Alonso-Caraballo Y, Li Y, Constantino N J, Neal M A, Driscoll G S, Mavrikaki M, Bolshakov V Y, Chartoff E H
Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
Department of Neuroscience & Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, MN, USA.
bioRxiv. 2024 Aug 7:2024.08.01.605459. doi: 10.1101/2024.08.01.605459.
Opioid use disorder is marked by a progressive change in the motivation to administer the drug even in the presence of negative consequences. After long periods of abstinence, the urge to return to taking the drug intensifies over time, known as incubation of craving. Conditioned responses to drug-related stimuli, can acquire motivational properties and exert control over motivated behaviors leading to relapse. Although, preclinical data suggest that the behavioral expression of opioid use is similar between male and female rodents, we do not have conclusive results on sex differences on craving and relapse across abstinence periods. Here, we investigated the effects of abstinence from oxycodone self-administration on neurotransmission in the paraventricular thalamus (PVT) to nucleus accumbens shell (NAcSh) pathway in male and female rats. Using optogenetics and electrophysiology, we assessed synaptic strength and glutamate release probability in this pathway, as well as NAcSh medium spiny neurons (MSN) intrinsic excitability, in slices from rats which were subjected to either 1 (acute) or 14 (prolonged) days of forced abstinence after self-administration. Our results revealed no sex differences in oxycodone self-administration or somatic withdrawal symptoms following acute abstinence. However, we found a sex-specific enhancement in cue-induced relapse after prolonged, but not acute, abstinence from oxycodone self-administration, with females exhibiting higher relapse rates. Notably, prolonged abstinence led to similar increases in synaptic strength at PVT-NAcSh inputs compared to saline controls in both sexes, which was not observed after acute abstinence. Thus, prolonged abstinence results in a time-dependent increase in PVT-NAcSh synaptic strength and sex-specific effects on cue-induced relapse rates. These findings suggest that prolonged abstinence leads to significant synaptic changes, contributing to heightened relapse vulnerability, highlighting the need for targeted therapeutic strategies in opioid use disorder.
阿片类物质使用障碍的特征是，即使存在负面后果，用药动机仍会逐渐改变。经过长时间戒断后，复吸药物的冲动会随着时间的推移而增强，这被称为渴求潜伏期。对与药物相关刺激的条件反应可获得动机属性，并对导致复发的动机行为施加控制。尽管临床前数据表明，雄性和雌性啮齿动物在阿片类物质使用的行为表现上相似，但我们尚未得到关于不同性别在不同戒断期的渴求及复发方面差异的确切结果。在此，我们研究了雄性和雌性大鼠从羟考酮自我给药中戒断后，对从室旁丘脑（PVT）到伏隔核壳（NAcSh）通路神经传递的影响。我们使用光遗传学和电生理学方法，评估了该通路中的突触强度和谷氨酸释放概率，以及在自我给药后经历1天（急性）或14天（延长）强制戒断的大鼠脑片中NAcSh中型多棘神经元（MSN）的内在兴奋性。我们的结果显示，急性戒断后，羟考酮自我给药或躯体戒断症状方面不存在性别差异。然而，我们发现，从羟考酮自我给药中延长（而非急性）戒断后，线索诱导的复发存在性别特异性增强，雌性的复发率更高。值得注意的是，与生理盐水对照组相比，延长戒断导致两性的PVT - NAcSh输入突触强度均有类似增加，急性戒断后未观察到这种情况。因此，延长戒断会导致PVT - NAcSh突触强度随时间增加，并对线索诱导的复发率产生性别特异性影响。这些发现表明，延长戒断会导致显著的突触变化，增加复发易感性，突出了针对阿片类物质使用障碍制定靶向治疗策略的必要性。
