Reducing levels of the GABA-synthesis enzyme GAD67 in the dorsal striatum of mice increased depression-like behavior but decreased anxiety. The reduction also heightened the rewarding effect of ketamine, measured by conditioned place preference, but did not alter the reward behavior triggered by the cannabinoid agonist JWH-018. The findings suggest that lower striatal GAD67 weakens GABAergic signaling, which may make the brain more vulnerable to ketamine's reward effects by enhancing NMDA receptor inhibition.
In mice, 18 abused drugs (including cocaine, methamphetamine, and several synthetic cannabinoids and cathinones) were tested using intracranial self-stimulation (ICSS) of the medial forebrain bundle to assess their reward-seeking potential. Dopamine transporter (DAT) availability in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) significantly correlated with the ICSS threshold after drug treatment. Extracellular dopamine and calcium levels in PC-12 cells also correlated with the ICSS threshold. The findings suggest that drug-induced reward-seeking behavior may be linked to DAT availability-mediated extracellular dopamine levels in the mPFC and NAc.