Alcohol Action on Neurons in the Brain Reward Circuit

酒精对大脑奖赏回路中神经元的作用

• 批准号: 7943743
• 负责人: HITOSHI MORIKAWA
• 金额: $ 3.43万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943743
• 关键词: Abstinence; Accounting; Acute; Address; Affect; Affective; Age; Alcohol consumption; Alcoholism; Alcohols; Aspartate; Behavior; Behavioral; Brain; Calcium; Cations; Cells; Chronic; Data; Development; Dopamine; Down-Regulation; Electric Stimulation; Ethanol; Exposure to; Fiber; Frequencies; Glutamates; Goals; Image; Individual; Injection of therapeutic agent; Inositol; Learning; Measures; Mediating; Membrane; Metabotropic Glutamate Receptors; Midbrain structure; Mus; Nature; Neurobiology; Neurons; Pacemakers; Pattern; Physiological; Plastics; Play; Potassium; Process; Property; Psychological reinforcement; Relative (related person); Rewards; Role; Saline; Shapes; Signal Transduction; Slice; Testing; Withdrawal; alcohol effect; alcohol exposure; alcohol sensitivity; dopaminergic neuron; drinking behavior; experience; flash photolysis; in vivo; mesolimbic system; postsynaptic; problem drinker; response; transmission process; treatment strategy; tripolyphosphate; voltage; voltage clamp

DESCRIPTION (provided by applicant): Dopaminergic neurons in the ventral midbrain are the key component of the brain reward circuit. Acute administration of ethanol enhances the firing of dopamine neurons, whereas withdrawal from repeated ethanol exposure leads to a marked reduction in their activity. These effects are thought to contribute to the rewarding/reinforcing action of alcohol and the negative affective state experienced during abstinence. Dopamine neurons display a spectrum of firing patterns, ranging from pacemaker-like to burst-pause. The tonic, pacemaker firing represents the intrinsic activity of dopamine neurons, whereas the phasic, burst-pause firing is triggered by afferent inputs impinging on them. The overriding hypothesis of this proposal is that ethanol regulates both tonic and phasic activities of dopamine neurons via distinct postsynaptic mechanisms to produce its behavioral actions. This will be addressed with electrophysiological recording in acutely prepared midbrain slices from mice. The pacemaker activity of dopamine neurons is controlled by two key voltage-gated ionic conductances: the hyperpolarization- activated cation current (Ih) and the A-type potassium current (IA). These conductances play counteracting roles in that Ih facilitates and IA suppresses pacemaker firing. The first goal is to determine the effects of acute (Aim 1) and repeated (Aim 2) ethanol treatments on Ih and IA and identify their contribution to the modulation of pacemaker firing. The second goal is to determine the effects of acute (Aim 3) and repeated (Aim 4) ethanol treatments on the pause of firing accompanying bursts. In these aims, the pause of firing between bursts is posited to limit, or gate, the occurrence of bursts. Stimulation of glutamatergic inputs to dopamine neurons evokes a burst of firing followed by a pause. This pause is mediated by metabotropic glutamate receptors (mGluRs), which activate a calcium-sensitive potassium conductance via release of calcium from intracellular stores to cause membrane hyperpolarization. We will test the hypothesis that acute ethanol suppresses, while withdrawal from repeated ethanol exposure enhances the mGluR-mediated hyperpolarization/pause. Confocal calcium imaging and flash photolysis of caged compounds will be performed to delineate the postsynaptic targets mediating the action of ethanol. The role of Ih and IA in shaping the ethanol sensitivity of the mGluR-mediated hyperpolarization will also be determined. The information obtained from this study will advance our understanding of the neurobiological processes underlying alcohol-drinking behavior and hence will help develop better treatment strategies for alcoholism.

描述（由申请人提供）：中脑腹侧的多巴胺能神经元是大脑奖赏回路的关键组成部分。急性给药乙醇增强多巴胺神经元的放电，而从重复乙醇暴露中撤出导致其活动显着减少。这些影响被认为有助于酒精的奖励/强化作用和禁欲期间经历的负面情感状态。多巴胺神经元显示出一系列的放电模式，从起搏器样到爆发-暂停。紧张性起搏器放电代表多巴胺神经元的内在活动，而相位性爆发-暂停放电则由撞击它们的传入输入触发。这个提议的主要假设是，乙醇通过不同的突触后机制调节多巴胺神经元的紧张性和相位性活动，以产生其行为作用。这将通过在急性制备的小鼠中脑切片中进行电生理记录来解决。多巴胺神经元的起搏活动由两个关键的电压门控离子电导控制：超极化激活的阳离子电流（Ih）和A型钾电流（IA）。这些电导在Ih促进和IA抑制起搏器放电中起抵消作用。第一个目标是确定急性（目标1）和重复（目标2）乙醇治疗对Ih和IA的影响，并确定其对起搏器放电调制的贡献。第二个目标是确定急性（目标3）和重复（目标4）乙醇处理对伴随爆发的放电暂停的影响。在这些目标中，突发之间的发射暂停被设定为限制或门控突发的发生。对多巴胺神经元的多巴胺能输入的刺激会引起一次放电，然后是一次停顿。这种暂停是由代谢型谷氨酸受体（mGluRs）介导的，其通过从细胞内储存释放钙来激活钙敏感性钾电导，从而引起膜超极化。我们将测试的假设，急性乙醇抑制，而从反复乙醇暴露的撤退增强mGluR介导的超极化/暂停。将进行共聚焦钙成像和笼状化合物的闪光光解，以描绘介导乙醇作用的突触后靶点。还将确定Ih和IA在塑造mGluR介导的超极化的乙醇敏感性中的作用。从这项研究中获得的信息将促进我们对饮酒行为背后的神经生物学过程的理解，从而有助于开发更好的酒精中毒治疗策略。