Dopamine receptors polymorphisms

With respect to other ethnic groups, African Americans may have a differential sensitivity to weight gain on clozapine (de Leon etal, 2007). They may also require lower doses than Caucasians (Kelly et al, 2006) and inter-individual as well as ethnic responsiveness maybe partly explained by differences in dopamine receptor polymorphisms (Hwang et al, 2005). It is conceivable that side effects may also be differentially expressed based on pharmacodynamic differences resulting from polymorphisms in other receptor types (histaminergic, muscarinic, etc.). This area remains largely unexplored with respect to ethnic differences in antipsychotic side effects. 

Xing, Q., Qian, X., Li, H., et al. (2006) The relationship between the therapeutic response to risperidone and the dopamine receptor polymorphism in Chinese schizophrenia patients. Int. J. Neuropsychopharmacol. 10, 631-637. 

Scharfetter, J. Dopamine receptor polymorphisms and drug response in schizophrenia. Pharmacogenomics 2001,... 

Ritchie T, Noble EP (1996) [3H]naloxone binding in the human brain alcoholism and the TaqI A D2 dopamine receptor polymorphism. Brain Res 718 193-197... 

Caporaso N et al. The genetics of smoking the Dopamine receptor (DRD2) and transporter polymorphisms in a smoking cessation study. Proc Am Assoc Cancer Res 1997 38(March 1997) 168. 

Thompson J et al. D2 dopamine receptor gene (DRD2) Taql A polymorphism reduced dopamine D2 receptor binding in the human striatum associated with the Al allele. Pharmacogenetics 1997 7(6) 479-484. 

Essential Hypertension GRK4 Polymorphisms and Excessive Phosphorylation of the Dopamine Receptor... 

Caveats aside, the five dopamine receptors remain candidates in disease. The pharmacological properties that have been used to group them into dopamine Dj-like and dopamine D -like receptors may also be useful to consider when surveying the dopamine receptor gene association studies. For the most part, the D -like dopamine receptors Dj (50-52) and Dj (53) have not been as widely associated with disease as the D dopamine receptors. The D -like receptors D (54), D3 (55), and D (56) have similar dopamine sensitivities and are much more polymorphic than the Dj-like receptors (49,57). 

The dopamine D -like receptor polymorphisms include SNPs, variable-number tandem repeats (VNTRs), and splice variants (58,59). The polymorphic forms of the dopamine D receptor, for example, manifest as variable numbers of 48-bp repeat sequences (denoted D j to D., ) (49). 

By contrast, studies of the dopamine D -like receptors have found evidence for the association of the receptor with disease (66) these studies have been replicated (41,42). From among the multitude of these studies, only selected examples are reviewed here. For example, evidence both for and against the association of the dopamine D -like receptors with schizophrenia has been reported. Polymorphisms of the dopamine receptor, including the third intracellular loop VNTR, alter dopamine receptor expression. In addition to association with schizophrenia (3,67-70), the dopamine polymorphisms have been associated with the genetic basis of the variable efficacy of antipsychotics such as clozapine (or neuromuscular toxicity—tardive dyskinesia) (69,71,72). Similarly, promoter SNPs have been associated with altered clozapine efficacy (67,68,73). 

The gene encoding the pj-adrenergic receptor displays a fair degree of polymorphism in the human population. Like the dopamine receptors, the p -adrenergic receptor variants are often relevant to pharmacogenetics. Constitutively active mutant (CAM) and loss-of-function (LOF) variants are in evidence. 

Dmitrzak-Weglarz, M., Rybakowski, J. K., Slopien, A., et al. (2006) Dopamine receptor D gene —48A/G polymorphism is associated with bipolar fllness but not with schizophrenia in a Polish population. Neuropsychobiology. 53, 46-50. 

Strobel, A., Lesch, K. P., Hohenberger, K., et al. (2002) No association between dopamine receptor gene exon III and -521C/T polymorphism and novelty seeking. Mol. Psychiatry. 7, 537-538. 

Lerer, B., Segman, R. H., Fangerau, H., et al. (2002) Pharmacogenetics of tardive dyskinesia combined analysis of 780 patients supports association with dopamine receptor gene Ser9Gly polymorphism. Neuropsychopharmacology. 27, 105-119. 

Wu X, Hudmon KS, Detry MA, et al (2000) D2 dopamine receptor gene polymorphisms among African-Americans and Mexican-Americans a lung cancer case-control study. Cancer Epidemiol Biomarkers Prev 9 1021-1026... 

Rowe, D., Stever, C., Giedinghagen, L., Gard, J., Cleveland, H., Terris, S., Mohr, J., Sherman, S., Abramowitz, A., and Waldman, I. (1998) Dopamine DRD4 receptor polymorphism and attention-deficit hyperactivity disotdet. Mol Psychiatry 3 419-426. 

Smith, Stevens S., Bruce F. O Hara, Antonio M. Persico, David A. Gorelick, David B. Newlin, David Vlahov, Liza Solomon, Roy Pickens, and George R. Uhl. 1992. "Genetic Vulnerability to Drug Abuse The D2 Dopamine Receptor Taq I B1 Restriction Fragment Length Polymorphism Appears More Frequently in Polysubstance Abuse." Archives of General Psychiatry 49 723-27. 

Noble, E.P. Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene a review. Eur. Psychiatry 2000, 15, 79-89. 

Makoff AJ, Graham JM, Arranz MJ, Forsyth J, Li T, Aitchison KJ, Shaikh S, Grunewald RA. Association study of dopamine receptor gene polymorphisms with drug-induced hallucinations in patients with idiopathic Parkinson s disease. Pharmacogenetics 2000 10(l) 43-8. 

Reports of association of the dopamine D2-like receptors with psychiatric phenotypes are more common [57, 66]. One such finding is an association between schizophrenia and dopamine D4 receptor variants that appear to alter dopamine D4 receptor expression. Dopamine D4 polymorphisms also appear relevant to the efficacy and the neuromuscular toxicity (tardive dyskinesia) of antipsychotics such as clozapine [67-73]. 

In contrast to these data on the dopamine D2, the contribution of dopamine D4 polymorphisms to disease is less well understood— although increased levels of dopamine D4 receptor expression in schizophrenia appear to be reproducible in independent studies [71, 72] and may be associated with a Vall94Gly polymorphism [68, 69]. Disorders such as attention-deficit/hyperactivity disorder (ADHD) [74-77] and novelty-seeking behavior [78-80] have also been associated with the D4 dopamine receptor, albeit not consistently [74-80]. 

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