Alcohol-induced conditioned place preference negatively correlates with anxiety-like behavior in adolescent mice: inhibition by a neurokinin-1 receptor antagonist

Rationale Although alcohol use disorder and anxiety disorders are highly comorbid in humans, controversy remains regarding whether anxiety predisposes individuals to alcohol reward, and the relationship with neurokinin-1 receptor (NK1R) is unclear. Objectives The objectives of the study are to investigate the association between anxiety-like behavior and alcohol-induced conditioned place preference (CPP) and to examine the effect of NK1R antagonist L-703,606 on this preference and levels of NK1R protein in different brain regions in adolescent mice. Methods The anxiety-like behavior of adolescent male C57BL/6 mice was assessed using the elevated plus maze (EPM) test, and the animals were then allocated into high-anxiety mouse (HAM) and low-anxiety mouse (LAM) groups based on the percent of open arm time (OT%). After the reinforcement of ethanol was established by alcohol-induced CPP (2 g/kg), NK1R expression was quantified in the hippocampus, prefrontal cortex, and amygdala. Finally, the effect of L-703,606 (10 mg/kg) on the alcohol-induced CPP was examined. Results LAM showed a greater ethanol preference (P = 0.004) and a higher level of NK1R protein in the hippocampus (P = 0.026) than HAM group. Interestingly, the CPP score positively correlated with OT% (r = 0.520, P = 0.016) and the level of NK1R protein (r = 0.476, P = 0.029) in the hippocampus. Moreover, L-703,606 attenuated alcohol-induced CPP (P < 0.001) in both groups. Conclusions The present results highlight the negative correlation between anxiety-like behavior and the propensity for alcohol and the critical role for NK1R in alcohol reward in adolescent mice. Importantly, the NK1R antagonist L-703,606 might be a promising therapeutic target for alcohol use disorder.