D4 receptor

In the periphery, dopamine receptor levels are generally lower than those observed in brain, particularly in comparison to striatal dopamine receptor levels. Due to these low levels, knowledge of receptor distribution in the periphery is not yet comprehensive. Nevertheless, Dl-like receptors have been reported in the parathyroid gland and in the tubular cells of the kidney. D2-like dopamine receptors have also been observed in the kidney. In addition, dopamine D2 and D4 receptors have been found in the adrenal cortex, where they modulate aldosterone secretion. The... 

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. 

The GABAB-receptors, the muscarinic M2- and IVU-receptors for acetylcholine, the dopamine D2-, D3-and D4-receptors, the a2-adrenoceptors for noradrenaline, the 5-HTiA F-receptors for serotonin, and the opioid p-, 8- and K-receptors couple to G proteins of the Gi/o family and thereby lower [1] the cytoplasmic level of the second messenger cyclic AMP and [2] the open probability ofN- andP/Q-type Ca2+ channels (Table 1). The muscarinic Mr, M3- and M5-receptors for acetylcholine and the ai-adrenoceptors for noradrenaline couple to G proteins of the Gq/11 family and thereby increase the cytoplasmic levels of the second messengers inositol trisphosphate and diacylglycerol (Table 1). The dopamine Dr and D5-receptors and the (3-adrenoceptors for noradrenaline, finally, couple to Gs and thereby increase the cytoplasmic level of cyclic AMP. 

Table 7.3 (a) Dissociation constants (Aj) for various agonists and antagonists at the different dopamine receptors, (b) Indication of specificity for D2 compared with Dj receptors and between D2 (i.e. D2, D3 and D4) receptors... 

Hidaka, K, Tada, S, Matsumoto, M, Ohmori, J, Tasaki, Y, Nomura, T, Usuda, S and Yamaguchi, T (1996) In vitro pharmacological profile of YM-43611, a novel D2-like receptor antagonist with high affinity and selectivity for dopamine D3 and D4 receptors. Brit. J. Pharmacol. 117 1625-1632. 

Strange, PG (1994) Dopamine D4 receptors curiouser and curiouser. Trends Pharmacol. Sci. 15 ... 

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. 

Finnerty, J.P., Wood-Baker, R., Thompson, H. and Holgate, S.T. (1992). Role of leukotrienes in exercise-induced asthma. Inhibitory effect of ICI 204,219, a potent leukotriene D4 receptor antagonist. Am. Rev. Resp. Dis. 145, 746-749. 

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. 

Meador-Woodruff J., Little K., Damask S., Watson S. Effects of cocaine on D3 and D4 receptor expression in the human striatum. Biol. Psych, 38 263, 1995. 

Table 11.4 shows that clozapine has approximately 10 times higher affinity for the D4 and 5-HT2A-receptors than the D2-receptor and shows a greater occupancy of the 5-HT2 than the D2-like receptors. The other atypical neuroleptic risperidone has a similar affinity for the two D2-like receptors but an affinity for the 5-HT2a-receptor that is just over 3 times lower than for the D2-receptor. Receptor occupancy in vivo shows a similar profile to clozapine. In contrast, haloperidol s affinity for the D4-receptor is just under 3 times lower and over 100 times lower for the 5-HT2a-receptor, with no binding to the latter in vivo. The fractional occupancy of striatal... 

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... 

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