PDF(Pubmed)
Abstract：
Adolescence marks a sensitive period for neurodevelopment wherein exposure to drugs of abuse may disrupt maturation and induce persistent changes in neurophysiology which may exacerbate the risk for developing substance use disorders in adulthood. Adolescent nicotine exposure (ANE) enhances motivation to obtain drugs of abuse, particularly opioids, and increases vulnerability for the development of opioid use disorder (OUD). Here, we characterized ANE effects on learning about the adverse consequences of opioid consumption in adulthood in the absence of further nicotine administration. First, we show that ANE engenders punishment resistant fentanyl self-administration in a heterogenous seeking-taking chain schedule of reinforcement at least at the tested dose of fentanyl (0.75 μg/kg). We found that ANE rats consumed significantly more fentanyl and contingent foot shock punishment was less efficacious in limiting fentanyl seeking in ANE rats, relative to nicotine-naïve controls. Next, we demonstrated that ANE limits learning about the deleterious consequences of acute opioid intoxication in adulthood. In a combined conditioned taste avoidance and place preference paradigm we found that ANE resulted in significant reductions in the strength of morphine-induced CTA, and a simultaneous enhancement of CPP at a higher dose that was less capable of driving reinforcement in naïve controls. Finally, we examined the expression of perineuronal nets (PNNs) within insular cortex (IC) and found ANE rats to have increased density of PNNs across the anterior IC and significantly more parvalbumin-labeled IC cells relative to naïve controls. Together, these data lay the framework for a mechanistic explanation of the extreme comorbidity between nicotine use and development of OUDs.
摘要：
青春期标志着神经发育的敏感期，其中暴露于滥用药物可能会破坏成熟并引起神经生理学的持续变化，这可能会加剧成年后发生物质使用障碍的风险。青少年尼古丁暴露（ANE）增强了获得滥用药物的动机，尤其是阿片类药物，并增加了阿片类药物使用障碍（OUD）发展的脆弱性。这里,我们描述了在没有进一步服用尼古丁的情况下,在成年后服用阿片类药物的不良后果方面的ANE效应.首先,我们表明,ANE至少在芬太尼的测试剂量(0.75μg/kg)下,在非均匀的寻求-服用链强化方案中,产生了抗惩罚的芬太尼自我给药.我们发现ANE大鼠消耗了更多的芬太尼，并且偶然的足部休克惩罚在限制ANE大鼠寻求芬太尼方面效果较差，相对于尼古丁天真的对照。接下来,我们证明,ANE限制了对成年期急性阿片类药物中毒的有害后果的了解.在一个组合的条件性味觉回避和位置偏好范例中，我们发现ANE导致吗啡诱导的CTA强度显着降低，并且在较高剂量下同时增强CPP，而在幼稚对照中驱动增强的能力较低。最后,我们检查了岛叶皮质(IC)中神经周网状物(PNNs)的表达,发现ANE大鼠在整个前IC中的PNNs密度增加,并且与未处理过的对照组相比,小清蛋白标记的IC细胞明显增多.一起,这些数据为对尼古丁使用和OUDs发展之间极端共病的机理解释奠定了框架.
