Cognitive impairment is a debilitating feature of psychiatric disorders including schizophrenia, mood disorders and substance use disorders for which there is a substantial lack of effective therapies. d-Govadine (d-GOV) is a tetrahydroprotoberberine recently shown to significantly enhance working memory and behavioural flexibility in several prefrontal cortex (PFC)-dependent rodent tasks. d-GOV potentiates dopamine (DA) efflux in the mPFC and not the nucleus accumbens, a unique pharmacology that sets it apart from many dopaminergic drugs and likely contributes to its effects on cognitive function. However, specific mechanisms involved in the preferential effects of d-GOV on mPFC DA function remain to be determined. The present study employs brain dialysis in male rats to deliver d-GOV into the mPFC or ventral tegmental area (VTA), while simultaneously sampling DA and norepinephrine (NE) efflux in the mPFC. Intra-PFC delivery or systemic administration of d-GOV preferentially potentiated medial prefrontal DA vs NE efflux. This differential effect of d-GOV on the primary catecholamines known to affect mPFC function further underscores its specificity for the mPFC DA system. Importantly, the potentiating effect of d-GOV on mPFC DA was disrupted when glutamatergic transmission was blocked in either the mPFC or the VTA. We hypothesize that d-GOV acts in the mPFC to engage the mesocortical feedback loop through which prefrontal glutamatergic projections activate a population of VTA DA neurons that specifically project back to the PFC. The activation of a PFC-VTA feedback loop to elevate PFC DA efflux without affecting mesolimbic DA release represents a novel approach to developing pro-cognitive drugs.

认知障碍是包括精神分裂症、情绪障碍和物质使用障碍在内的精神疾病的一个使人衰弱的特征，而这些疾病基本上缺乏有效的治疗方法。d-Govadine (d-GOV) 是一种四氢原小檗碱，最近被证明可以在几种前额皮质 (PFC) 依赖性啮齿动物任务中显着增强工作记忆和行为灵活性。d-GOV 增强 mPFC 中的多巴胺 (DA) 流出，而不是伏隔核，这是一种独特的药理学，使其有别于许多多巴胺能药物，并可能有助于其对认知功能的影响。然而，d-GOV 对 mPFC DA 功能的优先影响的具体机制仍有待确定。本研究采用雄性大鼠脑透析将 d-GOV 输送至 mPFC 或腹侧被盖区 (VTA)，同时对 mPFC 中的 DA 和去甲肾上腺素 (NE) 流出进行采样。PFC 内递送或 d-GOV 全身给药优先增强内侧前额叶 DA 与 NE 流出。d-GOV 对已知影响 mPFC 功能的初级儿茶酚胺的这种差异效应进一步强调了其对 mPFC DA 系统的特异性。重要的是，当 mPFC 或 VTA 中的谷氨酸传递被阻断时，d-GOV 对 mPFC DA 的增强作用就会被破坏。我们假设 d-GOV 在 mPFC 中发挥作用，参与中皮质反馈环路，通过该环路，前额叶谷氨酸能投射激活一群专门投射回 PFC 的 VTA DA 神经元。激活 PFC-VTA 反馈环路以提高 PFC DA 流出而不影响中脑边缘 DA 释放，代表了开发促认知药物的新方法。