Abstract
Low dopamine D2 receptor (D2R) levels in the striatum are consistently reported in cocaine abusers; inter-individual variations in the degree of the decrease suggest a modulating effect of genetic makeup on vulnerability to addiction. The PER2 (Period 2) gene belongs to the clock genes family of circadian regulators; circadian oscillations of PER2 expression in the striatum was modulated by dopamine through D2Rs. Aberrant periodicity of PER2 contributes to the incidence and severity of various brain disorders, including drug addiction. Here we report a newly identified variable number tandem repeat (VNTR) polymorphism in the human PER2 gene (VNTR in the third intron). We found significant differences in the VNTR alleles prevalence across ethnic groups so that the major allele (4 repeats (4R)) is over-represented in non-African population (4R homozygosity is 88%), but not in African Americans (homozygosity 51%). We also detected a biased PER2 genotype distribution among healthy controls and cocaine-addicted individuals. In African Americans, the proportion of 4R/three repeat (3R) carriers in healthy controls is much lower than that in cocaine abusers (23% vs 39%, P=0.004), whereas among non-Africans most 3R/4R heterozygotes are healthy controls (10.5% vs 2.5%, P=0.04). Analysis of striatal D2R availability measured with positron emission tomography and [11C]raclopride revealed higher levels of D2R in carriers of 4R/4R genotype (P<0.01). Taken together, these results provide preliminary evidence for the role of the PER2 gene in regulating striatal D2R availability in the human brain and in vulnerability for cocaine addiction.
Highlights
Low D2 receptor (D2R) density has been associated with decreased metabolism in the orbital frontal cortex.[6]
We developed and tested the hypothesis that the PER2 (Period 2) clock gene might contribute to the regulation of D2R expression in the brain and, as such, might be associated with cocaine addiction, based on the following lines of evidence: (1) DA release in the striatum is subject to circadian oscillation;[23] (2) PER2 modulates the reinforcing effects of cocaine in laboratory animals;[24] and (3) individuals suffering from substance-use disorders[25,26] have aberrant patterns of sleep and circadian rhythmicity
We found an association between the PER2 genotype and striatal D2R availability, as well as significant differences in variable number tandem repeat (VNTR) allele frequencies between cocaine abusers and healthy controls that, in combination, point out that this genetic variation can contribute to vulnerability for cocaine addiction and other disorders of behavioral control that are associated with low striatal D2R levels.[39]
Summary
Low striatal dopamine D2 receptor (D2R) levels have consistently been reported in cocaine abusers[1,2,3] and animal models of addiction.[4,5] In humans, low D2R density has been associated with decreased metabolism in the orbital frontal cortex.[6]. Marked differences in individual responses to both acute and chronic cocaine administration are likely to reflect an impact of individual genomic makeup that is modulated by environmental factors.[12,13] Drug addiction is highly heritable (estimated heritability is about 0.72).[14] As a complex nonMendelian disorder, it is likely influenced by many genes;[14] the known candidate genes cannot, explain this level of heritability.[15] Among the most studied candidate genes for substance-use disorders[14] is the DRD2 gene. The individual differences in the DRD2 expression are well established,[16] it is not clear as to how the level of expression is regulated. Many human studies have focused on a single genetic variant, the DRD2/ANKK1 polymorphism (reviewed in ref.17), but inconsistency of the results of those studies[18,19,20] creates the need to identify new genetic targets that have regulatory relationships with the DRD2
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