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At least 19 recordsLinked to original sources
PubMed2005

Novel heterocyclic trans olefin analogues of N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as selective probes with high affinity for the dopamine D3 receptor.

Dopamine D3 receptor subtypes have been hypothesized to play a pivotal role in modulating the reinforcing and drug-seeking effects induced by cocaine. However, definitive pharmacological investigations have been hampered by the lack of highly D3 receptor selective compounds that can be used in vivo. To address this problem, the potent and D3-receptor-selective antagonist NGB 2904 (1, 9H-fluorene-2-carboxylic acid {4-[(2,3-dichlorophenyl)-piperazin-1-yl]-butyl}-amide, Ki (hD3) = 2.0 nM, Ki (hD2L) = 112 nM, D2/D3 selectivity ratio of 56) was chosen as a lead structure for chemical modification in an attempt to reduce its high lipophilicity (c log D = 6.94) while optimizing D3 receptor binding affinity and D2/D3 selectivity. A series of >30 novel analogues were synthesized, and their binding affinities were evaluated in competition binding assays in HEK 293 cells transfected with either D2(L), D3, or D4 human dopamine receptors using the high affinity, selective D2-like receptor antagonist (125)I-IABN. Structural diversity in the aryl amide end of the molecule was found to have a major influence on (sub)nanomolar D3 receptor affinity and D2/D3 selectivity, which was optimized using a more rigid trans-butenyl linker between the aryl amide and the piperazine. Several analogues demonstrated superior D3 receptor binding affinities and selectivities as compared to the parent ligand. Compound 29 (N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide) displayed the most promising pharmacological profile (Ki (hD3) = 0.7 nM, Ki (hD2L) = 93.3 nM, D2/D3 selectivity ratio of 133). In addition, this ligand inhibited quinpirole stimulation of mitogenesis at human dopamine D3 receptors transfected into Chinese hamster ovary (CHO) cells, with an EC50 value of 3.0 nM. Compound 29 was a nearly 5 times more potent antagonist at the D3 receptor than 1 (EC50 = 14.4 nM). Moreover, a decrease in c log D value of approximately 2 orders of magnitude was determined for this novel D3-receptor-preferring ligand, compared to 1. In summary, chemical modification of 1 has resulted in compounds with high affinity and selectivity for D3 receptors. The most promising candidate, compound 29, is currently being evaluated in animal models of cocaine abuse and will provide an important tool with which to elucidate the role of D3 receptors in drug reinforcement in vivo.

Animals↗
PubMed2003

Association analysis for dopamine D3 receptor, dopamine D4 receptor and dopamine transporter genetic polymorphisms and P300 event-related potentials for normal young females.

OBJECTIVE: It has been demonstrated that the P300 components, a positive event-related potential, are heritable and are influenced by dopaminergic activity. We tested the genetic effects of the dopaminergic system in P300 components by association study. METHODS: In a sample population consisting of 120 normal young Han-Chinese females, we explored the association between the P300 components, and, the genetic polymorphisms including the dopamine D3 receptor (serine-to-glycine polymorphism in exon I), the dopamine D4 receptor (variable number tandem repeat polymorphism in exon III), and the dopamine transporter (variable number tandem repeat polymorphism in promoter region). RESULTS: No associations were demonstrated between the polymorphisms of these three genes and the P300 components. CONCLUSIONS: Our negative findings suggest that these genetic polymorphisms do not play a major role in the modulation of P300 event-related potentials.

Adult↗
PubMed2005

D3 dopamine receptor mRNA is elevated in T cells of schizophrenic patients whereas D4 dopamine receptor mRNA is reduced in CD4+ -T cells.

The expression of dopamine receptors was examined in purified human neutrophils, monocytes, B cells, natural killer cells and CD4+ - and CD8+ -T lymphocytes by RT-PCR. In healthy subjects, D1 and D2 receptors were not expressed in leukocytes. Real Time PCR for dopamine receptors D3 and D4 disclosed that D3 receptors are expressed in T cells and natural killer cells and D4 receptors in CD4+ -T cells. The comparison of schizophrenic patients with sex- and age-matched controls revealed a significantly higher expression of D3 receptor mRNA in T cells of schizophrenic patients, whereas D4 receptor mRNA in CD4+ -T cells was downregulated.

Adult↗
PubMed1996

Expression of the D3 dopamine receptor in peptidergic neurons of the nucleus accumbens: comparison with the D1 and D2 dopamine receptors.

The D3 dopamine receptor, belonging to the D2-like receptor subfamily, displays both specific pharmacology and a unique pattern of expression, especially compared to the D1 and D2 receptors. A rat D3 complementary RNA probe labelled with [35S]UTP was used to map the neurons expressing the D3 receptor gene in the rat brain. In particular, we identified the phenotype of the neurons containing D3 messenger. RNA in the nucleus accumbens, with respect to the striatal segregated populations of enkephalin and substance P neurons, by using strategies of double in situ hybridization. In addition, comparison with D1 and D2 receptor gene expression was performed to study the potential co-localization of several dopamine receptors within the same neurons in the ventral striatum. The highest level of D3 messenger RNA was detected in the islands of Calleja and the nucleus accumbens. Other areas such as the caudate-putamen, some hypothalamic, thalamic and cortical areas and lobule 10 of the cerebellum also contained low but significant levels of D3 messenger RNA. Our results demonstrate that the D3 receptor is co-expressed either with D1 or with D2 receptor, both in the core and shell regions, in a subpopulation of substance P and enkephalin neurons, respectively. They also suggest that a significant part of the accumbal neurons only express either D1 or D2, without co-expression with the D3 receptor. These data imply that dopamine in the nucleus accumbens may act on each population of efferent neurons via the co-expression of two distinct dopamine receptors (D1+D3 or D2+D3), and that synergistic D1-like/D2-like effects may occur at the level of a single neuron, through the co-expression of D1 and D3 receptors in a significant proportion of substance P neurons (16% or 26% in the core and shell regions, respectively.

Animals↗
PubMed1991

Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA.

The messenger RNA (mRNA) of the recently characterized D3 dopamine receptor was visualized on rat brain sections using in situ hybridization with a 32P-labeled ribonucleic acid probe corresponding to a major part of the third cytoplasmic loop, a domain in which D2 and D3 dopamine receptors display little homology. For the purpose of comparison, D2 receptor mRNA was also specifically visualized on adjacent sections. The areas that expressed D2 and/or D3 receptors were also compared with those previously detected using [125I]iodosulpride, a ligand that binds to both D2 and D3 receptors with a similar affinity. The localization of D3 receptor mRNa markedly differs from that of D2 receptor mRNA. Whereas D2 receptor mRNA is expressed in all major brain areas receiving dopaminergic projections, particularly in the whole striatal complex, D3 receptor mRNA is expressed in a more restricted manner. It is mainly detected in telencephalic areas receiving dopaminergic inputs from the A10 cell group, e.g. accumbens nucleus, islands of Calleja, bed nucleus of the stria terminalis and other limbic areas such as the hippocampus and the mammillary nuclei. D2 and D3 receptor mRNAs were also detected at the level of the substantia nigra, suggesting that these receptors function as both autoreceptor and postsynaptic receptors. In several dopaminergic projection areas, e.g. ventral straitum, septal or mammillary nuclei, the distributions of D2 and D3 receptor mRNAs appeared complementary without overlap. The distribution of [125I]iodosulpride binding sites generally overlapped that of D2 or D3 receptor mRNAs, the latter being most abundant in dopaminergic areas known to be associated with cognitive and emotional functions.

Animals↗
PubMed1999

Association between the dopamine D3 receptor gene locus (DRD3) and unipolar affective disorder.

Dopamine neurotransmission has been implicated in the pathophysiology of schizophrenia and, more recently, affective disorders. Among the dopamine receptors, D3 can be considered as particularly related to affective disorders due to its neuroanatomical localization in the limbic region of the brain and its relation to the serotoninergic activity of the CNS. The possible involvement of dopamine receptor D3 in unipolar (UP) major depression was investigated by a genetic association study of the D3 receptor gene locus (DRD3) on 36 UP patients and 38 ethnically matched controls. An allelic association of DRD3 (Bal I polymorphism) and UP illness was observed, with the Gly-9 allele (allele '2', 206/98 base-pairs long) being more frequent in patients than in controls (49% vs 29%, P < 0.02). The genotypes containing this allele (1-2 and 2-2) were found in 75% of patients vs 50% of controls (P < 0.03, odds ratio = 3.00, 95% CI = 1.12-8.05). The effect of the genotype remained significant (P < 0.02) after sex and family history were controlled by a multiple linear regression analysis. These results further support the hypothesis that dopaminergic mechanisms may be implicated in the pathogenesis of affective disorder. More specifically, the '2' allele of the dopamine receptor D3 gene seems to be associated with unipolar depression and can be considered as a 'phenotypic modifier' for major psychiatric disorders.

Adult↗
PubMed2003

Altered behavioral response to dopamine D3 receptor agonists 7-OH-DPAT and PD 128907 following repetitive amphetamine administration.

Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, is mediated in part by dopaminergic pathways. Increased locomotor response to drug treatment, a sensitizable behavior, is modulated by an opposing balance of dopamine receptor subtypes, with D1/D2 dopamine receptor stimulation increasing and D3 dopamine receptor activation inhibiting amphetamine-induced locomotion. We hypothesize that tolerance of D3 receptor locomotor inhibition contributes to behavioral sensitization. In order to test the hypothesis that expression of behavioral sensitization results in part from release of D3 receptor-mediated inhibition, thereby resulting in decreased response to D3 receptor agonists, we examined the effect of repetitive amphetamine administration on the behavioral response to the D3 receptor preferring agonists 7-OH-DPAT and PD 128907. D3-selective effects have recently been described for both drugs at a low dose. At 1 week following completion of a repetitive treatment regimen, amphetamine-pretreated rats displayed a decreased response to D3-selective doses of both 7-OH-DPAT and PD 128907, when compared to animals receiving saline pretreatment. Moreover, in addition to the quantitative alteration in response, there was a change in the inter-relation between response to amphetamine and D3 agonist. A highly significant inverse relation between locomotor inhibitory response to PD 128907 and the locomotor-stimulant response to amphetamine was observed prior to amphetamine treatment. In contrast, 10 days following repetitive amphetamine treatment, the relation between response to PD 128907 and amphetamine was not detected. The observed behavioral alteration could not be accounted for by changes in D3 receptor binding in ventral striatum. These findings suggest a persistent release of D3 receptor-mediated inhibitory influence contributes to the expression of behavioral sensitization to amphetamine.

Amphetamine↗
PubMed1993

No association between schizophrenia and homozygosity at the D3 dopamine receptor gene.

The D3 dopamine receptor gene is an important candidate gene for schizophrenia, since (because of its almost exclusive expression in the limbic system) it combines the dopamine receptor hypothesis with the limbic system hypothesis of schizophrenia. A BalI restriction fragment length polymorphism of the D3 dopamine receptor gene has been typed in 107 schizophrenic patients and 98 normal controls from Sichuan (China). With regard to alleles or genotypes, no significant differences were obtained between controls from Europe and China, between patients and controls, and between patient subgroups and controls. These results indicate a lack of association between schizophrenia and the D3 dopamine receptor gene in our sample. Our findings are at variance with reports of a significant excess of homozygosity at the D3 dopamine receptor gene in schizophrenic patients from Wales (United Kingdom) and Alsace (France). In conclusion, further studies will be needed with larger samples of patients from Wales and Alsace as well as with samples of different racial groups to prove or disprove the initial positive association between schizophrenia and genotypes of the D3 dopamine receptor gene.

Adolescent↗
PubMed1994

Activation of heterologously expressed D3 dopamine receptors: comparison with D2 dopamine receptors.

Recombinant rat D3 dopamine receptors heterologously expressed in Chinese hamster ovary (CHO) cells are functionally coupled to endogenous G proteins. The affinity of the receptors for agonists is regulated by guanine nucleotides in the same manner as that of other G protein-linked receptors. The magnitude of the change in affinity induced by GTP is much less, however, than what is observed for recombinant rat D2 receptors expressed in CHO cells at similar densities. The striking difference is that the low affinity state (uncoupled D3 receptors) has a much higher affinity for agonists than does the low affinity state (uncoupled) of D2 receptors. Both receptors in the high affinity state (G protein coupled) have similar affinities for dopamine. Three functional responses result from activation of D3 or D2 receptors expressed in CHO cells. Both receptor subtypes mediate inhibition of adenylyl cyclase activity, increases in extracellular acidification rates that are prevented by removal of external Na+ and by amiloride analogs, and stimulation of cell division. However, these three functional results of D3 and D2 receptor activation are both quantitatively and qualitatively different. Dopamine activation of D3 receptors is always 2-5-fold less efficacious than dopamine activation of D2 receptors, despite similar densities of receptors. Both D3 and D2 receptor-mediated increases in extracellular acidification rates are blocked by pertussis toxin; however, the D3 response and not the D2 response is partially attenuated by membrane-soluble cAMP analogs. D3 and D2 receptor-mediated stimulation of mitogenesis is blocked by pertussis toxin and unaffected by cAMP analogs. The results show that D2 and D3 dopamine receptors mediate similar signaling events and are additional examples of G protein-linked receptors that can activate more than one pathway. Having functionally coupled D2 and D3 receptors expressed in the same cell type enabled determinations of agonist potencies at both D2 and D3 receptors. Comparison of the potencies at the two receptors reveals that none of the agonists is as selective for D3 receptors as was previously thought based on radioligand binding data.

Animals↗
PubMed2001

The dopamine D3 receptor partial agonist, BP 897, is an antagonist at human dopamine D3 receptors and at rat somatodendritic dopamine D3 receptors.

Recent studies have fueled the interest in dopamine D3 receptor antagonists and partial agonist for the treatment of psychosis and drug abuse, respectively. N-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide (BP 897) is a dopamine D3 receptor selective ligand recently described as partial agonist with potential effects on drug-dependence. The aim of the present study was to determine both the functional activity of BP 897 at human dopamine D3 receptors expressed in Chinese hamster ovary (CHO) cells and in an electrophysiological in vivo model of dopaminergic activity. BP 897 failed to stimulate the human dopamine D3 receptor and showed antagonistic effects (cpIC(50)=9.51) in a [(35)S]GTPgammaS binding assay in cells expressing the human dopamine D3 receptor. In vivo, BP 897 up to 8.2 mg/kg, i.v., had no agonistic effects on firing rate of substantia nigra dopaminergic neurons and antagonized the quinpirole-induced inhibition of firing (DID(50)=1.1 mg/kg). Our data demonstrate that BP 897 acts, in vivo and in vitro, as a dopamine D3 receptor antagonist.

Animals↗
PubMed2007

No association between the Ser9Gly polymorphism of the dopamine D3 receptor gene and schizophrenia in a Spanish sample.

This study aims to further evaluate the controversial association between the Ser9Gly polymorphism in codon 9 of the D3 dopamine receptor gene (DRD3) and schizophrenia in psychiatric inpatients acutely hospitalized in two general hospitals in Madrid, Spain. The Ser9Gly polymorphism of the DRD3 was examined in 178 schizophrenic patients, 286 patients with other psychiatric diagnoses, and 132 controls recruited. Genotype frequencies were in Hardy-Weinberg equilibrium. No association was found between schizophrenia and the Ser9Gly polymorphism of the D3 dopamine receptor gene.

Case-Control Studies↗
PubMed2001

Synthesis and structure-activity relationships of naphthamides as dopamine D3 receptor ligands.

A series of naphthamides were synthesized, and the affinities of these compounds were determined for dopamine D2 and D3 receptors using radioligand binding techniques. The naphthamide compounds that were prepared include N-(1-alkylpiperidin-4-yl)-4-bromo-1-methoxy-2-naphthamides (1-6), (S)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (7-12), (R)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (13-18), (S)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (19-25), (R)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (26-31), and N-(9-alkyl-9-azabicyclo[3.3.1]nonan-3beta-yl)-4-bromo-1-methoxy-2-naphthamides (32, 33). The results of in vitro radioligand binding studies indicated that the majority of the naphthamide analogues bound with high affinity at both the D2 and D3 dopamine receptor subtypes and most of the compounds demonstrated some selectivity for the dopamine D3 dopamine receptor subtype. These results demonstrated that both the structure of the central amine moiety (piperidine, pyrrolidine, and 9-azabicyclo[3.3.1]nonane) ring and the N-(alkyl) substitution on the amine significantly effects the binding affinity at D2 and D3 dopamine receptors. The bulkiness of the N-(1-alkyl) substituent was found to (a) have no effect on pharmacologic selectivity, (b) increase the affinity at D3 receptors, or (c) decrease the affinity at D2 receptors. The most potent analogue in this series was (S)-N-(1-cycloheptylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamide (10), which had equilibrium dissociation (K(i)) values of 1.8 and 0.2 nM for D2 and D3 receptors, respectively. The most selective analogue was (R)-N-(1-cycloheptyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamide (30), which had K(i) values of 62.8 and 2.4 nM for D2 and D3 receptors, respectively. Radioligand binding results for sigma receptors indicated that the structure of the amine moiety and the N-(1-alkyl) substitutions also significantly influence the affinity and selectivity of these compounds at the sigma1 and sigma2 sigma receptor subtypes. The two naphthamides containing a 9-azabicyclo[3.3.1]nonan-3beta-yl central ring were found to be selective for sigma2 receptors.

Animals↗
PubMed2000

The dopamine D3 receptor antagonist nafadotride inhibits development of locomotor sensitization to amphetamine.

Behavioral sensitization is a well-studied model of behavioral plasticity mediated at least in part by dopaminergic systems believed to play an important role in several psychiatric conditions. In the rodent, locomotion is regulated by the opposing balance of D3 and D2 receptors, with D2 activation increasing and D3 stimulation inhibiting locomotion. However, receptor occupancy of D3 dopamine receptors is far greater than D2 or D1 occupancy at typical post-stimulant dopamine concentrations. We therefore hypothesized that tolerance of D3 receptor inhibition of locomotion contributes to the development of sensitization. To test this hypothesis, we examined the effect of the D3 receptor antagonist nafadotride on sensitization. As predicted, nafadotride inhibits augmentation of the locomotion response to repetitive amphetamine. This finding is consistent with the proposed model of adaptive down-regulation of D3 dopamine receptor function contributing to the development of behavioral sensitization.

Amphetamine↗
PubMed1996

Decrease of the D3 dopamine receptor mRNA expression in lymphocytes from patients with Parkinson's disease.

We investigated the dopamine receptor (DAR) mRNA expression in peripheral blood lymphocytes from 45 patients with Parkinson's disease (PD) and 21 age-matched controls using the quantitative reverse transcription and polymerase chain reaction method. Beta-actin mRNA was used as an internal control to evaluate the relative expression level of the DAR mRNA. There was a statistically significant decrease of the D3 dopamine receptor (D3R) mRNA expression in PD patients compared with that in controls. There was no change in expression of the D5 dopamine reception mRNA in PD patients. A further binding study showed reduction of the D3R binding sites in PD lymphocytes. The decrease of the D3R mRNA expression correlated with the degree of clinical severity in PD patients.

Actins↗
PubMed2000

The dopamine D3 receptor interacts with itself and the truncated D3 splice variant d3nf: D3-D3nf interaction causes mislocalization of D3 receptors.

We have generated a stable cell line expressing FLAG epitope-tagged D3 dopamine receptors and used this cell line to study D3 receptor-protein interactions. To analyze protein interactions, we separately introduced into the stable cell line either D3 receptors carrying an hemagglutinin (HA) epitope tag, or an HA-tagged version of the D3 receptor splice variant D3nf. A combination of confocal laser microscopy and coimmunoprecipitation was used to assay the formation and expression pattern of D3-D3 homodimers or D3-D3nf heterodimers. When coexpressed in HEK 293 cells, FLAG- and HA-tagged D3 receptors exhibited a similar plasma membrane distribution. Using an HA epitope tag-specific antibody, we coimmunoprecipitated HA- and FLAG-tagged D3 receptors, suggesting that D3 receptors are capable of forming homodimers. Epitope-tagged D3nf polypeptides exhibited a markedly different cellular distribution than D3 receptors. When expressed in HEK 293 cells, either alone or in combination with FLAG-tagged D3 receptors, D3nf exhibited a punctate perinuclear distribution. When D3nf was introduced into the stable D3-expressing cell line, D3 receptors were no longer visualized at the plasma membrane. Instead, D3 and D3nf showed a similar, predominantly cytosolic, localization. Using the HA-specific antibody, we were able to coimmunoprecipitate D3 and D3nf polypeptides from transfected cells. These data suggest the existence of physical interaction between D3 and D3nf. This interaction appears to result in the mislocalization of D3 receptors from the plasma membrane to an intracellular compartment, a finding that could be of significance in the etiology of schizophrenia.

Alternative Splicing↗
PubMed1996

Aminotetralin drugs and D3 receptor functions. What may partially selective D3 receptor ligands tell us about dopamine D3 receptor functions?

The dopamine D3 receptor gene was identified by Sokoloff and colleagues in 1990. This finding rapidly gained the interest of the scientific community because this unexpected dopamine receptor subtype may play an important role in the antipsychotic activity of neuroleptic drugs. It recognizes most neuroleptics with a high affinity, and its brain distribution is restricted mainly to the ventral part of the striatal complex. However, the characterization and the subsequent identification of functions of the D3 receptor were hampered initially by at least four important factors that are still partially unresolved: (1) the absence of selective drugs that can discriminate between the D2 and D3 receptor subtype functions in vivo, (2) the lack of apparent coupling with GTP-dependent proteins, (3) the absence of effects on second messenger systems, and (4) the low level of expression of this receptor in brain tissue; these factors have contributed to tempering the interest of scientists. However, this situation has begun to change with the identification of [3H]7-hydroxy-N,N-(di-n-propyl)-2-aminotetralin ([3H]7-OH-DPAT), the first selective ligand for the dopamine D3 receptor. Although its binding selectivity for the D3 versus the D2 receptor is somewhat artificial, the potentially important impact of identification of a function for the D3 receptor encouraged scientists to use this aminotetralin compound for in vivo studies with, however, limited success. This commentary is focused on the impact and controversies generated by the use of 7-OH-DPAT and its congeners, on new conceptual views that may arise from this research, and on what partially selective D3 receptor ligands may tell us about dopamine D3 receptor functions.

Animals↗
PubMed2006

Dopamine D3 receptor modulation of dopamine efflux in the rat nucleus accumbens.

The effect of antipsychotics on electrically evoked dopamine efflux in the rat nucleus accumbens core and shell was investigated, using in vitro fast cyclic voltammetry. In the nucleus accumbens core, the dopamine D2/D3 receptor agonist, (+/-)7-OH-DPAT ((+/-)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene), inhibited dopamine efflux with a pEC50 of 8.1. Clozapine, haloperidol, sulpiride and the selective dopamine D3 receptor antagonist, SB-277011-A, had no effect on dopamine efflux per se but all attenuated the (+/-)7-OH-DPAT-induced-inhibition of dopamine efflux, with pA2 values of 6.6, 7.9, 7.0 and 7.6, respectively. In the nucleus accumbens shell, (+/-)7-OH-DPAT inhibited dopamine efflux with a pEC50 of 8.3. Clozapine and SB-277011-A had no effect on dopamine efflux. In contrast, haloperidol and sulpiride significantly increased dopamine efflux through a D2 receptor-mediated mechanism. Clozapine, haloperidol, sulpiride and SB-277011-A attenuated the (+/-)7-OH-DPAT-induced inhibition with pA2 values of 7.3, 8.6, 7.6 and 8.2, respectively. These data demonstrate that dopamine efflux is modulated by both dopamine D2 and D3 receptors in the rat nucleus accumbens.

Animals↗
PubMed2004

Role of dopamine D3 receptor (DRD3) and dopamine transporter (DAT) polymorphism in cognitive dysfunctions and therapeutic response to atypical antipsychotics in patients with schizophrenia.

Molecular components of the dopaminergic system may play an important role in the pathophysiology of schizophrenia. In this study, we investigated the relationship of the Ser9Gly (S/G) polymorphism of the dopamine D3 receptor (DRD3) and the variable number of tandem repeats (VNTR) polymorphism of the dopamine transporter (DAT) with therapeutic response to atypical antipsychotics (clozapine, olanzapine, quetiapine, risperidone) and cognitive functions. No associations were found between the DRD3 and DAT polymorphisms and schizophrenia. The S/S genotype and the S allele were more frequent in the non-responder patients (n = 28) than in the group of responders (n = 47) (cut-off: >20-point improvement in Global Assessment of Functioning (GAF) scale). The patients with S/S genotype completed fewer categories and had more perseverative errors in the Wisconsin Card Sorting Test (WCST) compared with the S/G patients. The S/S and S/G patients did not differ in positive and negative symptoms, GAF scores, WCST failure to maintain set, and verbal learning. No differences in symptoms or WCST measures were observed in the patients with different DAT genotypes. These results suggest that the S/S genotype of the DRD3 is associated with worse therapeutic response and more severe executive dysfunctions in patients with schizophrenia.

Adult↗