Toussaint Andre B, Ellis Alexandra S, Bongiovanni Angela R, Peterson Drew R, Bavley Charlotte C, Karbalaei Reza, Mayberry Hannah L, Bhakta Shivam, Dressler Carmen C, Imperio Caesar G, Maurer John J, Schmidt Heath D, Chen Chongguang, Bland Kathryn, Liu-Chen Lee-Yuan, Wimmer Mathieu E
Department of Psychology, Program in Neuroscience Temple University, Philadelphia, PA, USA.
Department of Psychiatry and Behavioral Science, Temple University, Philadelphia, PA, USA.
bioRxiv. 2023 Jan 4:2023.01.03.522600. doi: 10.1101/2023.01.03.522600.
A growing body of preclinical studies report that preconceptional experiences can have a profound and long-lasting impact on adult offspring behavior and physiology. However, less is known about paternal drug exposure and its effects on reward sensitivity in the next generation.
Adult male rats self-administered morphine for 65 days; controls received saline. Sires were bred to drug-naïve dams to produce first-generation (F1) offspring. Morphine, cocaine, and nicotine self-administration were measured in adult F1 progeny. Molecular correlates of addiction-like behaviors were measured in reward-related brain regions of drug naïve F1 offspring.
Male, but not female offspring produced by morphine-exposed sires exhibited dose-dependent increased morphine self-administration and increased motivation to earn morphine infusions under a progressive ratio schedule of reinforcement. This phenotype was drug-specific as self-administration of cocaine, nicotine, and sucrose were not altered by paternal morphine history. The male offspring of morphine-exposed sires also had increased expression of mu-opioid receptors in the ventral tegmental area but not in the nucleus accumbens.
Paternal morphine exposure increased morphine addiction-like behavioral vulnerability in male but not female progeny. This phenotype is likely driven by long-lasting neural adaptations within the reward neural brain pathways.
越来越多的临床前研究报告称，孕前经历可对成年后代的行为和生理产生深远且持久的影响。然而，关于父源药物暴露及其对下一代奖赏敏感性的影响，我们所知甚少。
成年雄性大鼠自行注射吗啡65天；对照组注射生理盐水。让雄鼠与未接触过药物的雌鼠交配，以产生第一代（F1）后代。对成年F1后代进行吗啡、可卡因和尼古丁自行注射测量。在未接触过药物的F1后代的奖赏相关脑区测量类似成瘾行为的分子相关指标。
由接触过吗啡的雄鼠所产的雄性后代（而非雌性后代），在渐进式比率强化程序下，表现出剂量依赖性的吗啡自行注射增加以及获取吗啡注射的动机增强。这种表型具有药物特异性，因为可卡因、尼古丁和蔗糖的自行注射并未因父源吗啡暴露史而改变。接触过吗啡的雄鼠的雄性后代在腹侧被盖区的μ-阿片受体表达也增加，但伏隔核中未增加。
父源吗啡暴露增加了雄性而非雌性后代类似吗啡成瘾的行为易感性。这种表型可能是由奖赏神经脑通路内持久的神经适应性变化驱动的。
