Relevance of dopamine D(2)/neurotensin NTS1 and NMDA/neurotensin NTS1 receptor interaction in psychiatric and neurodegenerative disorders

The existence of functional NT/dopamine interactions in the central nervous system has been extensively documented. Among others, a possible molecular mechanism underlying the NT-induced modulation of dopamine release is a direct antagonistic NTS(1)/D(2) receptor interaction. More recently, neurochemical experiments also supported the existence of a possible interaction between NT and N-methyl-d-aspartate (NMDA) receptors. In particular, it has been suggested that NT, by amplifying NMDA receptor signaling, could be involved in neurodegeneration. The present article attempts to provide a summary of current knowledge, mainly emerging from our studies, on the existence of receptor-receptor interactions between NT receptor subtype 1 (NTS1) and dopamine D(2) or NMDA receptors in the brain. Special emphasis is placed on the pre and post-synaptic neurochemical mechanisms possibly underlying the involvement of these interactions in the physiopathology of schizophrenia and acute neurodegenerative disorders.     

Interaction between dopamine and glutamate receptors following treatment with NMDA receptor antagonists

Interactions between dopamine and glutamate neurotransmission have been reported to play an important role in a number of different systems. We were interested in examining the effects of sub-chronic treatment with NMDA receptor antagonists (dizocilpine [MK-801], and 3-carboxy-piperazin-propyl phosphonic acid [CPP]) on dopamine D(1)-like, dopamine D(2)-like, as well as glutamate receptors of the NMDA and AMPA receptor subtypes in the neostriatum and substantia nigra of rats that had received a massive dopamine denervation at 3 days of age. Using quantitative ligand binding autoradiography, we demonstrated that the two NMDA receptor antagonists did not have different profiles of action. Furthermore, while we found a significant negative relationship between NMDA receptors and dopamine receptors (both dopamine D(1)-like and D(2)-like receptor subtypes) in the neostriatum, AMPA receptors were positively correlated with dopamine D(1)-like binding sites in all regions investigated. These findings suggest that the interrelationship between dopamine and glutamate receptors is highly controlled and that the nigrostriatal dopamine systems play an important role in this interaction.     

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release.

Pharmacological manipulation of N-methyl-D-aspartate (NMDA) receptors may be critical for the treatment of many neurological and psychiatric disorders. Metabotropic glutamate (mGlu5) receptors are abundant in corticolimbic circuitry, where they modulate NMDA receptor-mediated signal transduction. Therefore, pharmacological manipulation of mGlu5 receptor may provide a treatment strategy for cognitive disorders that are associated with NMDA receptor dysfunction. We sought to determine whether the recently described molecular and cellular interactions between NMDA and mGlu5 receptors coregulate higher order behaviors. We examined the interaction of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the use-dependent NMDA antagonist MK-801, on locomotion, stereotypy, working memory, instrumental learning, and corticolimbic dopamine release. MPEP, at 10 mg/kg, but not 3 mg/kg, impaired working memory and instrumental learning, transiently increased dopamine release in prefrontal cortex and nucleus accumbens, and augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with 3 mg/kg of MPEP enhanced the detrimental effects of MK-801 on cognition. These results demonstrate that an mGlu5 receptor antagonist can potentiate the motoric, cognitive, and dopaminergic effects of an NMDA receptor antagonist. Thus, mGlu5 receptors appear to play a major role in regulating NMDA receptor-dependent cognitive functions such as learning and working memory. By extension, these results suggest that pharmacological potentiation of mGlu5 receptors may ameliorate the cognitive and other behavioral abnormalities associated with NMDA receptor deficiency.     

Co-activation of glutamate and dopamine receptors within the nucleus accumbens is required for spatial memory consolidation in mice

Rationale The nucleus accumbens receives glutamatergic and dopaminergic inputs converging onto common dendrites. Recent behavioral data demonstrated that intra-accumbens administrations of either glutamate or dopamine (DA) antagonist impair spatial memory consolidation. Thus, also based on the biochemical and molecular findings demonstrating interactions among the different receptors subtypes for glutamate and dopamine, it is conceivable that memory consolidation within this structure might be modulated by glutamate–dopamine receptor interactions.Objectives The purpose of this study was to examine the effects of intra-accumbens co-administrations of glutamate and DA antagonists on the consolidation of spatial information.Methods On day 1, CD1 male mice were placed in an open field containing five different objects and immediately after three sessions of habituation the animals were injected intra-accumbens with either vehicle or low doses of the N-methyl-d-aspartate (NMDA; AP-5 50 ng/side), the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; DNQX 5 ng/side), the D1 (SCH23390 12.5 ng/side) and the D2 (sulpiride 25 ng/side) antagonists that were ineffective alone in disrupting object displacement. Separate groups were then focally injected with a combination of one of the glutamate antagonists with one of the dopamine antagonists. Twenty-four hours later, the ability of mice to discriminate object displacement was assessed.Results Controls and mice injected with ineffective doses of the NMDA, the AMPA, the D1 or the D2 antagonists were always able to react to the object displacement. On the contrary, the groups administered with the different combinations (AP-5 and SCH23390, AP-5 and sulpiride, DNQX and SCH23390, DNQX and sulpiride) of glutamate and dopamine antagonists did not discriminate the spatial change.Conclusions These results demonstrate that glutamate–dopamine receptor interactions within the accumbens are essential for the consolidation process of spatial information.     

Modulation of the locomotor responses induced by D1-like and D2-like dopamine receptor agonists and D-amphetamine by NMDA and non-NMDA glutamate receptor agonists and antagonists in the core of the rat nucleus accumbens

Dopamine and glutamate interactions in the nucleus accumbens (NAcc) play a crucial role in both the development of a motor response suitable for the environment and in the mechanisms underlying the motor-activating properties of psychostimulant drugs such as amphetamine. We investigated the effects of the infusion in the NAcc of NMDA and non-NMDA receptor agonists and antagonists on the locomotor responses induced by the selective D(1)-like receptor agonist SKF 38393, the selective D(2)-like receptor agonist quinpirole, alone or in combination, and D-amphetamine. Infusion of either the NMDA receptor agonist NMDA, the NMDA receptor antagonist D-AP5, the non-NMDA receptor antagonist CNQX, or the non-NMDA receptor agonist AMPA resulted in an increase in basal motor activity. Conversely, all of these ionotropic glutamate (iGlu) receptor ligands reduced the increase in locomotor activity induced by focal infusion of D-amphetamine. Interactions with dopamine receptor activation were not so clear: (i). infusion of NMDA and D-AP5 respectively enhanced and reduced the increase in locomotor activity induced by the infusion of the D(1)-like receptor agonist of SKF 38393, while AMPA or CNQX decreased it; (ii). infusion of NMDA, D-AP5, and CNQX reduced the increase in locomotor activity induced by co-injection of SKF 38393+quinpirole--a pharmacological condition thought to activate both D(1)-like and D(2)-like presynaptic and postsynaptic receptors, while infusion of AMPA potentiated it; (iii). infusion of either NMDA, D-AP5 or CNQX, but not of AMPA, potentiated the decrease in motor activity induced by the D(2)-like receptor agonist quinpirole, a compound believed to act only at presynaptic D(2)-like receptors when injected by itself. Our results show that NMDA receptors have an agonist action with D(1)-like receptors and an antagonist action with D(2)-like receptors, while non-NMDA receptors have the opposite action. This is discussed from a anatamo-functional point of view.     

Differential effects of antipsychotic and glutamatergic agents on the phMRI response to phencyclidine.

Acute administration of NMDA receptor (NMDAR) antagonists such as phencyclidine (PCP) or ketamine induces symptoms that closely resemble those of schizophrenia in humans, a finding that has led to the hypothesis that a decreased NMDAR function may be a predisposing or even causative factor in schizophrenia. However, the precise neuropharmacological mechanisms underlying these effects remain to be fully elucidated. Here, we applied pharmacological MRI (phMRI) to examine the brain circuitry underlying the psychotomimetic action of PCP in the anesthetized rat, and investigated how these functional changes are modulated by drugs that possess distinct pharmacological mechanisms. Acute administration of PCP (0.5 mg/kg i.v.) produced robust and sustained positive relative cerebral blood volume (rCBV) changes in discrete cortico-limbo-thalamic regions. Pretreatment with the selective D2 dopamine antagonist raclopride (0.3 mg/kg i.p.) did not significantly affect the rCBV response to PCP, while the atypical antipsychotic clozapine (5 mg/kg i.p.) produced region-dependent effects, with complete suppression of the rCBV response in the thalamus, and weaker attenuation of the response in cortical and hippocampal structures. The response to PCP was strongly suppressed in all regions by pretreatment with two drugs that can inhibit aberrant glutamatergic activity: the anticonvulsant lamotrigine (10 mg/kg i.p.) and the mGluR2/3 agonist LY354740 (10 mg/kg i.p.). Taken together, our findings corroborate the pivotal role of dysfunctional glutamatergic neurotransmission in the functional response elicited by PCP, while the lack of effect of raclopride argues against a primary role of dopamine D2 receptor activation in this process. Finally, the thalamic effect of clozapine could be key to elucidating the functional basis of its pharmacological action.     

Loss of synaptic D1 dopamine/N-methyl-D-aspartate glutamate receptor complexes in L-DOPA-induced dyskinesia in the rat

Glutamate-mediated mechanisms are related to the motor complications of L-DOPA therapy in Parkinson's disease (PD). In striatal postsynaptic densities (PSD), the dopamine D1 receptor (D1R) is part of an oligomeric complex with the glutamate N-methyl-D-aspartate receptor (NMDAR), determining the strength of corticostriatal transmission. We studied D1R/NMDAR complex alterations induced by L-DOPA in the 6-hydroxydopamine-lesioned rat model of PD. L-DOPA-treated hemiparkinsonian rats were determined to be dyskinetic or nondyskinetic based on behavioral testing. D1R/NMDAR assemblies containing NR1-C2 and NR2B subunits were decreased in the PSD of lesioned striatum. Short-term L-DOPA administration improved akinesia and restored the synaptic abundance of D1R, NR1-C2 and NR2B. Prolonged L-DOPA treatment also normalized synaptic D1R/NMDAR complexes in nondyskinetic rats, but remarkably reduced them in the dyskinetic group without changing their interaction. This decrease involved NR1-C2, NR1-C2', NR2A, and NR2B subunits. The composition of residual synaptic D1R/NMDAR complexes in dyskinetic rats may thus be different from that observed in lesioned rats, suggesting that expression of different motor dysfunctions might be related to the receptor profile at corticostriatal synapses. The levels of D1R/NMDAR complexes were unchanged in total striatal membrane proteins, suggesting that the decrease of these species in the PSD is likely to reflect an altered receptor trafficking. In human embryonic kidney 293 cells expressing the D1R/NMDAR, complex costimulation of both D1R and NMDAR, but not individual receptor activation, promoted internalization, suggesting that development of dyskinesias might be related to agonist-mediated down-regulation of the D1R/NMDAR complex at corticostriatal synapses.     

The potential role of lamotrigine in schizophrenia

Rationale Atypical antipsychotic drugs are the drugs of choice for the treatment of schizophrenia. However, despite advances, no treatments have been established for patients who fail to improve with the most effective of these, clozapine. The inhibition of dopamine transmission through blockade of dopamine D2 receptors is considered to be essential for antipsychotic efficacy, but it is postulated that modulation of glutamate transmission may be equally important. In support of this, symptoms similar to schizophrenia can be induced in healthy volunteers using N-methyl-d-aspartate (NMDA) antagonist drugs that are also known to enhance glutamate transmission. Furthermore, lamotrigine, which can modulate glutamate release, may add to or synergise with atypical antipsychotic drugs, some of which may themselves modulate glutamate transmission. Objectives We examine the evidence for the efficacy of lamotrigine. We consider how this fits with a glutamate neuron dysregulation hypothesis of the disorder. We discuss mechanisms by which lamotrigine might influence neuronal activity and glutamate transmission, and possible ways in which the drug might interact with antipsychotic medications. Results Data from four clinical studies support the efficacy of adjunctive lamotrigine in the treatment of schizophrenia. In addition, and consistent with a glutamate neuron dysregulation hypothesis of schizophrenia, lamotrigine can prevent the psychotic symptoms or behavioural disruption induced by NMDA receptor antagonists in healthy volunteers or rodents. Conclusions The efficacy of lamotrigine is most likely explained within the framework of a glutamate neuron dysregulation hypothesis, and may arise primarily through the drugs ability to influence glutamate transmission and neural activity in the cortex. The drug is likely to act through inhibition of voltage-gated sodium channels, though other molecular interactions cannot be ruled out. Lamotrigine may add to or synergise with some atypical antipsychotic drugs acting on glutamate transmission; alternatively, they may act independently on glutamate and dopamine systems to bring about a combined therapeutic effect. We propose new strategies for the treatment of schizophrenia using a combination of anti-dopaminergic and anti-glutamatergic drugs.     

Local dopaminergic modulation of the motor activity induced by N-methyl-D-aspartate receptor stimulation in the ventral hippocampus.

Dopaminergic neurotransmission has been implicated in the motor activating effects induced by the local infusion of NMDA in the ventral hippocampus (VH). The nucleus accumbens and the ventral tegmental area (VTA) have been proposed to be the main loci where dopamine is acting as a positive modulator of the VH NMDA receptor-mediated motor activating effects. However, the existence of a relatively high dopamine innervation and dopamine receptor density in the VH suggests the possibility of local dopamine/NMDA receptor interactions. This hypothesis was tested by studying the effects of the bilateral local VH infusion of NMDA (0.05, 0.1, 0.5 and 1.0 microg/side), the dopamine D1/D5 receptor antagonist SCH 23390 (1 microg/side) and the dopamine D2 receptor antagonist raclopride (1 and 5 microg/side). Neither SCH 23390 nor raclopride induced any significant change in motor activity compared with the vehicle control group, but both compounds significantly antagonized the motor activation induced by NMDA. SCH 23390 (1 microg/side) was more potent that raclopride (minimal effective dose: 5 microg/side). These results demonstrate the existence of a strong tonic facilitating effect of dopamine, acting preferentially at dopamine D1/D5 receptors, on NMDA receptor-mediated effects in the VH.     

Involvement of dopaminergic receptor signaling in the effects of glutamatergic receptor antagonists on conditioned place aversion induced by naloxone in single-dose morphine-treated rats

A better understanding of the neurochemical mechanisms mediating the aversive consequences of drug withdrawal is important for understanding drug addiction. We previously demonstrated that the inhibitory effect of glutamate receptor antagonists on the conditioned place aversion (CPA) induced by naloxone-precipitated withdrawal after a single morphine exposure could be blocked by dopamine receptor antagonists. Thus, a glutamatergic-dopaminergic interaction may participate in this phenomenon. The current study was undertaken to further characterize this interaction by employing both D(1) (SCH 23390) and D(2) (raclopride and eticlopride) dopamine receptor antagonists. The influence of these antagonists on the attenuation of CPA by MK-801 (NMDA receptor antagonist), GYKI 52466 (AMPA receptor antagonist), and MCPG (metabotropic glutamate receptor antagonist) was determined in rats receiving a single dose of morphine. The dopamine antagonists showed either a significant reversal or a tendency to reverse the effects of MK-801 on CPA. The effect of GYKI 52466 was also attenuated by the blockade of either D(1) or D(2) receptors. The effect of MCPG, however, was only blocked by D(2) antagonists and not by the D(1) antagonist SCH 23390. These results add evidence to the hypothesis that a glutamatergic-dopaminergic interaction may be involved in the CPA induced by naloxone-precipitated withdrawal following a single morphine exposure and suggest that both D(1) and D(2) dopamine receptor signaling mechanisms play a role in mediating the aversive aspects of acute dependence.     

Antischizophrenic activity independent of dopamine D2 blockade

Currently, the drug therapy of schizophrenia consists of blockade of central dopamine D2 receptors. There is, however, an urgent medical need for alternative, more effective treatments. Clinical and preclinical literature suggests that stimulation of AMPA-type glutamate receptors may be involved in positive symptoms of schizophrenia, whereas hypofunctionality of NMDA-type glutamate receptors may be involved in negative symptoms and cognitive deficits. Several pharmacological approaches are conceivable to prevent stimulation of AMPA receptors (AMPA receptor blockade, metabotropic glutamate receptors (mGlu(2) receptor) stimulation or lamotrigine-like Na(+)/Ca(2+) channel blockade). Similarly, several pharmacological principles are conceivable to enhance neurotransmission at NMDA receptors (catechol-o-methyl transferase inhibition, glycine uptake blockade, glutathione suppletion and others). In this review, the possible pharmacological approaches and their respective advantages and disadvantages are discussed.     

RGS4 modulates serotonin signaling in prefrontal cortex and links to serotonin dysfunction in a rat model of schizophrenia

Regulator of G protein signaling 4 (RGS4) has recently been identified as one of the genes linked to the susceptibility of schizophrenia. However, the functional roles of RGS4 and how it may be involved in the pathophysiology of schizophrenia remain largely unknown. In this study, we investigated the possible impact of RGS4 on the function of serotonin and dopamine receptors, two main targets for schizophrenia treatment. Activation of serotonin 5-HT(1A) receptors or dopamine D(4) receptors down-regulates the function of NMDA receptor (NMDAR) channel, a key player controlling cognition and emotion, in pyramidal neurons of prefrontal cortex (PFC). Blocking RGS4 function significantly potentiated the 5-HT(1A) regulation of NMDAR current; conversely, overexpression of RGS4 attenuated the 5-HT(1A) effect. In contrast, the D(4) regulation of NMDAR current was not altered by RGS4 manipulation. Moreover, the 5-HT(1A) regulation of NMDA receptors was significantly enhanced in a subset of PFC pyramidal neurons from rats treated with subchronic phencyclidine, an animal model of schizophrenia, which was found to be associated with specifically decreased RGS4 expression in these cells. Thus, our study has revealed an important coupling of RGS4 to serotonin signaling in cortical neurons and provided a molecular and cellular mechanism underlying the potential involvement of RGS4 in the pathophysiology of schizophrenia.     

The effects of isolation rearing on glutamate receptor NMDAR1A mRNA expression determined by in situ hybridization in Fawn hooded and Wistar rats

Rats reared in social isolation exhibit a syndrome of behavioral and biochemical effects indicative of enhanced mesolimbic dopamine (DA) function. The precise nature of the neurodevelopmental changes that produce this state are unknown but result in enhanced DA neurotransmission in the nucleus accumbens (NAC). It was hypothesized that this may be the indirect result of chronic changes in glutamate NMDA receptor function. The same prediction has been made for Fawn hooded (FH) rats that exhibit some of the characteristic effects of isolation-reared rats when compared to Wistar rats. Therefore, mRNA levels of the NMDAR1A receptor subunit were determined by in situ hybridization and were quantified in the striatum, hippocampus and prefrontal cortex of FH and Wistar rats. Isolation rearing alone was not found to have an effect on the expression of NMDAR1A, while FH rats had reduced levels across most brain regions examined. In some areas of the striatum and prefrontal cortex, this effect was greater in FH isolates than in FH socials, while in the hippocampus, the opposite was observed.     

Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons

The molecular basis for the known intramembrane receptor/receptor interactions among G protein-coupled receptors was postulated to be heteromerization based on receptor subtype-specific interactions between different types of receptor homomers. The discovery of GABAB heterodimers started this field rapidly followed by the discovery of heteromerization among isoreceptors of several G protein-coupled receptors such as delta/kappa opioid receptors. Heteromerization was also discovered among distinct types of G protein-coupled receptors with the initial demonstration of somatostatin SSTR5/dopamine D2 and adenosine A1/dopamine D1 heteromeric receptor complexes. The functional meaning of these heteromeric complexes is to achieve direct or indirect (via adapter proteins) intramembrane receptor/receptor interactions in the complex. G protein-coupled receptors also form heteromeric complexes involving direct interactions with ion channel receptors, the best example being the GABAA/dopamine D5 receptor heteromerization, as well as with receptor tyrosine kinases and with receptor activity modulating proteins. As an example, adenosine, dopamine, and glutamate metabotropic receptor/receptor interactions in the striatopallidal GABA neurons are discussed as well as their relevance for Parkinson's disease, schizophrenia, and drug dependence. The heterodimer is only one type of heteromeric complex, and the evidence is equally compatible with the existence of higher order heteromeric complexes, where also adapter proteins such as homer proteins and scaffolding proteins can exist. These complexes may assist in the process of linking G protein-coupled receptors and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular basis for some forms of learning and memory.     

Voltage-dependent block of N-methyl-D-aspartate receptors by dopamine D1 receptor ligands

Accumulating evidence indicates that dopamine and D1 receptor ligands modulate N-methyl D-aspartate (NMDA) receptors through a variety of D1 receptor-dependent mechanisms. In this study, we reveal a distinct D1 receptor-independent mechanism by which NMDA receptors are modulated. Using the human embryonic kidney (HEK) cell recombinant system and dissociated neurons, we have discovered that dopamine and several D1 ligands act as voltage-dependent, open-channel blockers for NMDA receptors, regardless of whether they are agonists or antagonists for D1 receptors. Analysis of structural and functional relationships of D1 ligands revealed the elements that are critical for their binding to NMDA receptors. Furthermore, using D1 receptor knockout mice, we verified that this channel-blocking effect was independent of D1 receptors. Finally, we demonstrated that D1 ligands functionally interact with Mg(2+) block through multiple sites, implying a possible role of the direct channel block under physiological conditions. Our results suggest that the direct inhibition of NMDA receptors by dopamine D1 receptor ligands is due to the channel pore block rather than receptor-receptor interactions.     

Dopamine-mediated changes in central nervous system neurotensin systems: a role for NMDA receptors

A role for N-methyl-D-aspartate (NMDA)-type glutamate receptors in mediating the dopaminergic regulation of neurotensin (NT) systems was observed in extrapyramidal and limbic structures. Blockade of the NMDA receptor with the non-competitive antagonist, MK801, prevented increases in striatal and nigral levels of NT following both single and multiple administrations of methamphetamine. Significant attenuation of the methamphetamine-induced changes in the striatal NT system were observed with MK801 doses as low as 0.01 mg/kg per dose. In contrast, administration of NMDA caused significant increases in both striatal and nigral NT. The NMDA-induced increase in striatal NT content, like that caused by methamphetamine, was blocked by MK801. The NT system associated with the nucleus accumbens responded in a similar manner in that MK801 (0.1 mg/kg per dose) totally blocked the methamphetamine-induced increases and NMDA administration elevated the NT levels in this structure. Since the methamphetamine-related changes in NT content have been previously shown to be due to increased activity at dopamine D1 receptors, these results strongly suggest that NMDA receptors play an important role in mediating the dopamine D1 regulation of neurotensin systems. Interestingly, the presence of MK801 had no impact on sulpiride-mediated changes in striatal NT levels, suggesting that the NMDA receptor is not linked with the dopamine D2 receptor regulation of NT pathways.     

Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia

Several lines of evidence implicate NMDA receptor dysfunction in the cognitive deficits of schizophrenia, suggesting that pharmacological manipulation of the NMDA receptor may be a feasible therapeutic strategy for treatment of these symptoms. Although direct manipulation of regulatory sites on the NMDA receptor is the most obvious approach for pharmacological intervention, targeting the G-protein coupled metabotropic glutamate (mGlu) receptors may be a more practical strategy for long-term regulation of abnormal glutamate neurotransmission. Heterogeneous distribution, both at structural and synaptic levels, of at least eight subtypes of mGlu receptors suggests that selective pharmacological manipulation of these receptors may modulate glutamatergic neurotransmission in a regionally and functionally distinct manner. Two promising targets for improving cognitive functions are mGlu5 or mGluR2/3 receptors, which can modulate the NMDA receptor-mediated signal transduction by pre- or postsynaptic mechanisms. Preclinical studies indicate that activation of these subtypes of mGlu receptors may be an effective strategy for reversing cognitive deficits resulting form reduced NMDA receptor mediated neurotransmission.     

The novel antipsychotic drug lurasidone enhances N-methyl-D-aspartate receptor-mediated synaptic responses

N-Methyl-D-aspartate (NMDA) receptor (NMDAR) hypofunction has been postulated to contribute to the cognitive deficit of schizophrenia. In this study, we examined the effect of lurasidone (Latuda; Dainippon Sumitomo Pharma Co. Ltd., Tokyo, Japan), a newly approved atypical antipsychotic drug (APD), on NMDAR synaptic function in rat frontal cortical pyramidal neurons. In vivo administration of lurasidone produced a significant and selective enhancement of NMDAR-mediated synaptic responses and surface expression of NR2A and NR2B subunits. Lurasidone has high affinity for serotonin 5-HT(1A), 5-HT(2A), and 5-HT(7) receptors and dopamine D(2) receptors. In vivo administration of the 5-HT(7) receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2 -(2-(4-methyl-1-piperidinyl)ethyl)pyrrolidine (SB-269970) mimicked the enhancing effect of lurasidone on NMDAR responses, whereas the D(2) receptor antagonist haloperidol failed to do so. Previous studies have found that short-term administration of lurasidone reverses the cognitive impairment induced by subchronic administration of phencyclidine (PCP), an NMDAR noncompetitive antagonist. In this study, we found that lurasidone, as well as the prototypical atypical APD clozapine, restored NMDAR-mediated synaptic responses to normal levels in the PCP model of schizophrenia. These results suggest that NMDAR is the potential key molecular target of lurasidone, possibility via antagonizing 5-HT(7) receptors, which is consistent with evidence that 5-HT(7) receptor antagonism contributes to cognitive enhancement by atypical APDs in patients with schizophrenia.     

Competitive and noncompetitive NMDA antagonist effects in rats trained to discriminate lever-press counts

The glutamate activated N-methyl-D-aspartate (NMDA) receptor may play a role in short-term memory processing. Among the evidence for this is that NMDA antagonists can impair accuracy in fixed consecutive number (FCN) tasks. This study was designed to further characterize this effect by examining NMDA antagonists differing in their cellular mechanisms of action. Rats were trained to respond under an FCN operant schedule, which required eight presses on one lever (counting lever) before one press at an alternate lever (reinforcement lever) would produce food reinforcement. The effects of three noncompetitive [MK-801 (0.01-0.56 mg/kg); phencyclidine (0.3-3.0 mg/kg); memantine (1-10 mg/kg)] and two competitive [SDZ EAA 494 (0.3-3.0 mg/kg) and NPC 17742 (2.0-16 mg/kg)] NMDA antagonists were analyzed. MK-801 and phencyclidine decreased accuracy at doses not reducing response rates. Memantine, and both of the competitive antagonists, also reduced accuracy, but did so only at doses that markedly reduced response rates. These results suggest that both the affinity and the site bound on the NMDA glutamate receptor by antagonists can determine their effects on FCN performance. Subsequent studies investigated whether SCH 23390, a dopamine D1 receptor antagonist, and NMDA could modulate the effects by phencyclidine and SDZ EAA 494, respectively, on FCN performance.     

New targets for pharmacological intervention in the glutamatergic synapse

Excitotoxicity is thought to be a major mechanism in many human disease states such as ischemia, trauma, epilepsy and chronic neurodegenerative disorders. Briefly, synaptic overactivity leads to the excessive release of glutamate that activates postsynaptic cell membrane receptors, which upon activation open their associated ion channel pore to produce ion influx. To date, although molecular basis of glutamate toxicity remain uncertain, there is general agreement that N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors plays a key role in mediating at least some aspects of glutamate neurotoxicity. On this view, research has focused in the discovery of new compounds able to either reduce glutamate release or activation of postsynaptic NMDA receptors. Although NMDA receptor antagonists prevent excitotoxicity in cellular and animal models, these drugs have limited usefulness clinically. Side effects such as psychosis, nausea, vomiting, memory impairment, and neuronal cell death accompany complete NMDA receptor blockade, dramatizing the crucial role of the NMDA receptor in normal neuronal processes. Recently, however, well-tolerated compounds such as memantine has been shown to be able to block excitotoxic cell death in a clinically tolerated manner. Understanding the biochemical properties of the multitude of NMDA receptor subtypes offers the possibility of developing more effective and clinically useful drugs. The increasing knowledge of the structure and function of this postsynaptic NMDA complex may improve the identification of specific molecular targets whose pharmacological or genetic manipulation might lead to innovative therapies for brain disorders.