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- (8 repeats) and H- (9 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 and in 54 we additionally measured [11C]raclopride after a challenge with intravenous methylphenidate to measure dopamine release. Dopamine release was quantified as the difference in specific binding of [11C]raclopride (non-displaceable binding potential) between baseline and methylphenidate.
There was an effect of AKT1 genotype on DRD2 availability at baseline for caudate (F2,90=8.2, p=.001) and putamen (F2,90=6.6, p=.002), but not ventral striatum (p=.3). For caudate and putamen, LL showed higher DRD2 availability than HH; HL were in between. There was also a significant effect of AKT1 genotype on DA increases in ventral striatum (F2,53=5.3, p=.009), with increases being stronger in HH > HL > LL. However, no DA increases were observed in caudate (p=.1) or putamen (p=.8) following methylphenidate. 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.
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 we identified a new variable number tandem repeat (VNTR) marker in the AKT1 gene that was associated with baseline striatal dopamine D2/D3 receptor availability and with methylphenidate-induced striatal dopamine increases in healthy volunteers using PET with [11C]raclopride. Our results corroborate 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.
The authors declare no conflict of interest.
PET studies were carried out at Brookhaven National Laboratory with infrastructure support from the Department of Energy and the NIH Intramural Program (Y1AA3009). We thank Karen Apelskog-Torres for study protocol preparation, and Barbara Hubbard, Maynard Jane and Pauline Carter for participant care. This research was not possible without our study participants.