Abstract

Addiction results from drug-elicited alterations of synaptic plasticity mechanisms in dopaminergic reward circuits. Impaired metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) and accumulation of synaptic Ca²⁺-permeable AMPA receptors (CP-AMPARs) following drug exposure have emerged as important mechanisms underlying drug craving and relapse. Here we show that repeated cocaine exposure in vivo causes transient but complete loss of mGluR1- and mTOR (mammalian target of rapamycin)-dependent LTD in layer 5 pyramidal neurons of mouse prefrontal cortex (PFC), a major dopaminergic target in the reward circuitry. This mGluR1-LTD impairment was prevented by in vivo administration of an mGluR1 positive allosteric modulator (PAM) and rescued by inhibition of dopamine D1 receptors, suggesting that impaired mGluR1 tone and excessive D1 signaling underlie this LTD deficit. Concurrently, CP-AMPARs were generated, indicated by increased sensitivity to the CP-AMPAR inhibitor Naspm and rectification of synaptic AMPAR currents, which were reversed by PAM in cocaine-exposed mice. Finally, these CP-AMPARs mediate an abnormal spike-timing-dependent long-term potentiation enabled by cocaine exposure. Our findings reveal a mechanism by which cocaine impairs LTD and remodels synaptic AMPARs to influence Hebbian plasticity in the PFC. Failure to undergo LTD may prevent the reversal of drug-potentiated brain circuits to their baseline states, perpetuating addictive behaviors.

• HIGHLIGHTS

• A mGluR1- and mTOR-dependent LTD is present in the mouse medial prefrontal cortex.

• Repeated cocaine exposure in vivo temporally but completely abolishes prefrontal mGluR1-LTD.

• Impaired mGluR1 function and excessive D1 DA signaling likely underlie cocaine impairment of mGluR1-LTD.

• Ca²⁺-permeable AMPA receptors are generated by cocaine exposure, likely resulting from mGluR1-LTD impairment, and contribute to a cocaine-induced extended spike timing LTP.

摘要

成瘾是由药物引起的多巴胺能奖励回路中突触可塑性机制的改变引起的。受损的代谢型谷氨酸受体 (mGluR) 依赖性长期抑郁症 (LTD) 和突触 Ca ^2+的积累药物暴露后可渗透的 AMPA 受体 (CP-AMPAR) 已成为药物渴望和复发的重要机制。在这里，我们表明体内反复接触可卡因会导致小鼠前额叶皮层 (PFC) 的第 5 层锥体神经元中 mGluR1- 和 mTOR（雷帕霉素的哺乳动物靶点）依赖性 LTD 短暂但完全丧失，PFC 是奖励回路中的主要多巴胺能靶点。这种 mGluR1-LTD 损伤可通过体内施用 mGluR1 正变构调节剂 (PAM) 来预防，并通过抑制多巴胺 D1 受体来挽救，这表明受损的 mGluR1 基调和过度的 D1 信号是这种 LTD 缺陷的基础。同时，产生了 CP-AMPAR，表现为对 CP-AMPAR 抑制剂 Naspm 的敏感性增加和突触 AMPAR 电流的整流，在暴露于可卡因的小鼠中，PAM 逆转了这一点。最后，这些 CP-AMPAR 介导了可卡因暴露导致的异常尖峰时间依赖性长时程增强。我们的研究结果揭示了可卡因损害 LTD 并重塑突触 AMPAR 以影响 PFC 中的 Hebb 可塑性的机制。未能接受 LTD 可能会阻止药物强化脑回路逆转至其基线状态，从而使成瘾行为永久化。

• 强调

• mGluR1 和 mTOR 依赖性 LTD 存在于小鼠内侧前额叶皮层中。

• 体内反复接触可卡因会暂时但完全消除前额叶 mGluR1-LTD。

• mGluR1 功能受损和过度的 D1 DA 信号可能是 mGluR1-LTD 可卡因受损的基础。

• Ca ²⁺ -可渗透的 AMPA 受体由可卡因暴露产生，可能由 mGluR1-LTD 损伤引起，并有助于可卡因诱导的延长尖峰时间 LTP。