McLaurin Kristen A, Illenberger Jessica M, Li Hailong, Booze Rosemarie M, Mactutus Charles F
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.
Cognitive and Neural Science Program, Department of Psychology, Barnwell College, University of South Carolina, Columbia, SC, USA.
NeuroImmune Pharm Ther. 2025 Jun 30;4(2):237-252. doi: 10.1515/nipt-2025-0002. eCollection 2025 Jun.
Diagnostic criteria for substance use disorder, cocaine type (i.e., cocaine use disorder), outlined in the 5th edition of the , imply that the disorder arises, at least in part, from the maladaptive allocation of behavior to drug use. To date, however, the neural circuits involved in the allocation of behavior have not been systematically evaluated. Herein, a chemogenetics approach (i.e., designer receptors exclusively activated by designer drugs (DREADDs)) was utilized in combination with a concurrent choice self-administration experimental paradigm to evaluate the role of the mesolimbic neurocircuit in the allocation of behavior. Pharmacological activation of hM3D(G) DREADDs in neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (AcbSh) induced a sex-dependent shift in the allocation of behavior in rodents transduced with DREADDs. Specifically, male DREADDs animals exhibited a robust increase in responding for a natural (i.e., sucrose) reward following pharmacological activation of the VTA-AcbSh circuit; female DREADDs rodents, in sharp contrast, displayed a prominent decrease in drug-reinforced (i.e., cocaine) responding. The sequential activation of hM3D(G) and KORD DREADDs within the same neuronal population validated the role of the VTA-AcbSh circuit in reinforced responding for concurrently available natural and drug rewards. Collectively, the VTA-AcbSh circuit is fundamentally involved in behavioral allocation affording a key target for the development of novel pharmacotherapies.
《精神疾病诊断与统计手册》第5版中概述的物质使用障碍（可卡因类型，即可卡因使用障碍）的诊断标准表明，该障碍至少部分源于行为对药物使用的适应不良分配。然而，迄今为止，参与行为分配的神经回路尚未得到系统评估。在此，我们将化学遗传学方法（即仅由设计药物激活的设计受体（DREADDs））与同时选择自我给药实验范式相结合，以评估中脑边缘神经回路在行为分配中的作用。对从腹侧被盖区（VTA）投射到伏隔核（AcbSh）的神经元进行hM3D（G）DREADDs的药理学激活，在转导了DREADDs的啮齿动物中诱导了行为分配的性别依赖性转变。具体而言，雄性DREADDs动物在VTA-AcbSh回路药理学激活后，对天然（即蔗糖）奖励的反应显著增加；与之形成鲜明对比的是，雌性DREADDs啮齿动物在药物强化（即可卡因）反应方面显著减少。在同一神经元群体中依次激活hM3D（G）和KORD DREADDs，验证了VTA-AcbSh回路在对同时可得的天然和药物奖励的强化反应中的作用。总体而言，VTA-AcbSh回路在行为分配中起着根本性作用，为新型药物疗法的开发提供了一个关键靶点。
