Parvalbumin-expressing fast-spiking interneurons (PV-INs) within feedforward microcircuits in the nucleus accumbens (NAc) coordinate goal-directed motivational behavior. Feedforward inhibition of medium spiny projection neurons (MSNs) is initiated by glutamatergic input from corticolimbic brain structures. While corticolimbic synapses onto MSNs are targeted by the psychostimulant, cocaine, it remains unknown whether cocaine also exerts acute neuromodulatory actions at collateralizing synapses onto PV-INs. Using whole-cell patch-clamp electrophysiology, optogenetics, and pharmacological tools in transgenic reporter mice, we found that cocaine decreases thalamocortical glutamatergic drive onto PV-INs by engaging a monoamine-independent mechanism. This mechanism relies on postsynaptic sigma-1 (σ₁) activity, leading to the mobilization of intracellular Ca²⁺ stores that trigger retrograde endocannabinoid signaling at presynaptic type-1 cannabinoid receptors (CB₁R). Cocaine-evoked CB₁R activity occludes the expression of CB₁R-dependent long-term depression (LTD) at this synaptic locus. These findings provide evidence that acute cocaine exposure targets feedforward microcircuits in the NAc and extend existing models of cocaine action on mesolimbic reward circuits.

伏隔核 (NAc) 中前馈微电路中表达小清蛋白的快速尖峰中间神经元 (PV-IN) 协调目标导向的动机行为。中型多刺投射神经元 (MSN) 的前馈抑制是由来自皮质边缘脑结构的谷氨酸能输入启动的。虽然 MSN 上的皮质边缘突触是精神兴奋剂可卡因的目标，但尚不清楚可卡因是否也在 PV-IN 上的抵押突触中发挥急性神经调节作用。在转基因报告小鼠中使用全细胞膜片钳电生理学、光遗传学和药理学工具，我们发现可卡因通过采用一种单胺非依赖性机制来减少丘脑皮质谷氨酸能对 PV-IN 的驱动。这种机制依赖于突触后 sigma-1 (σ ₁) 活性，导致细胞内 Ca ²⁺储存的动员​​，从而触发突触前 1 型大麻素受体 (CB ₁ R) 的逆行内源性大麻素信号传导。可卡因诱发的 CB ₁ R 活性会阻止 CB ₁ R 依赖性长期抑郁症 (LTD) 在该突触位点的表达。这些发现提供的证据表明，急性可卡因暴露以 NAc 中的前馈微电路为目标，并扩展了现有的可卡因作用模型对中脑边缘奖励回路的影响。