Dopamine D4 receptors

Neuroleptics or antipsychotics suppress the positive symptoms of schizophrenia such as combativeness, hallucinations and formal thought disorder. Some also alleviate the negative symptoms such as affective blunting, withdrawal and seclusiveness. Neuroleptics also produce a state of apathy and emotional indifference. Most neuroleptics block dopamine D2-receptors but some, like clozapine, also block dopamine D4-receptors or serotonin 5-hydroxytryptamine2A-receptors. 

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Bristow, LJ, Kramer, MS, Kulagowski, J, Patel, S, Ragan, Cl and Seabrook, GR (1997) Schizophrenia and L745,870, a novel dopamine D4 receptor antagonist. Trends Pharmacol. Sci. 18 186-188. 

Kaiser, R., Konneker, M., Henneken, M. et al. (2000). Dopamine D4 receptor 48-bp repeat polymorphism no association with response to antipsychotic treatment, but association with catatonic schizophrenia. Mol. Psychiatry, 5, 418-24. 

Zhao, A. L., Zhao, J. P., Xue, Z. M. et al. (2005). Association between polymorphism in the dopamine D4 receptor gene and qualitative and quantitative characters of schizophrenia in Chinese. Chinese Journal of Psychiatry, 38( 1), 3-6. 

Floran B., Floran L., Erlij D., Aceves J. (2004). Activation of dopamine D4 receptors modulates [3H]GABA release in slices of the rat thalamic reticular nucleus. Neuropharmacology 46, 497-503. 

Wong, A.H.C., VanTol, H.H.M. The dopamine D4 receptors and mechanisms of antipsychotic atypicality. Prog. Neuropsychopharmacol. Biol. Psychiatry. 27 1091, 2003. 

Okuyama, S., Kawashima, N., Chaki, S. et al. A selective dopamine D4 receptor antagonist, NRA0160 a preclinical neuropharmacological profile. Life Sci. 65 2109, 1999. 

DBH, dopamine / -hydroxylase DRD2, dopamine D2 receptor DRD4, dopamine D4 receptor CYP2A6, cytochrome P450 2A6 CYP2D6, cytochrome P450 2D6. 

Clozapine is the prototype of atypical antipsychotic drugs, and it has been used effectively to treat patients with schizophrenia who are unresponsive or intolerant to typical antipsychotics [7]. Clozapine is characterized as atypical by its preferential binding to serotonin (5-HT2) and dopamine D4 receptors (D4) relative to dopamine D2 receptors [8]. A recent body of work also suggests that atypicality may be defined by the rate at which clozapine dissociates from D2 receptors. Specifically, clo-... 

Ozdemir V, Masellis M, Basile VS, Kalow W, Meltzer HY, Lieberman JA et al. Variability in response to clozapine Potential role of cytochrome P450 1A2 and the dopamine D4 receptor gene. 

Shaikh S, Collier D, Kerwin RW, Pilowsky LS, Gill M, Xu WM et al. Dopamine D4 receptor subtypes and response to clozapine [letter]. Lancet 1993 341 (8837) 116. 

Shaikh S, Collier DA, Sham P, Pilowsky L, Sharma T, Lin LK et al. Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients. American J ournal of Medical Genetics (Neuropsychiatric Genetics) 1995 60 541-545. 

Shields PG et al. Dopamine D4 receptors and the risk of cigarette smoking in... 

Rubinstein, M., Phillips, T. J., Bunzow, J. R. etal. Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 90 991-1001, 1997. 

No new calculations were specifically devoted to this heterocylic system since CHEC-II(1996) <1996CHEC-II(8)249>. However, modeling of bioactive compounds containing this heterocycle have been published as exemplified by the the use of the highly potent dopamine D4 receptor ligand FAUCI 13 as template for comparative molecular field analysis (CoMFA) of dopamine D4 receptor antagonists <2001JME1151 >. 

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Of the genes for the dopamine receptors which have been studied, the candidate gene for the dopamine D4 receptor has been shown to be positively associated with ADHD. However, not all investigators have verified this finding. 

Auerbach, J., Geller, V., Lezer, S., Shinwell, E., Belmaker, R.H., Levine, J., and Ebstein, R. (1999) Dopamine D4 receptor (D4DR) and serotonin transporter promoter (5-HTTLPR) polymorphisms in the determination of temperament in 2-month-old infants. Mol Psychiatry 4 369-373. 

Ebstein, R.P., Novick, O., Umansky, R., Priel, B., Osher, Y., Blaine, D., Bennett, E.R., Nemanov, L., Katz, M., and Belmaker, R.H. (1996) Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of novelty seeking. Nat Genet 12 78-80. 

Faraone, S.V., Doyle, A.E., Mick, E., and Bierderman, J. (2001) Meta-analysis of the association between the 7-repeat allele of the dopamine D4 receptor gene and attention deficit hyperactivity disorder. Am J Psychiatry 158 1052-1057. 

Kohn, Y., Ebstein, R.P., Heresco-Levy, U., Shapira, B., Nemanov, L., Gritenko, I., Avnon, M., and Lerer, B. (1997) Dopamine D4 receptor gene polymorphisms relation to ethnicity., no association with schizophrenia and response to clozapine in Israeli subjects. Eur Neuropsychopharmacol, 7 39-43. 

LaHoste, G., Swanson, J., Wigal, S., Glabe, C., Wigal, T, King, N., and Kennedy, J. (1996) Dopamine D4 receptor gene polymorphism is associated with attention-deficit hyperactivity disorder. Mol Psychiatry 1 128-131. 

Lerman, C., Caporaso, N., Main, D., Audrain, J., Boyd, N.R., Bowman, E.D., and Shields, P.G. (1998) Depression and self-medication with nicotine the modifying influence of the dopamine D4 receptor gene. Health Psychol 17 56-62. 

Hinney, A., Schneider, J., Ziegler, A., Lehmkuhl, G., Poustka, F., Schmidt, M.H., Mayer, H., Siegfried, W., Remschmidt, H., and Hebebrand, J. (1999b) No evidence for involvement of polymorphisms of the dopamine D4 receptor gene in anorexia nervosa, underweight, and obesity. Am J Med Genet, 88 594-597. 

Ebstein, Richard P.,and Robert H. Belmaker. 1997. "Saga of an Adventure Gene Novelty Seeking, Substance Abuse, and the Dopamine D4 Receptor (D4DR) Exon 111 Repeat Polymorphism." Molecular Psychiatry 2 381-84. 

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