Department of Biomedical Sciences, Tufts University Cummings School of Veterinary Medicine, 200 Westboro Road, North Grafton, MA 01536, USA.
Psychopharmacology (Berl). 2013 May;227(2):263-72. doi: 10.1007/s00213-012-2960-1. Epub 2013 Jan 13.
The use and misuse of prescription opiates in adolescent populations, and in particular, adolescent female populations, has increased dramatically in the past two decades. Given the significant role that opioids play in neuroendocrine function, exposure to opiates during this critical developmental period could have significant consequences for the female, as well as her offspring.
In the current set of studies, we utilized the female rat to model the transgenerational impact of adolescent opiate exposure.
We examined locomotor sensitization in response to the dopamine D2/D3 receptor agonist quinpirole in the adult male progeny (F1 and F2 generations) of females exposed to morphine during adolescence. All females were drug-free for at least 3 weeks prior to conception, eliminating the possibility of direct fetal exposure to morphine.
Both F1 and F2 progeny of morphine-exposed females demonstrated attenuated locomotor sensitization following repeated quinpirole administration. These behavioral effects were coupled with increased quinpirole-induced corticosterone secretion and upregulated kappa opioid receptor and dopamine D2 receptor (D2R) gene expression within the nucleus accumbens.
These results suggest significant modifications in response to repeated D2R activation in the progeny of females exposed to opiates during adolescence. Given the significant role that the D2R plays in psychopathology, adolescent opiate exposure could shift the vulnerability of future offspring to psychological disorders, including addiction. Moreover, that effects are also observed in the F2 generation suggests that adolescent opiate exposure can trigger transgenerational epigenetic modifications impacting systems critical for motivated behavior.
在过去的二十年中，青少年人群，尤其是青春期女性人群中，处方类阿片的使用和滥用急剧增加。鉴于阿片类药物在神经内分泌功能中发挥着重要作用，在这一关键发育时期接触阿片类药物可能会对女性及其后代产生重大影响。
在当前的一系列研究中，我们利用雌性大鼠来模拟青春期暴露于阿片类药物对后代的跨代影响。
我们检测了处于青春期的雌性大鼠暴露于吗啡后，其雄性后代（F1 和 F2 代）对多巴胺 D2/D3 受体激动剂喹吡罗的运动敏化反应。所有雌性大鼠在受孕前至少有 3 周的时间没有接触药物，从而消除了胎儿直接接触吗啡的可能性。
暴露于吗啡的雌性大鼠的 F1 和 F2 代后代在反复给予喹吡罗后，运动敏化反应均减弱。这些行为效应伴随着喹吡罗诱导的皮质酮分泌增加，以及伏隔核内κ阿片受体和多巴胺 D2 受体（D2R）基因表达上调。
这些结果表明，青春期暴露于阿片类药物的雌性大鼠的后代对重复 D2R 激活的反应发生了显著改变。鉴于 D2R 在精神病理学中起着重要作用，青春期接触阿片类药物可能会增加后代易患心理障碍（包括成瘾）的风险。此外，在 F2 代中也观察到了这些效应，这表明青春期阿片类药物暴露可以引发影响动机行为关键系统的跨代表观遗传修饰。
