may be neuroprotective since it reduces NMDA responses [64,111]. Other mechanisms may be also considered. For example, the interactions of D1 and NMDARs independent of cAMP production and the D2–NR2B interaction both reduce NMDA currents and excitotoxicity.49 The diffusion trap system may represent a fast and efficient way to prevent excessive potentiation of NMDA responses if it makes D1 receptors less functional—a conclusion that remains to be verified. One drawback is that this mechanism is more or less random; the effectiveness of the trap depends on the availability of the prey. If D1 receptors are abundant and nearby, the trap will work, but it is nonetheless subject to haphazard encounters.

3.9. CONCLUSIONS

It has been 15 years since the enhancement of NMDA responses by D1 receptor activation was first observed [31]. As generally occurs with any scientific observation or hypothesis, explanations become more complex than initially assumed. The potential mechanisms and even the outcomes of D1–NMDAR interactions continue to multiply. We may speculate that various interactions accomplish different functions. Some may be intended to enhance, whereas others may be designed to inhibit the outcomes of receptor interactions. The traditional pathway involving D1 receptor activation and the cAMP–PKA–DARPP-32 cascade produces various effects that enhance NMDAR function [47,48].

Physical interactions among these receptors, in the cytoplasm or in membranes, add new levels of complexity. Two pathways in the formation of D1–NMDA heteroreceptor complexes are envisaged. One is G protein- and Ca2+-dependent, occurs in the cytoplasm, and delivers the complex in a regulated manner to the plasma membrane, in particular the PSD [57]. The other is G protein- and Ca2+-independent, is membrane delimited, and may function as an inhibitory mechanism or brake to prevent and dampen continuous positive feedback [49,52,53]. These interactions in conjunction with the more traditional interactions through signaling pathways fine-tune neuronal function. Alterations of these interactions that occur in some pathological states jeopardize functional and structural neuronal integrity. Understanding these interactions and their possible consequences in normal and diseased states is essential for designing better therapeutic approaches to treat psychiatric and neurological disorders.

ACKNOWLEDGMENTS

This work has benefited from USPHS Grants NS41574 and NS33538 and contracts with the High Q Foundation and CHDI, Inc.

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