TY - JOUR
T1 - New repeat polymorphism in the AKT1 gene predicts striatal dopamine D2/D3 receptor availability and stimulant-induced dopamine release in the healthy human brain
AU - Shumay, Elena
AU - Wiers, Corinde E.
AU - Shokri-Kojori, Ehsan
AU - Kim, Sung Won
AU - Hodgkinson, Colin A.
AU - Sun, Hui
AU - Tomasi, Dardo
AU - Wong, Christopher T.
AU - Weinberger, Daniel R.
AU - Wang, Gene Jack
AU - Fowler, Joanna S.
AU - Volkow, Nora D.
N1 - Funding Information:
PET studies were performed at Brookhaven National Laboratory with infrastructure support from the Department of Energy and the National Institutes of Health Intramural Program (Y1AA3009). We thank Karen Apelskog-Torres for study protocol preparation, and Barbara Hubbard, Maynard Jane and Pauline Carter for participant care. We also thank our study participants
Publisher Copyright:
© 2017 the authors.
PY - 2017/5/10
Y1 - 2017/5/10
N2 - 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.
AB - 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.
KW - AKT1
KW - Dopamine
KW - Dopamine receptor
KW - Methylphenidate
KW - PET
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U2 - 10.1523/JNEUROSCI.3155-16.2017
DO - 10.1523/JNEUROSCI.3155-16.2017
M3 - Article
C2 - 28416594
AN - SCOPUS:85018929431
SN - 0270-6474
VL - 37
SP - 4982
EP - 4991
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 19
ER -