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Sex differences in striatal dopamine D2/D3 receptor availability in smokers and non-smokers.

ABSTRACT: In previous research, nicotine-dependent men exhibited lower putamen D2/D3 dopamine-receptor availability than non-smokers (Fehr et al. 2008), but parallel assessments were not performed in women. Women and men (19 light smokers, 18 non-smokers) were tested for differences due to sex and smoking in striatal D(2)/D(3) dopamine-receptor availability, using positron emission tomography with [(18)F]fallypride. Receptor availability was determined using a reference region method, in striatal volumes and in whole-brain, voxel-wise analysis. Significant sex × smoking interactions were observed in the caudate nuclei and putamen. Post-hoc t tests showed that male smokers had significantly lower D(2)/D(3) dopamine-receptor availability than female smokers (-17% caudate, -21% putamen) and male non-smokers (-15% caudate, -16% putamen). Female smokers did not differ from non-smokers. Whole-brain analysis demonstrated no statistically significant voxels or clusters. These results suggest that low receptor availability may confer vulnerability to nicotine dependence or that smoking selectively affects D2/D3 receptor down-regulation in men but not women.

SUBMITTER: Brown AK

PROVIDER: S-EPMC4113216 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Sex differences in striatal dopamine D2/D3 receptor availability in smokers and non-smokers.

Brown Amira K AK Mandelkern Mark A MA Farahi Judah J Robertson Chelsea C Ghahremani Dara G DG Sumerel Brittany B Moallem Nathasha N London Edythe D ED

The international journal of neuropsychopharmacology 20120116 7

In previous research, nicotine-dependent men exhibited lower putamen D2/D3 dopamine-receptor availability than non-smokers (Fehr et al. 2008), but parallel assessments were not performed in women. Women and men (19 light smokers, 18 non-smokers) were tested for differences due to sex and smoking in striatal D(2)/D(3) dopamine-receptor availability, using positron emission tomography with [(18)F]fallypride. Receptor availability was determined using a reference region method, in striatal volumes ...[more]

PMID: 22243762

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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

Sex differences in striatal dopamine D2/D3 receptor availability in smokers and non-smokers.

Publications

Sex differences in striatal dopamine D2/D3 receptor availability in smokers and non-smokers.

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