Dopaminergic drug response and the genotype (Taq IA polymorphism) of the dopamine D2 receptor
The genotype of the receptor with which a particular drug interacts may be a between- subject factor that modifies the pharmacodynamic and consequently the therapeutic response to drugs. Subjects with A1 allele (Taq IA restriction fragment length polymorphism) of the gene encoding for the dopamine D2 receptor (DRD2) seem to express lower number of DRD2 compared to subjects who do not have this allele. We investigated whether subjects homozygous for the A1 allele of the DRD2 gene have decreased response to DRD2 stimulation by apomorphine when compared with those homozygous for the A2 allele. Two hundred and two Caucasian subjects were genotyped for DRD2 Taq IA polymorphism, 6.9 % had the genotype A1A1 and 65% A2A2. Nine homozygous subjects/group were selected for the apomorphine study. Five, 10 and 20 μg/kg of apomorphine were administered subcutaneously according to a randomized crossover design. The main pharmacodynamic criterion was the plasma growth hormone increase induced by apomorphine. Secondarily, we measured oral temperature responses and yawns in response to apomorphine. Plasma apomorphine concentrations were similar for the two matched and only genotypically different groups. Apomorphine dose-dependently increased serum growth hormone concentration, and significant effect of time, dose by time interaction but no effect of genotype or genotype by dose interaction was shown. Apomorphine decreased body temperature, significant effect of dose, time, dose by time interaction but no effect of genotype or genotype by dose interaction were observed. The number of apomorphine-induced yawns increased dose-dependently but no significant difference between groups occurred. Thus, in this study apomorphine-induced responses were not modified by DRD2 Taq IA polymorphism although the power of the study could be insufficient to detect subtle differences.(Received July 26 1999)
(Reviewed September 13 1999)
(Revised October 27 1999)
(Accepted December 3 1999)
Key Words: Dopamine D2 receptor; Taq IA polymorphism; pharmacodynamic response; healthy subjects.
c1 Address for correspondence: Dr I. Berlin, Département de Pharmacologie, Hôpital Pitié-Salpêtrière, 47 bd de l'Hôpital, 75013 Paris, France. Tel.: 33 1 42 16 16 78 Fax: 33 1 42 16 16 88 E-mail: [email protected]
p1 Present address: SANOFI, Gentilly, France.