Opioid addiction has been declared a public health emergency, with fatal overdoses following relapse reaching epidemic proportions and disease-associated costs continuing to escalate. Relapse is often triggered by re-exposure to drug-associated cues, and though the neural substrates responsible for relapse in vulnerable individuals remains ambiguous, the nucleus accumbens (NAc) has been shown to play a central role. NAc direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) can have oppositional control over reward-seeking and associative learning and are critically involved in reinstatement of psychostimulant-seeking. However, whether these pathways similarly regulate reinstatement of opioid-seeking remains unknown, as is their role in modulating motivation to take opioids. Here, we describe a method for classifying addiction severity in outbred rats following intermittent-access heroin self-administration that identifies subgroups as addiction-vulnerable (high-risk) or addiction-resistant (low-risk). Using dual viral-mediated gene transfer of DREADDs, we show that transient inactivation of dMSNs or activation of iMSNs is capable of suppressing cue-induced reinstatement of heroin-seeking in high- but not low-risk rats. Surprisingly, however, the motivation to self-administer heroin was unchanged, indicating a divergence in the encoding of heroin-taking and heroin-seeking in rats. We further show that transient activation of dMSNs or inactivation of iMSNs exacerbates cue-induced reinstatement of heroin-seeking in high- but not low-risk rats, again with no effect on motivation. These findings demonstrate a critical role for dMSNs and iMSNs in encoding vulnerability to reinstatement of heroin-seeking and provide much needed insight into the specific neurobiological changes that occur in vulnerable groups following heroin self-administration.

阿片类药物成瘾已被宣布为公共卫生紧急事件，复发后致命的过量用药已达到流行病的程度，与疾病相关的费用继续上升。复发通常是由重新暴露于与药物相关的线索引发的，尽管导致易感个体复发的神经基质仍然不明确，但伏隔核（NAc）已被证明发挥着核心作用。NAc 直接和间接通路中型多棘神经元（dMSN 和 iMSN）可以对奖励寻求和联想学习具有反向控制，并且在精神兴奋剂寻求的恢复中发挥重要作用。然而，这些途径是否同样调节阿片类药物寻求的恢复以及它们在调节服用阿片类药物的动机中的作用仍然未知。在这里，我们描述了一种对间歇性海洛因自我给药后的近交大鼠成瘾严重程度进行分类的方法，该方法将亚组识别为易成瘾（高风险）或抗成瘾（低风险）。使用 DREADD 的双重病毒介导的基因转移，我们发现 dMSN 的瞬时失活或 iMSN 的激活能够抑制高风险大鼠中线索诱导的海洛因寻求恢复，但对低风险大鼠则不然。然而，令人惊讶的是，自我服用海洛因的动机并没有改变，这表明老鼠吸食海洛因和寻求海洛因的编码存在差异。我们进一步表明，dMSN 的短暂激活或 iMSN 的失活会加剧高风险大鼠（而非低风险大鼠）中线索诱导的海洛因寻求恢复，同样对动机没有影响。这些发现证明了 dMSN 和 iMSN 在编码恢复海洛因寻求的脆弱性方面发挥着关键作用，并为弱势群体在自我服用海洛因后发生的特定神经生物学变化提供了急需的见解。