An examination of human post-mortem amygdalae reported a strong positive correlation between GluA1 and PSD-95 mRNA expression in heroin dependent cases, but not in controls (CNIH3 expression was not reported).25 Another study55 observed positive correlations for these proteins with CNIH3 (GluA1 0.43; DLG4 0.28) in (unexposed) mammalian brains. Thus, human25 and animal26 studies provide evidence of altered amygdala GluA1 expression in opioid dependence. The post-mortem report noted25 that similar changes in AMPAR GluA1 subunits occur in the amygdala with associative learning of opioid reward26 and fear conditioning.43–45 Importantly, both processes involve epigenetically-mediated changes in gene expression following an environmental exposure.39,46 We thus examined the effects of our most strongly associated SNP using imaging genetics46,60 and observed significantly greater right amygdala habituation to threat-related facial expression in rs10799590 A allele carriers. Consistent with the reduced risk we observed in opioid exposed individuals, the polymorphism’s protective neural effects were apparent with subsequent, but not initial, exposures to environmental stimuli. The association of this SNP with ODE likely represents a similar protective process involving greater habituation to the neural effects of opioids that impacts additional opioid use.
