Cannabis use can induce acute psychotic symptoms1 and increase the long-term risk of schizophrenia,2 but there is a marked interindividual variability in the susceptibility to these effects. The latter is thought to have a genetic basis, but it is unclear which particular genes are responsible. Here we show that the acute psychotogenic effects of cannabis are moderated by two genes that code for proteins that influence dopamine metabolism, and modulate the effects of the drug on midbrain and striatal function.
The effects of cannabis on psychosis are mediated by its constituent δ-9-tetrahydrocannabinol (δ-9–THC).1 Induction of psychotic symptoms by δ-9-THC is related to its effect on the striatum,1 a brain region rich in dopaminergic terminals. Direct measurement of the effects of δ-9-THC on central dopaminergic transmission in man have been less clear, with two studies showing evidence of an increase in the striatum3 and extrastriatal regions,4 and another showing no effect in the striatum.5 However, animal studies (reviewed in ref. 6) have unequivocally demonstrated an effect of δ-9-THC on central dopaminergic transmission. The marked interindividual variation in the psychotic effects of cannabis may therefore reflect differences in genes that influence the transmission or metabolism of brain dopamine. We tested this hypothesis by examining the effects of variation in the genes for the dopamine transporter (DAT1, which removes dopamine from central synapses7) and the protein kinase B (AKT1, an integral component of the dopamine signaling cascade8) on the symptomatic and neurophysiological response to δ-9-THC. The human DAT1 gene has a polymorphic 40 bp variable number of tandem repeats (VNTR) in the 3′ untranslated region (UTR), with several alleles ranging from 3 to 11 copies of the 40-bp repeats, the 9-repeat and 10-repeat alleles being the most common. The DAT1 3′ UTR VNTR modulates activity in the striatum7, 9 and midbrain,9 and its 9-repeat allele is associated with higher synaptic dopamine levels than the 10-repeat counterpart.10 AKT1 has recently been implicated in mediating the effects of cannabis on psychosis,11 and variants of both genes have been linked with schizophrenia in genetic association studies.12, 13, 14
Employing an established repeated measures, placebo-controlled, within-subject design1 (Supplementary Material), we examined the acute effects of δ-9-THC on psychotic symptoms and regional brain activation in 35 healthy volunteers who had minimal previous cannabis use and had been genotyped for the DAT1 3′ UTR VNTR and the AKT1 rs1130233 polymorphisms. Symptomatic effects of δ-9-THC were recorded using standard psychopathological instruments. The blood oxygen level dependent response was measured while subjects performed a verbal learning task1 inside a magnetic resonance imaging scanner.
There was a main effect of DAT1 genotype (F1,31=7.46, P=0.01; 9-repeat carriers >10-repeat homozygotes) and a trend for a main effect of AKT1 genotype (F1,31=3.42, P=0.07; G homozygotes > heterozygotes) on the increase in psychotic symptoms induced by δ-9-THC. There was also an interaction (F1,31=4.49, P=0.04) between the effects of the DAT1 and AKT1 genotypes on the symptomatic effect of δ-9-THC; the increase in symptoms was greater in individuals who were G homozygotes of AKT1 rs1130233 and also carriers of the 9-repeat allele of the DAT1 3′UTR VNTR (hereafter referred to as GG/9-repeat carrier; n=7), relative to those that were not (hereafter referred to as REST; n=28) (P<0.001; post-hoc testing; Figure 1a and Supplementary Figures 1 and 2; Supplementary Tables 1–6).
This was associated with an interaction between the effects of DAT1 and AKT1 genotype and of δ-9-THC on activation in the striatum during encoding, and in the midbrain during recall (Supplementary Material). During encoding, following placebo, individuals who were G homozygotes of AKT1 and carriers of the 9-repeat allele (DAT1 3′UTR VNTR) showed strong striatal activation, whereas there was a little response in the REST (Figure 1b). δ-9-THC markedly attenuated the striatal activation in GG/9-repeat carrier individuals, but had a minimal effect in the REST group. Similarly, during the recall condition, following placebo, subjects who were homozygotes for the G allele of AKT1 and carriers of the 9-repeat allele for the DAT1 3′UTR VNTR showed strong activation in the midbrain, whereas there was only a modest response in the REST (Figure 1c). Administration of δ-9-THC led to deactivation in the midbrain in GG/9-repeat carrier individuals, but had little effect on the response in the REST group. This interaction at the neurophysiological level was not secondary to effects at the behavioral level, as there were no significant interactions between δ-9-THC and genotype on task performance.
To confirm the role of the striatum and midbrain in mediating the psychotic effects of δ-9-THC, we examined the relationship between its effect on activation in these regions and its effect on psychotic symptoms. In both areas, there was a correlation between the neurophysiological effects of δ-9-THC and the severity of psychotic symptoms it induced: the more δ-9-THC attenuated striatal and midbrain activation, the greater the severity of the psychotic symptoms (Figures 1d and e).
While these results should be considered as preliminary and need independent replication, they are consistent with the effects of the DAT1 3′UTR VNTR on midbrain and striatal activity7, 9 and the activation of striatal AKT115 by δ-9-THC. They are also consistent with independent epidemiological11, 16 and experimental17, 18 evidence that heritable variations in dopamine neurotransmission affecting the signaling cascade or synaptic availability of dopamine moderate sensitivity to the acute17, 18 and long-term11, 16 effects of cannabis on psychosis and extend this further by describing how such an effect may be mediated in the brain. Together, they suggest that individuals carrying the risk variants of either the DAT1 3′UTR VNTR or the AKT1 rs130233 polymorphisms have an increased sensitivity to the psychotic effects of δ-9-THC, but that this is especially increased in subjects who carry both these variants. Furthermore, this effect involves an alteration in the neural response to δ-9-THC in the dopamine-rich regions of striatum and midbrain, consistent with independent evidence that the psychotic effects of cannabis are mediated by dopamine.1, 3
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Dr Sagnik Bhattacharyya was supported by a Joint MRC/Priory Clinical research training fellowship from the Medical Research Council, UK. The authors also acknowledge financial support from Generalitat de Catalunya (SGR 2009/1435) and the National Institute for Health Research (NIHR) Specialist Biomedical Research Centre for Mental Health award to the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King's College London, and the ongoing support of the Wellcome Trust and EPSRC toward the Medical Engineering Centre within King's College London.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Bhattacharyya, S., Atakan, Z., Martin-Santos, R. et al. Preliminary report of biological basis of sensitivity to the effects of cannabis on psychosis: AKT1 and DAT1 genotype modulates the effects of δ-9-tetrahydrocannabinol on midbrain and striatal function. Mol Psychiatry 17, 1152–1155 (2012). https://doi.org/10.1038/mp.2011.187
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