Neuropharmacology of Dopamine Receptors : Implications in Neuropsychiatric Diseases

There has been an extraordinary recent accumulation of information concerning the neurobiology and neuropharmacology of dopamine (DA) receptors in the mammalian central nervous system. Many new DA molecular entities have been cloned, their gene, peptide sequences and structures have been identified, their anatomical distributions in the mammalian brain described, and their pharmacology characterized. Progress has been made toward developing selective ligands and drug-candidates for different DA receptors. The new discoveries have greatly stimulated preclinical and clinical studies to explore the neuropharmacology of DA receptors and their implications in the neuropathophysiology of different neuropsychiatric diseases including schizophrenia, Parkinson’s disease and attention- deficit hyperactivity disorder. Accordingly, it seems timely to review the salient aspects of this specialized area of preclinical neuropharmacology and its relevance to clinical neuropsychiatry.

Dopamine receptor subtypes: Differential regulation after 8 months treatment with antipsychotic drugs.

ABSTRACT Regulation of dopamine receptor subtypes was determined after long-term (8 mo) administration of typical and atypical antipsychotic drugs using 3 H-nemonapride, 3 H-raclopride,

Longterm effects of olanzapine, risperidone, and quetiapine on ionotropic glutamate receptor types: implications for antipsychotic drug treatment. J Pharmacol Exp Ther 2003; 306

ABSTRACT Levels of ionotropic glutamate (Glu) N-methyl-D-aspartate (NMDA), ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainic acid (KA) receptors in rat forebrain regions were compared by quantitative in vitro receptor autoradiography after continuous treatment for 28 days with the atypical antipsychotics olanzapine, risperidone, and quetiapine, or vehicle controls. All three treatments significantly decreased NMDA binding in caudate-putamen (CPu; by 30, 34, and 26%, respectively) but increased AMPA receptor levels in same region (by 22, 30, and 28%). Olanzapine and risperidone, but not quetiapine, also reduced NMDA receptor labeling in hippocampal CA1 (21 and 19%) and CA3 (23 and 22%) regions. KA receptors were unaltered by any treatment in the brain regions examined. These findings suggest that the antipsychotic effects of olanzapine and risperidone may be mediated in part by NMDA receptors in hippocampus, and perhaps AMPA receptors in CPu. The findings also support the hypothesis that down-regulation of NMDA receptors by atypical antipsychotic agents in CPu contributes to their low risk of extrapyramidal side effects. Inability of olanzapine, risperidone, and quetiapine to alter KA receptors suggests their minimal role in mediating the central nervous system actions of these drugs

Long-term effects of JL 13, a potential atypical antipsychotic, on rat dopamine and serotonin receptor subtypes

Changes in dopamine (DA) D-1, D-2, D-3, and D-4 receptors and serotonin 5-HT1A and 5-HT2A receptors in rat forebrain regions were autoradiographically quantified after continuous infusion of JL 13 [(5-(4-methylpiperazin-1-yl)8-chloro-pyrido[2,3-b][1,5]benzoxazepine fumarate] for 28 days with osmotic minipumps and compared with the effects of other typical (fluphenazine) and atypical (clozapine, olanzapine, and risperidone) antipsychotic drugs from previous studies. Similar to other typical and atypical antipsychotics, JL 13 increased labeling of D2 receptors in medial prefrontal cortex (MPC) and hippocampus (HIP) and D-4 receptors in nucleus accumbens (NAc), caudate-putamen (CPu), and HIP In addition, JL 13 increased 5-HT1A and decreased 5-HT2A receptors in MPC and dorsolateral frontal cortex (DFC), an effect shared by atypical antipsychotics, and may contribute to their psychopharmacological properties. Clozapine and JL 13, but not other antipsychotics, spared D2 receptors in CPu, which may reflect their ability to induce minimal extrapyramidal side effects. In addition, JL 13 but not other typical and atypical antipsychotic drugs increased abundance of D, receptors in CPu and NAc. JL 13 as well as other antipsychotic agents did not alter levels of forebrain D3 receptors. An atypical-like profile of JL 13 on DA and 5-HT receptor subtypes should encourage further development of this compound as a novel atypical anti psychotic drug. (c) 2006Wiley-Liss, Inc

Enhanced expression of dopamine D1 and glutamate NMDA receptors in dopamine D4 receptor knockout mice

Expression of dopamine ([DA] D1 and D2) and glutamate ([Glu], (N-methyl-D-aspartic acid [NMDA], α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid [AMPA], and kanaic acid [KA]) receptor types were analyzed autoradiographically in forebrain regions of D4 receptor knockout mice and their wild-type controls. Selective radioligand binding to D4 receptors was virtually absent in D4 receptor knockout mouse brain in contrast to significant specific D4 binding in forebrain tissue of wild-type controls. Labeling of D1 receptors was significantly increased in nucleus accumbens (NAc; 39%) and caudate putamen (CPu; 42%) of D4-knockout mice vs wild-type controls. In addition, NMDA receptor labeling was significantly increased in NAc (31%), CPu (40%), and hippocampal CA1 (21%) and CA3 (25%) regions of D 4 knockouts vs wild-type controls. No changes in D2, AMPA or KA receptors were found. The findings suggest that D1, D 4, and NMDA receptors might interact functionally and that developmental absence of D4 receptors might trigger compensatory mechanisms that enhance expression of D1 receptors in NAc and CPu, and NMDA receptors in NAc, CPu, and hippocampus. The findings also encourage cautious interpretation of results in knockout mice with targeted absence of specific genes, as complex adaptive changes not directly related to the missing gene might contribute to physiological and behavioral responses.Fil: Gan, Lu. McLean Division of Massachusetts General Hospital; Estados Unidos. Harvard Medical School; Estados UnidosFil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Zhang, Kehong. McLean Division of Massachusetts General Hospital; Estados Unidos. Harvard Medical School; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Baldessarini, Ross J.. McLean Division of Massachusetts General Hospital; Estados Unidos. Harvard Medical School; Estados UnidosFil: Tarazi, Frank I.. McLean Division of Massachusetts General Hospital; Estados Unidos. Harvard Medical School; Estados Unido