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The Regulation of D2 Dopamine Receptor Expression Molecular Psychiatry (1998) 3, 198–203 1998 Stockton Press All rights reserved 1359–4184/98 $12.00 NEWS & VIEWS The regulation of D2 dopamine receptor expression The question of whether or not there is a polymorphism in or near DRD2 which is associated with receptor density remains unanswered. Both clinical and animal data demonstrate that D2 dopamine receptor density is highly variable among individuals; differences of more than 100% are not uncommon. Among inbred mouse strains and F2 intercrosses produced from these strains, it appears that most of the genetic variation in receptor expression is not asso- ciated with polymorphisms in or near Drd2. Two reports in this issue of Molecular Psychiatry1,2 real. The schizophrenics actually showed a trend in the refocus our attention on an issue that has been contro- opposite direction, although these data may be con- versial for almost a decade, namely, ‘Is there a poly- founded by prior neuroleptic exposure. Overall, after morphism in or near DRD2 which is associated with reading these two reports, one is left in the rather the regulation of receptor density?’ Laruelle et al1 unsatisfying position of still being unsure as to whether examined the effects of both the Taq1 ‘A’ and ‘B’ poly- or not the A1 allele is associated with lower binding morphisms on D2 receptor-binding potential (Bmax/Kd) potential. using SPECT technology with the ligand 123I-IBZM in To understand the importance of this issue, it is 70 subjects; a previous postmortem study suggested necessary to put the studies in the proper historical that the A1 allele was associated with a mutation that perspective. Both studies trace their origin to the obser- decreases receptor expression.3 Laruelle et al1 found vation of Blum et al4 that there was an association that the A1 carriers (subjects homozygous or hetero- between the A1 allele and alcoholism. Some5–12 but not zygous for the allele) had the same binding potential all13–17 subsequent studies have confirmed this associ- as the non-carriers. Similarly, they found that the poly- ation for alcoholism and stimulant abuse. Population morphisms of the Taq1 ‘B’ system, which is in strong stratification is a potentially important confound in linkage disequilibrium with the ‘A’ system, had no studies of the A1 allele. Barr and Kidd18 examined 381 effect on binding potential. Pohjalainen et al2 exam- people from 16 different populations and found that ined the relationship between the Taq1 ‘A‘ system the frequency of the A1 allele varies widely from 0.09 polymorphisms and binding potential using PET and to 0.75. These significant differences make it impera- 11C-raclopride in 54 Finnish normal volunteers. A sig- tive that one should control for the ethnic origin of sub- nificant decrease (15–20%) in binding potential was jects when performing an association study with the found for the A1/A2 heterozygotes as compared to A1 allele; lack of concern for this issue appeared to be A2/A2 homozygotes; the effect was sustained after the a problem in some of the earlier studies. A recent study data were age or gender adjusted. Can the different by Chen et al19 illustrates the importance of this point. results between the two studies be explained? Both These authors examined the relationships among Taq1 groups used a substituted benzamide as the receptor and NcoI D2 receptor polymorphisms and alcoholism ligand, reported the data as binding potential and the in four aboriginal groups and the Han (Chinese) in Tai- A1 allele frequency was similar in the two study popu- wan. Haplotype analysis revealed a significant associ- lations. There was however, an important experimental ation of the A1N1 haplotype and alcoholism only in difference, namely the reduced coefficient of variation the Ami (one of the aboriginal populations) and the in the PET study. Thus, the Pohjalainen et al2 study Han. The authors conclude that the absence of the had significantly greater power to detect a small differ- association between the polymorphisms in DRD2 and ence. This point becomes important when one con- alcoholism in three of the aboriginal populations sug- siders that the study population used by Laruelle et al1 gests either a higher rate of phenocopies among abor- was composed of 47 normal controls and 23 schizo- iginal alcoholics or genetic heterogeneity in the suscep- phrenics. Among the normal control A1 carriers there tibility to alcoholism. was a trend to a lower binding potential but the sample The emphasis on the relationships between DRD2 size had insufficient power to detect the difference, if and alcohol/substance abuse builds from the proposed role of the D2 dopamine system in reward mech- anisms20 and from the in vivo observations that chronic Correspondence: Dr RJ Hitzemann, Dept of Psychiatry, SUNY at Stony Brook, Stony Brook, NY 11794-8101, USA. E-mail: rhitzem- alcoholics, cocaine and heroin abusers have a lower annȰmail.psychiatry.sunysb.edu D2 receptor-binding potential which persists (for up to Received and accepted 28 January 1998 months) after drug withdrawal.21–25 The receptor data News & Views 199 come largely from a single group of investigators.22–24 potential are due either to environmental effects or It is important to note that in these studies the genetic effects on receptor density. The strongest evi- alcoholics and cocaine addicts were a highly selected dence that some of this receptor variance is related to group. For example, the alcoholics needed to use Ͼ3g genetic factors comes from animal studies. A useful of ethanol kg−1 daily but needed to be otherwise medi- starting point for reviewing this literature is the work cally stable, not abusing other substances and with a of Helmeste and Seeman38 and Ciarenello and family history positive for alcoholism. Approximately Boehme.39 These authors used membrane-binding one out of 20 alcoholics screened met these study cri- assays to examine striatal D2 receptor density among teria. The selection of the cocaine addicts was similarly inbred mouse strains; a difference among inbred strains stringent; importantly, from the genetic perspective, all is presumed to be of genetic origin. Five inbred strains of these subjects were also family history positive for were common to both studies; importantly the relative substance or alcohol abuse. For the cocaine addicts the order of receptor density for the three most commonly reduction of D2 receptor-binding potential was used strains in biomedical research was similar with detected in two separate studies, using two different the BALB/cJ Ͼ C57BL/6J (C57) Ͼ DBA/2J (DBA). receptor ligands.23,24 In none of the studies was it poss- Receptor density in the BALB/cJ strain was 60–80% ible to determine if the binding potential returned to higher than in the DBA strain. Subsequent studies40– normal. Thus, there are no data which support either 44 have confirmed that there is a marked difference in a ‘state’ or ‘trait’ mechanism for the lower binding receptor density among inbred mouse strains. How- potential. ever, it is important to note that the relative difference Interest in D2 receptor genetics also builds from the among strains depends on the region examined. For putative role of the D2 receptor system in a wide variety example, the C57 strain has a higher receptor density of neuropsychiatric disorders. For example, some data than the DBA strain in the striatum43,44 but a lower suggest that schizophrenics have a higher receptor den- receptor density in the substantia nigra and ventral teg- sity than controls and this difference is not the result mental area;44 the latter difference in part is related to of neuroleptic exposure.26 However, most27–29 but not a higher number of midbrain dopamine neurons in the all studies30 have been unable to detect a significant DBA strain.45 Differences in receptor density have also association between polymorphisms in DRD2 and been found among inbred rat strains in some46–48 but schizophrenia. Negative results have also been not all studies.49 Luedtke et al49 also examined the dif- obtained for affective disorders,31,32 obsessive compul- ferences among five inbred rat strains in the ratio of D2 sive disorder33 and Tourettes’ syndrome;34 in contrast, receptor mRNA for the long and short splice variants a positive association has been reported for (the long and short splice variants differ by a 29-amino schizoid/avoidant behaviors.35 These largely negative acid insert in the third cytoplasmic loop). No differ- results should not be unexpected; as will be shown ence in the long and short isoforms of the mRNA was below, most of the variance in receptor expression is noted among the strains. Similarly, we have found no probably not associated with polymorphisms in DRD2. difference in the ratio of the splice variants between There is remarkable variation among individuals in the C57 and DBA inbred mouse strains; further the the apparent availability of D2 receptors. The coef- amino acid sequences in both strains are identical ficients of variation in the studies of Laruelle et al1 and (unpublished observations). Pohjalainen et al2 range from 30 to 50%. Thus, those An important confound to detecting differences in individuals more than and less than one standard devi- D2 receptor density is the age at which the measure- ation from the mean will differ from each other by ments are made. For example, Lephohon-Greenwood 50 more than 85% in receptor-binding potential. Some of and Cinader examined D2 receptor binding among the difference among individuals may be associated females of five inbred strains (C57BL/6, SJL, A, DBA/1 with differences in synaptic dopamine concentrations. and C3H/He). At 7–15 weeks of age (the time of Both raclopride and IBZM have a ‘relatively’ low affin- measurement in most laboratory experiments), the Ͻ Ͻ = ity for the D2 receptor and thus, significant receptor order of receptor binding was C57 SJL A DBA/1 competition is expected between either of these ligands = C3H and the range of receptor density values was and endogenous dopamine.
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