PLX3397 synthesis Importantly there is marked inter individu

Importantly, there is marked inter-individual variability in the susceptibility to the effects of cannabis (Atakan et al., 2013). One possibility is that inter-individual differences in the impact of cannabis are explained by genetic variation. In this context, an extensively studied vulnerability gene is catechol-methyl-transferase (COMT), which encodes the main catecholamine degrading enzyme COMT. A functional nucleotide polymorphism (SNP) in the COMT gene (rs4680) results in a valine-to-methionine mutation at position 158 (Val158Met). Variation of the COMT Val158Met is associated with dopamine turnover in the prefrontal cortex. Individuals with the COMT Val/Val allele show increased COMT enzyme activity and, consequently, reduced dopamine levels compared to Met homozygotes (Chen et al., 2004, Tunbridge et al., 2006). Epidemiological studies have demonstrated the COMT Val158Met PLX3397 synthesis as a moderator of the association between cannabis use and the later development of psychotic symptoms or schizophrenia (Caspi et al., 2005, Costas et al., 2011, Estrada et al., 2011, Nieman et al., 2016, Vinkers et al., 2013), although not all studies demonstrated consistent findings (De Sousa et al., 2013, van Winkel, 2011, Zammit et al., 2011). In cannabis users, the COMT Val158Met genotype was shown to moderate executive function, with the Val allele associated with poorer performance (Verdejo-Garcia et al., 2013). Experimental studies on COMT modulation of the impact of cannabis showed stronger responses to cannabis or THC in terms of acute psychotic effects and cognitive impairments in individuals with increased COMT activity, particularly in people with a (genetic risk for a) psychotic disorder (Henquet et al., 2006, Henquet et al., 2009). A study by Spronk et al. (2016) in healthy volunteers failed to demonstrate a moderating role of COMT genotype on cannabis-induced effects on reversal learning. Tunbridge et al. (2015) showed that COMT genotype affects the impact of acute THC on working memory performance but not on psychotic experiences in participants vulnerable to paranoia. However, it is unknown how COMT genotype modulates acute THC effects on resting state brain function. The aim of the present study was to investigate the acute effects of THC on resting state brain neurophysiology, and to examine the impact of COMT genotype on these effects. Thirty-nine healthy volunteers participated in a randomised, placebo-controlled, crossover pharmacological MRI study. Acute effects of THC were assessed on resting state perfusion measured with ASL and on resting state connectivity measured with functional MRI. Consistent with previous neuroimaging studies (Mathew et al., 1997, Mathew et al., 2002, van Hell et al., 2011a), we anticipated increased perfusion after THC administration in the insula and frontal cortex. Given the particular role of COMT in prefrontal dopamine degradation (Chen et al., 2004, Tunbridge et al., 2006), we further hypothesised that COMT genotype would modulate perfusion in the executive network, which includes the dorsolateral prefrontal cortex.