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 theAKT1gene influence dopamine neurotransmission is not well understood. Here we investigated the effect of a newly characterized variant number tandem repeat (VNTR) polymorphism inAKT1[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 ofAKT1genotype 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 ofAKT1genotype 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 theAKT1gene 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 characterizedAKT1VNTR merits investigation.SIGNIFICANCE STATEMENTTheAKT1gene 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 theAKT1gene 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 theAKT1gene in modulating striatal dopamine signaling in the human brain. Future studies are needed to assess the association of this new VNTRAKT1variant in schizophrenia and drug-induced psychoses.