Dopamine-glutamate Interactions Research Articles

Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia.

Treatment-resistant schizophrenia (TRS) or suboptimal response to antipsychotics affects almost 30% of schizophrenia (SCZ) patients, and it is a relevant clinical issue with significant impact on the functional outcome and on the global burden of disease. Among putative novel treatments, glycine-centered therapeutics (i.e. sarcosine, glycine itself, D-Serine, and bitopertin) have been proposed, based on a strong preclinical rationale with, however, mixed clinical results. Therefore, a better appraisal of glycine interaction with the other major players of SCZ pathophysiology and specifically in the framework of dopamine – glutamate interactions is warranted. New methodological approaches at cutting edge of technology and drug discovery have been applied to study the role of glycine in glutamate signaling, both at presynaptic and post-synaptic level and have been instrumental for unveiling the role of glycine in dopamine-glutamate interaction. Glycine is a non-essential amino acid that plays a critical role in both inhibitory and excitatory neurotransmission. In caudal areas of central nervous system (CNS), such as spinal cord and brainstem, glycine acts as a powerful inhibitory neurotransmitter through binding to its receptor, i.e. the Glycine Receptor (GlyR). However, glycine also works as a co-agonist of the N-Methyl-D-Aspartate receptor (NMDAR) in excitatory glutamatergic neurotransmission. Glycine concentration in the synaptic cleft is finely tuned by glycine transporters, i.e. GlyT1 and GlyT2, that regulate the neurotransmitter's reuptake, with the first considered a highly potential target for psychosis therapy. Reciprocal regulation of dopamine and glycine in forebrain, glycine modulation of glutamate, glycine signaling interaction with postsynaptic density proteins at glutamatergic synapse, and human genetics of glycinergic pathways in SCZ are tackled in order to highlight the exploitation of this neurotransmitters and related molecules in SCZ and TRS.

Translating striatal activity from brain slice to whole animal neurophysiology: A guide for neuroscience research integrating diverse levels of analysis.

An important goal of this review is highlighting research in neuroscience as examples of multilevel functional and anatomical analyses addressing basic science issues and applying results to the understanding of diverse disorders. The research of Dr. Michael Levine, a leader in neuroscience, exemplifies this approach by uncovering fundamental properties of basal ganglia function and translating these findings to clinical applications. The review focuses on neurophysiological research connecting results from in vitro and in vivo recordings. A second goal is to utilize these research connections to produce novel, accurate descriptions for corticostriatal processing involved in varied, complex functions. Medium spiny neurons in striatum act as integrators combining input with baseline activity creating motivational "events." Basic research on corticostriatal synapses is described and links developed to issues with clinical relevance such as inhibitory gating, self-injurious behavior, and relative reward valuation. Work is highlighted on dopamine-glutamate interactions. Individual medium spiny neurons express both D1 and D2 receptors and encode information in a bivalent manner depending upon the mix of receptors involved. Current work on neurophysiology of reward processing has taken advantage of these basic approaches at the cellular and molecular levels. Future directions in studying physiology of reward processing and action sequencing could profit by incorporating the divergent ways dopamine modulates incoming neurochemical signals. Primary investigators leading research teams should mirror Mike Levine's efforts in "climbing the mountain" of scientific inquiry by performing analyses at different levels of inquiry, integrating the findings, and building comprehensive answers to problems unsolvable without this bold approach.

The role of the cerebellum in drug-cue associative memory: functional interactions with the medial prefrontal cortex.

Drug-induced Pavlovian memories are thought to be crucial for drug addiction because they guide behaviour towards environments with drug availability. Drug-related memory depends on persistent changes in dopamine-glutamate interactions in the medial prefrontal cortex (mPFC), basolateral amygdala, nucleus accumbens core and hippocampus. Recent evidence from our laboratory indicated that the cerebellum is also a relevant node for drug-cue associations. In the present study, we tested the role that specific regions of the cerebellum and mPFC play in the acquisition of cocaine-induced preference conditioning. Quinolinic acid was used to manage a permanent deactivation of lobule VIII in the vermis prior to conditioning. Additionally, lidocaine was infused into the prelimbic and infralimbic (IL) cortices for reversible deactivation before every training session. The present findings show, for the first time, that the cerebellum and mPFC might act together in order to acquire drug-cue Pavlovian associations. Either a dorsal lesion in lobule VIII or an IL deactivation encouraged cocaine-induced preference conditioning. Moreover, simultaneous IL-cerebellar deactivation prevented the effect of either of the separate deactivations. Therefore, similar to the IL cortex, neural activity in the cerebellum may be crucial for ensuring inhibitory control of the expression of cocaine-related memories.

Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies.

HIGHLIGHTS Many CNS targets are being explored for multi-target drug designNew databases and cheminformatic methods enable prediction of primary pharmaceutical target and off-targets of compoundsQSAR, virtual screening and docking methods increase the potential of rational drug designThe diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer‘s disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug-discovery programs. A probabilistic method, the Parzen-Rosenblatt Window approach, was used to build a “predictor” model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D1-R/D2-R/5-HT2A-R/H3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs.

Cognitive Aging and Time Perception: Roles of Bayesian Optimization and Degeneracy.

This review outlines the basic psychological and neurobiological processes associated with age-related distortions in timing and time perception in the hundredths of milliseconds-to-minutes range. The difficulty in separating indirect effects of impairments in attention and memory from direct effects on timing mechanisms is addressed. The main premise is that normal aging is commonly associated with increased noise and temporal uncertainty as a result of impairments in attention and memory as well as the possible reduction in the accuracy and precision of a central timing mechanism supported by dopamine-glutamate interactions in cortico-striatal circuits. Pertinent to these findings, potential interventions that may reduce the likelihood of observing age-related declines in timing are discussed. Bayesian optimization models are able to account for the adaptive changes observed in time perception by assuming that older adults are more likely to base their temporal judgments on statistical inferences derived from multiple trials than on a single trial’s clock reading, which is more susceptible to distortion. We propose that the timing functions assigned to the age-sensitive fronto-striatal network can be subserved by other neural networks typically associated with finely-tuned perceptuo-motor adjustments, through degeneracy principles (different structures serving a common function).

Switching antipsychotics: Imaging the differential effect on the topography of postsynaptic density transcripts in antipsychotic-naïve vs. antipsychotic-exposed rats

The postsynaptic density (PSD) has been regarded as a functional switchboard at the crossroads of a dopamine–glutamate interaction, and it is putatively involved in the pathophysiology of psychosis. Indeed, it has been demonstrated that antipsychotics may modulate several PSD transcripts, such as PSD-95, Shank, and Homer. Despite switching antipsychotics is a frequent strategy to counteract lack of efficacy and/or side effect onset in clinical practice, no information is available on the effects of sequential treatments with different antipsychotics on PSD molecules. The aim of this study was to evaluate whether a previous exposure to a typical antipsychotic and a switch to an atypical one may affect the expression of PSD transcripts, in order to evaluate potential neurobiological correlates of this common clinical practice, with specific regards to putative synaptic plasticity processes.We treated male Sprague-Dawley rats intraperitoneally for 15days with haloperidol or vehicle, then from the sixteenth day we switched the animals to amisulpride or continued to treat them with vehicle or haloperidol for 15 additional days. In this way we got six first treatment/second treatment groups: vehicle/vehicle, vehicle/haloperidol, vehicle/amisulpride, haloperidol/vehicle, haloperidol/haloperidol, haloperidol/amisulpride. In this paradigm, we evaluated the expression of brain transcripts belonging to relevant and interacting PSD proteins, both of the Immediate-Early Gene (Homer1a, Arc) and the constitutive classes (Homer1b/c and PSD-95).The major finding was the differential effect of amisulpride on gene transcripts when administered in naïve vs. antipsychotic-pretreated rats, with modifications of the ratio between Homer1a/Homer1b transcripts and differential effects in cortex and striatum.These results suggest that the neurobiological effects on PSD transcripts of amisulpride, and possibly of other antipsychotics, may be greatly affected by prior antipsychotic treatments and may impact significantly on the switching procedure.

Interactions between glutamate, dopamine, and the neuronal signature of response inhibition in the human striatum.

Response inhibition is a basic mechanism in cognitive control and dysfunctional in major psychiatric disorders. The neuronal mechanisms are in part driven by dopamine in the striatum. Animal data suggest a regulatory role of glutamate on the level of the striatum. We used a trimodal imaging procedure of the human striatum including F18-DOPA positron emission tomography, proton magnetic resonance spectroscopy, and functional magnetic resonance imaging of a stop signal task. We investigated dopamine synthesis capacity and glutamate concentration in vivo and their relation to functional properties of response inhibition. A mediation analysis revealed a significant positive association between dopamine synthesis capacity and inhibition-related neural activity in the caudate nucleus. This relationship was significantly mediated by striatal glutamate concentration. Furthermore, stop signal reaction time was inversely related to striatal activity during inhibition. The data show, for the first time in humans, an interaction between dopamine, glutamate, and the neural signature of response inhibition in the striatum. This finding stresses the importance of the dopamine-glutamate interaction for behavior and may facilitate the understanding of psychiatric disorders characterized by impaired response inhibition.

MicroRNAs in Schizophrenia: Implications for Synaptic Plasticity and Dopamine-Glutamate Interaction at the Postsynaptic Density. New Avenues for Antipsychotic Treatment Under a Theranostic Perspective.

Despite dopamine-glutamate aberrant interaction that has long been considered a relevant landmark of psychosis pathophysiology, several aspects of these two neurotransmitters reciprocal interaction remain to be defined. The emerging role of postsynaptic density (PSD) proteins at glutamate synapse as a molecular "lego" making a functional hub where different signals converge may add a new piece of information to understand how dopamine-glutamate interaction may work with regard to schizophrenia pathophysiology and treatment. More recently, compelling evidence suggests a relevant role for microRNA (miRNA) as a new class of dopamine and glutamate modulators with regulatory functions in the reciprocal interaction of these two neurotransmitters. Here, we aimed at addressing the following issues: (i) Do miRNAs have a role in schizophrenia pathophysiology in the context of dopamine-glutamate aberrant interaction? (ii) If miRNAs are relevant for dopamine-glutamate interaction, at what level this modulation takes place? (iii) Finally, will this knowledge open the door to innovative diagnostic and therapeutic tools? The biogenesis of miRNAs and their role in synaptic plasticity with relevance to schizophrenia will be considered in the context of dopamine-glutamate interaction, with special focus on miRNA interaction with PSD elements. From this framework, implications both for biomarkers identification and potential innovative interventions will be considered.

D1R/GluN1 complexes in the striatum integrate dopamine and glutamate signalling to control synaptic plasticity and cocaine-induced responses.

Convergent dopamine and glutamate signalling onto the extracellular signal-regulated kinase (ERK) pathway in medium spiny neurons (MSNs) of the striatum controls psychostimulant-initiated adaptive processes underlying long-lasting behavioural changes. We hypothesised that the physical proximity of dopamine D1 (D1R) and glutamate NMDA (NMDAR) receptors, achieved through the formation of D1R/NMDAR complexes, may act as a molecular bridge that controls the synergistic action of dopamine and glutamate on striatal plasticity and behavioural responses to drugs of abuse. We found that concomitant stimulation of D1R and NMDAR drove complex formation between endogenous D1R and the GluN1 subunit of NMDAR. Conversely, preventing D1R/GluN1 association with a cell-permeable peptide (TAT-GluN1C1) left individual D1R and NMDAR-dependent signalling intact, but prevented D1R-mediated facilitation of NMDAR–calcium influx and subsequent ERK activation. Electrophysiological recordings in striatal slices from mice revealed that D1R/GluN1 complexes control the D1R-dependent enhancement of NMDAR currents and long-term potentiation in D1R-MSN. Finally, intra-striatal delivery of TAT-GluN1C1 did not affect acute responses to cocaine but reduced behavioural sensitization. Our findings uncover D1R/GluN1 complexes as a major substrate for the dopamine–glutamate interaction in MSN that is usurped by addictive drugs to elicit persistent behavioural alterations. They also identify D1R/GluN1 complexes as molecular targets with a therapeutic potential for the vast spectrum of psychiatric diseases associated with an imbalance between dopamine and glutamate transmission.

Regulation of postsynaptic plasticity genes' expression and topography by sustained dopamine perturbation and modulation by acute memantine: Relevance to schizophrenia

A relevant role for dopamine-glutamate interaction has been reported in the pathophysiology and treatment of psychoses. Dopamine and glutamate may interact at multiple levels, including the glutamatergic postsynaptic density (PSD), an electron-dense thickening that has gained recent attention as a switchboard of dopamine-glutamate interactions and for its role in synaptic plasticity. Recently, glutamate-based strategies, such as memantine add-on to antipsychotics, have been proposed for refractory symptoms of schizophrenia, e.g. cognitive impairment. Both antipsychotics and memantine regulate PSD transcripts but sparse information is available on memantine's effects under dopamine perturbation. We tested gene expression changes of the Homer1 and PSD-95 PSD proteins in models of sustained dopamine perturbation, i.e. subchronic treatment by: a) GBR-12909, a dopamine receptor indirect agonist; b) haloperidol, a D2R antagonist; c) SCH-23390, a dopamine D1 receptor (D1R) antagonist; and d) SCH-23390+haloperidol. On the last day of treatment, rats were acutely treated with vehicle or memantine. The Homer1a immediate-early gene was significantly induced by haloperidol and by haloperidol+SCH-23390. The gene was not induced by SCH-23390 per se or by GBR-12909. Expression of the constitutive genes Homer1b/c and PSD-95 was less affected by these dopaminergic paradigms. Acute memantine administration significantly increased Homer1a expression by the dopaminergic compounds used herein. Both haloperidol and haloperidol+SCH-23390 shifted Homer1a/Homer1b/c ratio of expression toward Homer1a. This pattern was sharpened by acute memantine. Dopaminergic compounds and acute memantine also differentially affected topographic distribution of gene expression and coordinated expression of Homer1a among cortical-subcortical regions. These results indicate that dopaminergic perturbations may affect glutamatergic signaling in different directions. Memantine may help partially revert dopamine-mediated glutamatergic dysfunctions.

Dopamine denervation of the prefrontal cortex increases expression of the astrocytic glutamate transporter GLT‐1

Both dopamine and glutamate are critically involved in cognitive processes such as working memory. Astrocytes, which express dopamine receptors, are essential elements in the termination of glutamatergic signaling: the astrocytic glutamate transporter GLT-1 is responsible for >90% of cortical glutamate uptake. The effect of dopamine depletion on glutamate transporters in the prefrontal cortex (PFC) remains unknown. In an effort to determine if astrocytes are a locus of cortical dopamine-glutamate interactions, we examined the effects of chronic dopamine denervation on PFC protein and mRNA levels of glutamate transporters. PFC dopamine denervation elicited a marked increase in GLT-1 protein levels, but had no effect on levels of other glutamate transporters; high-affinity glutamate transport was positively correlated with the extent of dopamine depletion. GLT-1 gene expression was not altered. Our data suggest that dopamine depletion may lead to post-translational modifications that result in increased expression and activity of GLT-1 in PFC astrocytes. The glutamate transporter GLT-1 is expressed by astrocytes, which also express dopamine receptors. Regulation of prefrontal cortical (PFC) GLT-1 potentially offers a novel treatment approach to the cognitive deficits of schizophrenia. Partial PFC dopamine deafferentation increased membrane expression of GLT-1 protein and glutamate uptake, but did not alter levels of the other two neocortical glutamate transporters, GLAST and EAAC1.

Aberrant glutamate signaling in the prefrontal cortex and striatum of the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is thought to involve hypofunctional catecholamine systems in the striatum, nucleus accumbens, and prefrontal cortex (PFC); however, recent clinical evidence has implicated glutamate dysfunction in the pathophysiology of ADHD. Recent studies show that increased stimulation of dopamine D2 and D4 receptors causes inhibition of N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, respectively. The spontaneously hypertensive rat (SHR) model of ADHD combined type (C) has been found to have a hypofunctional dopamine system in the ventral striatum, nucleus accumbens, and PFC compared to the control Wistar Kyoto (WKY) strain. Based on the current understanding of typical dopamine-glutamate interactions, we hypothesized that the SHR model of ADHD would have a hyperfunctional glutamate system terminating in the striatum, nucleus accumbens, and PFC. High-speed amperometric recordings combined with four-channel microelectrode arrays to directly measure glutamate dynamics showed increased evoked glutamate release in the PFC (cingulate and infralimbic cortices, p < 0.05) and also in the striatum (p < 0.05) of the SHR (ADHD-C) as compared to the WKY. Finally, glutamate uptake was discovered to be aberrant in the PFC, but not the striatum, of the SHR when compared to the control WKY strain. These results suggest that the glutamatergic system in the PFC of the SHR model of ADHD is hyperfunctional and that targeting glutamate in the PFC could lead to the development of novel therapeutics for the treatment of ADHD.

The emerging role of dopamine–glutamate interaction and of the postsynaptic density in bipolar disorder pathophysiology: Implications for treatment

Aberrant synaptic plasticity, originating from abnormalities in dopamine and/or glutamate transduction pathways, may contribute to the complex clinical manifestations of bipolar disorder (BD). Dopamine and glutamate systems cross-talk at multiple levels, such as at the postsynaptic density (PSD). The PSD is a structural and functional protein mesh implicated in dopamine and glutamate-mediated synaptic plasticity. Proteins at PSD have been demonstrated to be involved in mood disorders pathophysiology and to be modulated by antipsychotics and mood stabilizers. On the other side, post-receptor effectors such as protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3) and the extracellular signal-regulated kinase (Erk), which are implicated in both molecular abnormalities and treatment of BD, may interact with PSD proteins, and participate in the interplay of the dopamine-glutamate signalling pathway. In this review, we describe emerging evidence on the molecular cross-talk between dopamine and glutamate signalling in BD pathophysiology and pharmacological treatment, mainly focusing on dysfunctions in PSD molecules. We also aim to discuss future therapeutic strategies that could selectively target the PSD-mediated signalling cascade at the crossroads of dopamine-glutamate neurotransmission.

Amphetamine stimulates movement through thalamocortical glutamate release.

The ventrolateral thalamus (VL) is a primary relay point between the basal ganglia and the primary motor cortex (M1). Using dual probe microdialysis and locomotor behavior monitoring, we investigated the contribution of VL input into M1 during amphetamine (AMPH)-stimulated monoamine release and hyperlocomotion in rats. Tetrodotoxin (10 μM) perfusion into the VL significantly lowered hyperactivity induced by AMPH (1 mg/kg i.p.). This behavioral response corresponded to reduced cortical glutamate and monoamine release. To determine which glutamate receptors the thalamocortical projections acted upon, we perfused either the α-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA)/kainate receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) (10 μM) or the N-methyl-D-aspartic acid (NMDA) receptor antagonist (MK-801) intracortically followed by systemic AMPH. The results show that AMPA/kainate, and to a lesser extent NMDA receptors, mediated the observed effects. As glutamate-monoamine interactions could possibly occur through local or circuit-based mechanisms, we isolated and perfused M1 tissue ex vivo to determine the extent of local glutamate-dopamine interactions. Taken together, these results demonstrate that AMPH generates hyperlocomotive states via thalamocortical signaling and that cortical AMPA receptors are an important mediator of these effects. This study utilizes dual probe microdialysis sampling and comprehensive LC-MS analysis to determine the effects of amphetamine (1 mg/kg i.p.) on thalamocortical neurotransmission. Using pharmacological tools such as local thalamic tetrodotoxin (TTX) perfusion and glutamate antagonist at the cortical level, we demonstrate that thalamocortical glutamate (acting primarily through cortical AMPA receptors) is an essential component in amphetamine-induced hyperlocomotion.

Ketamine increases striatal dopamine release and hyperlocomotion in adult rats after postnatal functional blockade of the prefrontal cortex

Schizophrenia is a complex psychiatric disorder that may result from defective connectivity, of neurodevelopmental origin, between several integrative brain regions. Different anomalies consistent with brain development failures have been observed in patients’ left prefrontal cortex (PFC). A striatal dopaminergic functional disturbance is also commonly acknowledged in schizophrenia and could be related to a dysfunctioning of dopamine–glutamate interactions. Non-competitive NMDA antagonists, such as ketamine, can induce psychotic symptoms in healthy individuals and worsen these symptoms in patients with schizophrenia. Our study set out to investigate the consequences of neonatal functional blockade of the PFC for dopaminergic and behavioral reactivity to ketamine in adult rats. Following tetrodotoxin (TTX) inactivation of the left PFC at postnatal day 8, dopaminergic responses induced by ketamine (5mg/kg, 10mg/kg, 20mg/kg sc) were monitored using in vivo voltammetry in the left part of the dorsal striatum in freely moving adult rats. Dopaminergic responses and locomotor activity were followed in parallel. Compared to PBS animals, in rats microinjected with TTX, ketamine challenge induced a greater release of dopamine in the dorsal striatum for the highest dose (20mg/kg sc) and the intermediate dose (10mg/kg sc). A higher increase in locomotor activity in TTX animals was observed only for the highest dose of ketamine (20mg/kg sc). These data suggest transient inactivation of the PFC during early development results in greater behavioral and striatal dopaminergic reactivity to ketamine in adulthood. Our study provides an anatomo-functional framework that may contribute toward a better understanding of the involvement of NMDA glutamatergic receptors in schizophrenia.

Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels

Opioid drugs are highly addictive and their abuse has a strong genetic load. Dopamine-glutamate interactions are hypothesized to be important for regulating neural systems central for addiction vulnerability. Balanced dopamine-glutamate interaction is mediated through several functional associations, including a physical link between discs, large homolog 4 (Drosophila) (DLG4, PSD-95) and dopamine receptor 1 (DRD1) within the postsynaptic density to regulate DRD1 trafficking. To address whether genetic associations with heroin abuse exist in relation to dopamine and glutamate and their potential interactions, we evaluated single-nucleotide polymorphisms of key genes within these systems in three populations of opiate abusers and controls, totaling 489 individuals from Europe and the United States. Despite significant differences in racial makeup of the separate samples, polymorphisms of DRD1 and DLG4 were found to be associated with opiate abuse. In addition, a strong gene-gene interaction between homer 1 homolog (Drosophila) (HOMER1) and DRD1 was predicted to occur in Caucasian subjects. This interaction was further analyzed by evaluating DRD1 genotype in relation to HOMER1b/c protein expression in postmortem tissue from a subset of Caucasian subjects. DRD1 rs265973 genotype correlated with HOMER1b/c levels in the striatum, but not cortex or amygdala; the correlation was inversed in opiate abusers as compared with controls. Cumulatively, these results support the hypothesis that there may be significant, genetically influenced interactions between glutamatergic and dopaminergic pathways in opiate abusers.

Calcyon Forms a Novel Ternary Complex with Dopamine D1 Receptor through PSD-95 Protein and Plays a Role in Dopamine Receptor Internalization

Calcyon, once known for interacting directly with the dopamine D(1) receptor (D(1)DR), is implicated in various neuropsychiatric disorders including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. Although its direct interaction with D(1)DR has been shown to be misinterpreted, it still plays important roles in D(1)DR signaling. Here, we found that calcyon interacts with the PSD-95 and subsequently forms a ternary complex with D(1)DR through PSD-95. Calcyon is phosphorylated on Ser-169 by the PKC activator phorbol 12-myristate 13-acetate or by the D(1)DR agonist SKF-81297, and its phosphorylation increases its association with PSD-95 and recruitment to the cell surface. Interestingly, the internalization of D(1)DR at the cell surface was enhanced by phorbol 12-myristate 13-acetate and SKF-81297 in the presence of calcyon, but not in the presence of its S169A phospho-deficient mutant, suggesting that the phosphorylation of calcyon and the internalization of the surface D(1)DR are tightly correlated. Our results suggest that calcyon regulates D(1)DR trafficking by forming a ternary complex with D(1)DR through PSD-95 and thus possibly linking glutamatergic and dopamine receptor signalings. This also raises the possibility that a novel ternary complex could represent a potential therapeutic target for the modulation of related neuropsychiatric disorders.

Brain stimulation reward is altered by affecting dopamine–glutamate interactions in the central extended amygdala

This work compares the effects on brain stimulation reward (BSR) when combining D2 dopamine receptor and AMPA glutamate receptor manipulations in the sublenticular central extended amygdala (SLEAc) and the nucleus accumbens shell (NAc shell). Thirty-seven male Long Evans rats received medial forebrain bundle (MFB) stimulation electrodes and bilateral injection guide cannulae aimed at either the SLEAc or the NAc shell. The rate-frequency paradigm was used to assess drug-induced changes in stimulation reward effectiveness and in response rate following 0.5μl infusions of 0.50μg of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX) (AMPA receptor antagonist), 10.0μg of quinpirole (D2 receptor agonist), 0.25μg of AMPA (AMPA receptor agonist), 3.0μg of eticlopride (D2 receptor antagonist), 0.50μg of NBQX with 10.0μg of quinpirole, and 0.25μg of AMPA with 3.0μg of eticlopride. The drugs were injected both ipsi- and contralateral to the stimulation site. AMPA blockade and D2 stimulation synergized to reduce BSR’s reward efficacy when directed at the SLEAc contralateral to the stimulation site whereas changes in reward efficacy were primarily D2-dependent following injections into the ipsilateral SLEAc. When injected into the NAc shell the drugs had only one significant effect on the frequency required to maintain half-maximal responding: injections of NBQX with quinpirole ipsilateral to the stimulation site increased required frequency significantly more than did injections of saline. Contrary to expectations, stimulating AMPA receptors with and without co-blockade of D2 receptors also decreased the stimulation’s reward efficacy, although these effects may reflect general behavioral disruption more than effects on reward per se. These results indicate a role for the SLEAc in BSR and also suggest that SLEAc neurons ipsi- and contralateral to the stimulated MFB play their roles in BSR through different mechanisms.

Calcium-Dependent Networks in Dopamine–Glutamate Interaction: The Role of Postsynaptic Scaffolding Proteins

Dopamine and glutamate systems are both involved in cognitive, behavioral, and motor processes. Dysfunction of dopamine-glutamate interplay has been suggested in several psychotic diseases, above all in schizophrenia, for which there exists a need for novel medications. Intracellular calcium-dependent transduction pathways are key determinants of dopamine-glutamate interactions, which take place mainly, albeit not exclusively, in the postsynaptic density (PSD), a highly specialized postsynaptic ultrastructure. Stimulation of dopamine and glutamate receptors modulates the gene expression and the function of specific PSD proteins, the "scaffolding" proteins (Homer, Shank, and PSD95), belonging to a complex Ca(2+)-regulated network that integrates and converges dopamine and glutamate signaling to appropriate nuclear targets. Dysfunction of scaffolding proteins leads to severe impairment of Ca(2+)-dependent signaling, which may underlie the dopamine-glutamate aberrations putatively implicated in the pathogenesis of psychotic disorders. Antipsychotic therapy has been demonstrated to directly and indirectly affect the neuronal Ca(2+)-dependent pathways through the modulation of PSD scaffolding proteins, such as Homer, therefore influencing both dopaminergic and glutamatergic functions and enforcing Ca(2+)-mediated long-term synaptic changes. In this review, we will discuss the role of PSD scaffolding proteins in routing Ca(2+)-dependent signals to the nucleus. In particular, we will address the implication of PSD scaffolding proteins in the intracellular connections between dopamine and glutamate pathways, which involve both Ca(2+)-dependent and Ca(2+)-independent mechanisms. Finally, we will discuss how new strategies for the treatment of psychosis aim at developing antipsychotics that may impact both glutamate and dopamine signaling, and what should be the possible role of PSD scaffolding proteins.

Potentiation of D‐Serine Involves Degeneration of Dopaminergic Neurons in MPTP/p Mouse Model of Parkinson's Disease

Potentiation of D‐Serine Involves Degeneration of Dopaminergic Neurons in MPTP/p Mouse Model of Parkinson's Disease