Opioid receptors modulate neurochemical and behavioral responses to drugs of abuse in nonclinical models. Samidorphan (SAM) is a new molecular entity that binds with high affinity to human mu- (μ), kappa- (κ), and delta- (δ) opioid receptors and functions as a μ-opioid receptor antagonist with partial agonist activity at κ- and δ-opioid receptors. Based on its in vitro profile, we hypothesized that SAM would block key neurobiological effects of drugs of abuse. Therefore, we assessed the effects of SAM on ethanol-, oxycodone-, cocaine-, and amphetamine-induced increases in extracellular dopamine (DA_ext) in the nucleus accumbens shell (NAc-sh), and ethanol and cocaine self-administration behavior in rats. In microdialysis studies, administration of SAM alone did not result in measurable changes in NAc-sh DA_ext when given across a large range of doses. However, SAM markedly decreased average and maximal increases in NAc-sh DA_ext produced by each of the drugs of abuse tested. In behavioral studies, SAM attenuated fixed-ratio ethanol self-administration and progressive ratio cocaine self-administration. These results highlight the potential of SAM to counteract the neurobiological and behavioral effects of several drugs of abuse with differing mechanisms of action.

阿片受体调节非临床模型中滥用药物的神经化学和行为反应。沙米多芬 (SAM) 是一种新的分子实体，以高亲和力与人类 mu- (μ)、κ- (κ) 和 δ- (δ) 阿片受体结合，并作为 μ-阿片受体拮抗剂发挥作用，在κ- 和 δ-阿片受体。根据其体外特征，我们假设 SAM 会阻断滥用药物的关键神经生物学效应。因此，我们评估了 SAM 对乙醇、羟考酮、可卡因和苯丙胺诱导的伏核壳 (NAc-sh)中细胞外多巴胺 (DA _ext )增加的影响，以及乙醇和可卡因自我给药行为的影响。老鼠。在微透析研究中，单独使用 SAM 不会导致 NAc-sh DA 发生可测量的变化_ext当在大剂量范围内给药时。然而，SAM 显着降低了所测试的每种滥用药物产生的NAc-sh DA _{ext 的}平均和最大增加。在行为研究中，SAM 减弱了固定比例乙醇自我给药和渐进比例可卡因自我给药。这些结果突出了 SAM 抵消具有不同作用机制的几种滥用药物的神经生物学和行为影响的潜力。