Involvement of dorsal striatal α1-containing GABAA receptors in methamphetamine-associated rewarding memories.

Rewarding memories induced by addictive drugs may contribute to persistent drug-seeking behaviors, which is an important contributing factor to drug addiction. However, the biological mechanisms underlying drug-associated rewarding memories have not yet been fully understood, especially the new synthetic drugs, such as amphetamine-type stimulants (ATS). In this study, using the rat-conditioned place preference (CPP) model, a classic animal model for the reward-associated effects of addictive drugs, we found that the expression level of GABAA α1 subunits was significantly decreased in the dorsal striatum (Dstr) after conditioned methamphetamine (METH) pairing, and no significant differences were observed in the other four rewarding memory-associated areas (medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala (Amy), and dorsal hippocampus (DH)). Intra-Dstr injection of either the GABAA receptor agonist muscimol or the specific α1GABAA receptor-preferring benzodiazepine (BDZ) agonist zolpidem significantly abolished METH CPP formation. Thus, this study extends previous findings by showing that GABAA receptors, particularly the α1-containing GABAA receptors, may be strongly implicated in METH-associated rewarding memories. This work provides us with a new perspective on the goal of treating ATS addiction.

p38 mitogen-activated protein kinase activation in amygdala mediates κ opioid receptor agonist U50,488H-induced conditioned place aversion.

κ opioid receptor agonists produce aversive effects in rodents, however the underlying mechanisms remain unclear. Activation of p38 mitogen-activated protein kinase (MAPK) has been discovered to play a critical role in the modulation of affective behaviors. The present study was undertaken to detect the possible involvement of p38 MAPK in the aversive effects induced by κ opioid receptor activation. We found that the κ opioid receptor agonist trans-(±)-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate salt (U50,488H) produced significant place aversion in mice as measured by the conditioned place preference procedure, accompanied with significant p38 MAPK activation in the amygdala, but not in the nucleus accumbens and hippocampus. Stereotaxic microinjection of the p38 MAPK inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridy-l)-1H-imidazole (SB203580) into amygdala significantly inhibited p38 MAPK activation and completely blocked the conditioned place aversion in mice. Thus, these results suggested that activation of p38 MAPK in the amygdala was required to mediate κ opioid receptor-induced aversive behavior.