Department of Psychology, The University of Memphis, Memphis, Tennessee 38152, USA.
Synapse. 2010 Mar;64(3):216-23. doi: 10.1002/syn.20717.
The reinforcing properties of cocaine have been related to increased extracellular concentrations of dopamine in the nucleus accumbens (NAc). M5 muscarinic acetylcholine receptors (mAChRs) on dopamine cells in the ventral tegmental area (VTA) facilitate mesoaccumbens dopamine transmission and are critically involved in mediating natural and drug reinforcement. We investigated the effects of pharmacological blockade of mAChRs in the VTA on cocaine's ability to enhance electrically evoked NAc dopamine efflux. Using fixed potential amperometry together with carbon fiber recording microelectrodes positioned in the NAc core, we quantified dopamine oxidation currents (dopamine efflux) evoked by brief stimulation (15 monophasic pulses at 50 Hz every 30 s) of the laterodorsal tegmentum (LDT) in urethane (1.5 g/kg, i.p.) anesthetized mice. Compared to predrug baseline responses, cocaine (5 or 10 mg/kg, i.p.) dose-dependently enhanced LDT stimulation-evoked NAc dopamine efflux, whereas the nonsubtype selective mAChR antagonist scopolamine (10 microg/0.5 microl) microinfused into the VTA diminished LDT-evoked NAc dopamine efflux. Preinfusion of scopolamine into the VTA diminished the facilitatory actions of cocaine on LDT stimulation-evoked NAc dopamine efflux, and when infused at the peak effect of cocaine attenuated LDT-evoked dopamine efflux to below predrug baseline levels. These findings suggest that LDT cholinergic inputs to dopamine neurons in the VTA, via activation of mAChRs (probably of the M5 subtype), are involved in modulating the facilitatory effects of cocaine on NAc dopamine neurotransmission. They also suggest that the development of antagonists aimed at selectively disrupting M5 receptor function may be valuable in reducing abuse liability of psychostimulants.
可卡因的强化作用与伏隔核（NAc）中外源性多巴胺浓度的增加有关。腹侧被盖区（VTA）多巴胺细胞上的 M5 毒蕈碱乙酰胆碱受体（mAChRs）促进中脑边缘多巴胺传递，并且在介导自然和药物强化方面起着至关重要的作用。我们研究了 VTA 中 mAChRs 的药理学阻断对可卡因增强 NAc 多巴胺外排能力的影响。使用固定电位安培法和碳纤维记录微电极，将其定位在 NAc 核心中，我们定量了由侧背盖核（LDT）短暂刺激（每 30 秒 50 Hz 刺激 15 个单相脉冲）引起的 NAc 多巴胺氧化电流（多巴胺外排）。与药物前基线反应相比，可卡因（5 或 10 mg/kg，ip）剂量依赖性地增强了 LDT 刺激诱发的 NAc 多巴胺外排，而非亚型选择性 mAChR 拮抗剂东莨菪碱（10 微克/0.5 微升）微注射到 VTA 中则减少了 LDT 诱发的 NAc 多巴胺外排。VTA 中预先注射东莨菪碱减弱了可卡因对 LDT 刺激诱发的 NAc 多巴胺外排的促进作用，并且当在可卡因的峰值作用时注入时，将 LDT 诱发的多巴胺外排减弱到低于药物前基线水平。这些发现表明，VTA 中的 LDT 胆碱能输入通过激活 mAChRs（可能是 M5 亚型）作用于多巴胺神经元，参与调节可卡因对 NAc 多巴胺神经传递的促进作用。它们还表明，开发旨在选择性破坏 M5 受体功能的拮抗剂可能有助于降低精神兴奋剂的滥用倾向。
