BACKGROUND Serotonin (5-HT) 1B/1D receptor (5-HT1B/1DR) agonists undergo an abstinence-induced switch in their effects on cocaine-related behaviors, which may involve changes in modulation of dopamine (DA) neurons in the ventral tegmental area (VTA). However, it is unclear how 5-HT1B/1DRs affect VTA DA neuronal function and whether modulation of these neurons mediates the abstinence-induced switch after chronic cocaine exposure. METHODS We examined the ability of 5-HT1B/1DRs to modulate D2 autoreceptors (D2ARs) and synaptic transmission in the VTA by slice recording and single unit recording in vivo in naïve mice and in mice with chronic cocaine treatment. RESULTS We report a bidirectional modulation of VTA DA neuronal firing through the interaction of VTA 5-HT1B/1DRs and D2ARs. In both VTA slices and the VTA of anesthetized mice, the 5-HT1B/1DR agonist CP94253 decreased DA neuronal firing rate and evoked excitatory postsynaptic currents to DA neurons in slice. Paradoxically, CP94253 decreased quinpirole-induced inhibition of DA neurons by reducing D2AR-mediated G protein-gated inwardly rectifying potassium current. This manifested decreased GABAA (gamma-aminobutyric acid A) receptor-mediated evoked inhibitory postsynaptic currents in slice, resulting in disinhibition of DA neurons, in opposition to the 5-HT1B/1DR-induced inhibition. This dual effect was verified in chronic cocaine-treated and mild stress-treated, male mice on days 1 and 20 posttreatment. CONCLUSIONS This study revealed dual effects of CP94253 on VTA DA neurons that are dependent on D2AR sensitivity, with anti-inhibition under normal D2AR sensitivity and inhibition under low D2AR sensitivity. These dual effects may underlie the ability of CP94253 to both enhance and inhibit cocaine-induced behaviors.

中文翻译：

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5-HT1B/1D 受体对腹侧被盖区多巴胺神经元的双重作用：慢性可卡因暴露后功能转换的意义

背景 血清素 (5-HT) 1B/1D 受体 (5-HT1B/1DR) 激动剂在其对可卡因相关行为的影响中经历了戒断诱导的转换，这可能涉及腹侧被盖区多巴胺 (DA) 神经元调节的变化区域 (VTA)。然而，尚不清楚 5-HT1B/1DR 如何影响 VTA DA 神经元功能，以及这些神经元的调节是否介导了慢性可卡因暴露后的戒断诱导转换。方法我们通过切片记录和单单位记录在幼稚小鼠和慢性可卡因治疗小鼠体内检测了 5-HT1B/1DRs 调节 VTA 中 D2 自身受体 (D2ARs) 和突触传递的能力。结果我们报告了通过 VTA 5-HT1B/1DRs 和 D2ARs 相互作用对 VTA DA 神经元放电的双向调节。在 VTA 切片和麻醉小鼠的 VTA 中，5-HT1B/1DR 激动剂 CP94253 降低了 DA 神经元放电率，并诱发了切片中 DA 神经元的兴奋性突触后电流。矛盾的是，CP94253 通过减少 D2AR 介导的 G 蛋白门控内向整流钾电流来减少喹吡罗诱导的 DA 神经元抑制。这表明切片中 GABAA（γ-氨基丁酸 A）受体介导的诱发抑制性突触后电流减少，导致 DA 神经元去抑制，与 5-HT1B/1DR 诱导的抑制相反。这种双重效应在慢性可卡因治疗和轻度应激治疗的雄性小鼠治疗后第 1 天和第 20 天得到验证。结论 本研究揭示了 CP94253 对依赖于 D2AR 敏感性的 VTA DA 神经元的双重作用，在正常 D2AR 敏感性下具有抗抑制作用，在低 D2AR 敏感性下具有抑制作用。