Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine and Science, Rochester MN, USA.
J Neurochem. 2021 Jan;156(2):212-224. doi: 10.1111/jnc.15106. Epub 2020 Jul 20.
The corticostriatal circuitry and its glutamate-γ-aminobuturic acid (GABA) interactions play an essential role in regulating neuronal excitability during reward-seeking behavior. However, the contribution of GABAergic interneurons in the corticostriatal circuitry remains unclear. To investigate the role of GABAergic interneurons, we focused on parvalbumin-expressing fast-spiking interneurons (Pv-FSI) in the corticostriatal circuitry using the designer receptors exclusively activated by designer drugs approach in a Pv-Cre mouse model. We hypothesize that Pv-FSI activation elicits changes in cortical glutamate levels and reward-seeking behaviors. To determine molecular and behavioral effects of Pv-FSI, we performed microdialysis and operant conditioning tasks for sucrose and alcohol rewards. In addition, we also examined how alcohol reward itself affects Pv-FSI functioning. Interestingly, our microdialysis results demonstrate that alcohol exposure inhibits Pv-FSI functioning in the medial prefrontal cortex (mPFC) and this consequently can regulate glutamate levels downstream in the nucleus accumbens. For sucrose reward-seeking behaviors, Pv-FSI activation in the mPFC increases sucrose self-administration whereas it does not promote alcohol seeking. For alcohol rewards, however, Pv-FSI activation in the mPFC results in increased compulsive head entry in operant chambers during devaluation procedures. Overall, our results suggest that not only do Pv-FSI contribute to changes in the cortical microcircuit and reward-seeking behaviors but also that alcohol affects Pv-FSI neurotransmission. Therefore, Pv-FSI has prompted interest in their role in maintaining a balance in neuronal excitation/inhibition and in regulating reward-seeking processes such as compulsivity, all of which are important factors for excessive alcohol seeking.
皮质纹状体回路及其谷氨酸-γ-氨基丁酸（GABA）相互作用在调节奖励寻求行为期间的神经元兴奋性方面发挥着重要作用。然而，皮质纹状体回路中 GABA 能中间神经元的贡献尚不清楚。为了研究 GABA 能中间神经元的作用，我们使用 Designer Receptors Exclusively Activated by Designer Drugs（DREADD）技术在 Pv-Cre 小鼠模型中专注于皮质纹状体回路中的表达 Parvalbumin 的快速放电中间神经元（Pv-FSI）。我们假设 Pv-FSI 的激活会引起皮质谷氨酸水平的变化和奖励寻求行为的改变。为了确定 Pv-FSI 的分子和行为效应，我们进行了微透析和蔗糖和酒精奖励的操作性条件反射任务。此外，我们还研究了酒精奖励本身如何影响 Pv-FSI 的功能。有趣的是，我们的微透析结果表明，酒精暴露抑制了内侧前额叶皮质（mPFC）中的 Pv-FSI 功能，这反过来又可以调节伏隔核下游的谷氨酸水平。对于蔗糖奖励寻求行为，mPFC 中的 Pv-FSI 激活增加了蔗糖的自我给药，而不会促进酒精寻求。然而，对于酒精奖励，mPFC 中的 Pv-FSI 激活导致在减值程序期间在操作性室中进行强迫性头部进入的增加。总体而言，我们的结果表明，Pv-FSI 不仅有助于改变皮质微电路和奖励寻求行为，而且酒精还会影响 Pv-FSI 的神经传递。因此，Pv-FSI 引起了人们对其在维持神经元兴奋/抑制平衡和调节奖励寻求过程（如强迫性）中的作用的兴趣，所有这些都是过度寻求酒精的重要因素。
