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

Abstract

of the myelin sheath, decreased levels of NA could reflect suboptimal myelin status in those ultra-high risk individuals who develop a psychotic disorder. This should be further investigated in imaging studies. The present data also suggest that these affected myelin pathways may in particular contribute to the negative symptoms of schizophrenia. Finally, in light of previously observed negative associations between NA and obesity-related risk factors, 12 it is unlikely that the present alterations in NA were simply an epiphenomenon of the metabolic syndrome. The results of our study would have been more convincing if fatty acid data of healthy nonhelp-seeking matched controls had been included in our design. Comparison with healthy well-matched controls has the potential to demonstrate the extent of the reductions in key membrane fatty acid levels and to further elucidate abnormalities of lipid metabolism in ultra-high-risk patients. Our previous observation that supplementation with omega-3 fatty acids may prevent transition to psychosis suggests that the effects of omega-3 fatty acids may offset the risk conferred by low levels of NA. The therapeutic effects of omega-3 fatty acids are complex and not fully understood. Their benefit may result from altered membrane fluidity and receptor responses following their incorporation into cell membranes as well as from interactions with neurotransmitter systems, the antioxidant defense system or the inflammatory system. 13 The efficacy of omega-3 supplementation in patients at ultra-high-risk of psychosis could also imply that the present study was underpowered to detect a significant group difference for DHA. The significant result for the sum of omega-3 fatty acids in the unadjusted analysis supports this view and underscores the importance of omega-3 fatty acids in the prodromal phase of psychosis.

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

“…However, unlike Fusar-Poli et al (2010) who employed dynamic causal modelling to investigate connectivity and reported that CBD but not delta-9-THC altered effective connectivity between the anterior cingulate cortex and the amygdala during emotional processing of fearful stimuli, we employed seed-based functional connectivity approach that allowed us to investigate druginduced changes in connectivity throughout the brain. Opposite effects of delta-9-THC and CBD on connectivity between the prefrontal and medial temporal cortex and striatum are also consistent with previous studies that have reported an acute effect of these drugs on the engagement of these regions during other cognitive and emotional processing paradigms (Bhattacharyya et al, 2009a(Bhattacharyya et al, , 2009b(Bhattacharyya et al, , 2012a(Bhattacharyya et al, , 2012bBorgwardt et al, 2008) as well as evidence from studies that have investigated the chronic effects of cannabis on brain structure and function . Results presented here are also consistent with the role of striatal dopamine in mediating salience processing (Floresco et al, 2003), evidence regarding the effect of cannabinoids on dopaminergic neurotransmission (see Kuepper et al, 2010 for a review) as well as evidence that variation in genes that regulate central dopamine neurotransmission may modulate the effect of delta-9-THC on striatal function that correlates with psychotic symptoms induced under its influence (Bhattacharyya et al, 2012a).…”

“…Opposite effects of delta-9-THC and CBD on connectivity between the prefrontal and medial temporal cortex and striatum are also consistent with previous studies that have reported an acute effect of these drugs on the engagement of these regions during other cognitive and emotional processing paradigms (Bhattacharyya et al, 2009a(Bhattacharyya et al, , 2009b(Bhattacharyya et al, , 2012a(Bhattacharyya et al, , 2012bBorgwardt et al, 2008) as well as evidence from studies that have investigated the chronic effects of cannabis on brain structure and function . Results presented here are also consistent with the role of striatal dopamine in mediating salience processing (Floresco et al, 2003), evidence regarding the effect of cannabinoids on dopaminergic neurotransmission (see Kuepper et al, 2010 for a review) as well as evidence that variation in genes that regulate central dopamine neurotransmission may modulate the effect of delta-9-THC on striatal function that correlates with psychotic symptoms induced under its influence (Bhattacharyya et al, 2012a). Together with the results of our previous study, results presented here suggest that a potential mechanism for the psychotogenic effects of delta-9-THC and in particular its effects on salience processing might lie in its effect on the functional integration of components of a network processing salient information.…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…Thus the use of high amounts of marijuana and ⌬ 9 -THC may produce psychotic symptoms in healthy individuals, including anxiety, hallucinations, and cognitive deficits, which resemble schizophrenia (174), and transiently exacerbate psychotic and cognitive deficits in schizophrenia patients (173). ⌬ 9 -THC can cause acute transient psychotic symptoms in both healthy individuals and schizophrenia patients (593), which may be related to dopamine release in the striatum as shown in humans (68,94) and in the nucleus accumbens and prefrontal cortex in animal models (847). Yet, schizophrenic patients often selfmedicate with marijuana.…”

Neurobiology of Comorbid Substance Use Disorders in Mental Illness: A Closer Look at the Underlying Commonalities between Cannabis and Schizophrenia

“…These investigators also reported an AKT1-cannabis interaction on cognitive performance in that patients with the C/C genotype performed significantly worse on a test of sustained attention compared with T/T carriers [74]. Preliminary experimental evidence has also implicated a different polymorphism of the AKT1 gene (the GG genotype of the SNP rs1130233) as a moderator of sensitivity to the acute psychosisinducing effect of THC [75]. Further characterization of these variants in this comorbidity is warranted.…”