George Mason University, Krasnow Institute for Advanced Study, Fairfax, VA, 22030-4444, USA.
Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, 20852, USA.
J Physiol. 2017 Aug 15;595(16):5637-5652. doi: 10.1113/JP274190. Epub 2017 May 26.
Both endogenous opioids and opiate drugs of abuse modulate learning of habitual and goal-directed actions, and can also modify long-term plasticity of corticostriatal synapses. Striatal projection neurons of the direct pathway co-release the opioid neuropeptide dynorphin which can inhibit dopamine release via κ-opioid receptors. Theta-burst stimulation of corticostriatal fibres produces long-term potentiation (LTP) in striatal projection neurons when measured using whole-cell patch recording. Optogenetic activation of direct pathway striatal projection neurons inhibits LTP while reducing dopamine release. Because the endogenous release of opioids is activity dependent, this modulation of synaptic plasticity represents a negative feedback mechanism that may limit runaway enhancement of striatal neuron activity in response to drugs of abuse.
Synaptic plasticity in the striatum adjusts behaviour adaptively during skill learning, or maladaptively in the case of addiction. Just as dopamine plays a critical role in synaptic plasticity underlying normal skill learning and addiction, endogenous and exogenous opiates also modulate learning and addiction-related striatal plasticity. Though the role of opioid receptors in long-term depression in striatum has been characterized, their effect on long-term potentiation (LTP) remains unknown. In particular, direct pathway (dopamine D1 receptor-containing; D1R-) spiny projection neurons (SPNs) co-release the opioid neuropeptide dynorphin, which acts at presynaptic κ-opioid receptors (KORs) on dopaminergic afferents and can negatively regulate dopamine release. Therefore, we evaluated the interaction of co-released dynorphin and KOR on striatal LTP. We optogenetically facilitate the release of endogenous dynorphin from D1R-SPNs in brain slice while using whole-cell patch recording to measure changes in the synaptic response of SPNs following theta-burst stimulation (TBS) of cortical afferents. Our results demonstrate that TBS evokes corticostriatal LTP, and that optogenetic activation of D1R-SPNs during induction impairs LTP. Additional experiments demonstrate that optogenetic activation of D1R-SPNs reduces stimulation-evoked dopamine release and that bath application of a KOR antagonist provides full rescue of both LTP induction and dopamine release during optogenetic activation of D1R-SPNs. These results suggest that an increase in the opioid neuropeptide dynorphin is responsible for reduced TBS LTP and illustrate a physiological phenomenon whereby heightened D1R-SPN activity can regulate corticostriatal plasticity. Our findings have important implications for learning in addictive states marked by elevated direct pathway activation.
内源性阿片类物质和滥用类鸦片药物均可调节习惯性和目标导向行为的学习，并能改变皮质纹状体突触的长期可塑性。直接通路纹状体投射神经元共同释放阿片神经肽强啡肽，通过κ-阿片受体抑制多巴胺释放。在全细胞膜片钳记录中，皮质纹状体纤维的θ爆发刺激产生纹状体投射神经元的长时程增强（LTP）。直接通路纹状体投射神经元的光遗传学激活抑制 LTP，同时减少多巴胺释放。由于内源性阿片类物质的释放依赖于活动，这种突触可塑性的调节代表了一种负反馈机制，可能限制了对滥用药物的反应中纹状体神经元活动的失控增强。
纹状体中的突触可塑性在技能学习过程中适应性地调节行为，或者在成瘾的情况下适应性地调节行为。正如多巴胺在正常技能学习和成瘾相关的纹状体可塑性的突触可塑性中起着关键作用一样，内源性和外源性阿片类物质也调节学习和成瘾相关的纹状体可塑性。虽然已经描述了阿片受体在纹状体长时程抑制（LTD）中的作用，但它们对长时程增强（LTP）的影响仍不清楚。特别是，直接通路（多巴胺 D1 受体含有；D1R-）棘突投射神经元（SPNs）共同释放阿片神经肽强啡肽，其作用于多巴胺能传入的突触前 κ-阿片受体（KORs），并可负调节多巴胺释放。因此，我们评估了共同释放的强啡肽和 KOR 对纹状体 LTP 的相互作用。我们在脑片上光遗传促进 D1R-SPN 内源性强啡肽的释放，同时使用全细胞膜片钳记录来测量皮质传入刺激后的 SPN 突触反应在皮质传入刺激后的变化。我们的结果表明，TBS 引发皮质纹状体 LTP，并且在诱导过程中光遗传激活 D1R-SPN 会损害 LTP。额外的实验表明，光遗传激活 D1R-SPN 会减少刺激诱发的多巴胺释放，并且在光遗传激活 D1R-SPN 期间，应用 KOR 拮抗剂可完全挽救 LTP 诱导和多巴胺释放。这些结果表明，阿片神经肽强啡肽的增加是 TBS LTP 减少的原因，并说明了一种生理现象，即 D1R-SPN 活性的增加可以调节皮质纹状体的可塑性。我们的发现对于以直接通路激活升高为特征的成瘾状态下的学习具有重要意义。
