Spodnick Mary B, Amirault Raymond T, Towner Trevor T, Varlinskaya Elena I, Spear Linda P, Karkhanis Anushree N
Developmental Exposure Alcohol Research Center, Center for Developmental and Behavioral Neuroscience, Department of Psychology, Binghamton University-SUNY, Binghamton, NY 13902, USA.
Brain Sci. 2020 Jul 23;10(8):472. doi: 10.3390/brainsci10080472.
Underage alcohol drinking increases the risk of developing alcohol use disorder (AUD). In rodents, adolescent ethanol exposure augments ethanol consumption and anxiety-like behavior while reducing social interaction. However, the underlying mechanisms driving these adaptations are unclear. The dopamine and kappa opioid receptor (KOR) systems in the nucleus accumbens (NAc) are implicated in affective disorders, including AUD, with studies showing augmented KOR function and reduced dopamine transmission in ethanol-dependent adult animals. Thus, here we examine the impact of adolescent intermittent ethanol (AIE) exposure on dopamine transmission and KOR function in the NAc. Rats were exposed to water or ethanol (4 g/kg, intragastrically) every other day during early (postnatal day (PD) 25-45) or late (PD 45-65) adolescence. While AIE exposure during early adolescence (early-AIE) did not alter dopamine release in male and female rats, AIE exposure during late adolescence (late-AIE) resulted in greater dopamine release in males and lower dopamine release in females. To determine the impact of AIE on KOR function, we measured the effect of KOR activation using U50,488 (0.01-1.00 µM) on dopamine release. Early-AIE exposure potentiated KOR-mediated inhibition of dopamine release in females, while late-AIE exposure attenuated this effect in males. Interestingly, no differences in KOR function were observed in early-AIE exposed males and late-AIE exposed females. Together, these data suggest that AIE exposure impact on neural processes is dependent on sex and exposure timing. These differences likely arise from differential developmental timing in males and females. This is the first study to show changes in KOR function following AIE exposure.
未成年人饮酒会增加患酒精使用障碍（AUD）的风险。在啮齿动物中，青春期接触乙醇会增加乙醇摄入量和焦虑样行为，同时减少社交互动。然而，驱动这些适应性变化的潜在机制尚不清楚。伏隔核（NAc）中的多巴胺和κ阿片受体（KOR）系统与包括AUD在内的情感障碍有关，研究表明，在乙醇依赖的成年动物中，KOR功能增强，多巴胺传递减少。因此，在这里我们研究青春期间歇性乙醇（AIE）暴露对NAc中多巴胺传递和KOR功能的影响。在青春期早期（出生后第（PD）25 - 45天）或晚期（PD 45 - 65天），每隔一天给大鼠经胃内给予水或乙醇（4 g/kg）。虽然青春期早期接触AIE（早期AIE）并未改变雄性和雌性大鼠的多巴胺释放，但青春期晚期接触AIE（晚期AIE）导致雄性大鼠多巴胺释放增加，雌性大鼠多巴胺释放减少。为了确定AIE对KOR功能的影响，我们测量了使用U50,488（0.01 - 1.00 μM）激活KOR对多巴胺释放的影响。早期AIE暴露增强了雌性大鼠中KOR介导的多巴胺释放抑制作用，而晚期AIE暴露则减弱了雄性大鼠中的这种作用。有趣的是，在早期AIE暴露的雄性大鼠和晚期AIE暴露的雌性大鼠中未观察到KOR功能的差异。总之，这些数据表明AIE暴露对神经过程的影响取决于性别和暴露时间。这些差异可能源于雄性和雌性不同的发育时间。这是第一项显示AIE暴露后KOR功能变化的研究。
