Dataset Information

Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability.

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 [(11)C]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.

SUBMITTER: Shumay E

PROVIDER: S-EPMC3309530 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other

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Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability.

Shumay E E Fowler J S JS Wang G-J GJ Logan J J Alia-Klein N N Goldstein R Z RZ Maloney T T Wong C C Volkow N D ND

Translational psychiatry 20120306

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 b ...[more]

PMID: 22832851

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Project description:The role of the protein kinase Akt1 in dopamine neurotransmission is well recognized and has been implicated in schizophrenia and psychosis. However, the extent to which variants in the AKT1 gene influence dopamine neurotransmission is not well understood. Here we investigated the effect of a newly characterized variant number tandem repeat (VNTR) polymorphism in AKT1 [major alleles: L- (eight repeats) and H- (nine repeats)] on striatal dopamine D2/D3 receptor (DRD2) availability and on dopamine release in healthy volunteers. We used PET and [11C]raclopride to assess baseline DRD2 availability in 91 participants. In 54 of these participants, we also measured intravenous methylphenidate-induced dopamine release to measure dopamine release. Dopamine release was quantified as the difference in specific binding of [11C]raclopride (nondisplaceable binding potential) between baseline values and values following methylphenidate injection. There was an effect of AKT1 genotype on DRD2 availability at baseline for the caudate (F(2,90) = 8.2, p = 0.001) and putamen (F(2,90) = 6.6, p = 0.002), but not the ventral striatum (p = 0.3). For the caudate and putamen, LL showed higher DRD2 availability than HH; HL were in between. There was also a significant effect of AKT1 genotype on dopamine increases in the ventral striatum (F(2,53) = 5.3, p = 0.009), with increases being stronger in HH > HL > LL. However, no dopamine increases were observed in the caudate (p = 0.1) or putamen (p = 0.8) following methylphenidate injection. Our results provide evidence that the AKT1 gene modulates both striatal DRD2 availability and dopamine release in the human brain, which could account for its association with schizophrenia and psychosis. The clinical relevance of the newly characterized AKT1 VNTR merits investigation.SIGNIFICANCE STATEMENT The AKT1 gene has been implicated in schizophrenia and psychosis. This association is likely to reflect modulation of dopamine signaling by Akt1 kinase since striatal dopamine hyperstimulation is associated with psychosis and schizophrenia. Here, using PET with [11C]raclopride, we identified in the AKT1 gene a new variable number tandem repeat (VNTR) marker associated with baseline striatal dopamine D2/D3 receptor availability and with methylphenidate-induced striatal dopamine increases in healthy volunteers. Our results confirm the involvement of the AKT1 gene in modulating striatal dopamine signaling in the human brain. Future studies are needed to assess the association of this new VNTR AKT1 variant in schizophrenia and drug-induced psychoses.

Dataset Information

Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability.

Publications

Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability.

Similar Datasets

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