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: 7857913
• 负责人: HITOSHI MORIKAWA
• 金额: $ 23.39万
• 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/7857913
• 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）：腹中脑中的多巴胺能神经元是大脑奖励电路的关键组成部分。急性施用乙醇可增强多巴胺神经元的发射，而从反复的乙醇暴露中退出会导致其活性显着降低。这些影响被认为有助于酒精的奖励/加强作用以及戒酒期间经历的负面情感状态。多巴胺神经元显示出各种射击图案，从起搏器般到爆发。补品，起搏器射击代表了多巴胺神经元的固有活性，而阶段性的，爆发的射击是由影响它们的传入输入触发的。该提议的重大假设是，乙醇通过不同的突触后机制来调节多巴胺神经元的滋补性和阶段性活性，以产生其行为作用。这将与来自小鼠的急性制备的中脑切片中的电生理记录来解决。多巴胺神经元的起搏器活性由两个关键电压门控离子电导控制：超极化激活阳离子电流（IH）和A型钾电流（IA）。这些电导在IH促进和抑制起搏器射击的情况下扮演着抵消角色。第一个目标是确定急性（AIM 1）的影响并重复（AIM 2）乙醇处理对IH和IA的影响，并确定它们对起搏器解散调节的贡献。第二个目标是确定急性（AIM 3）的影响并重复（AIM 4）乙醇处理对伴随爆发的暂停。在这些目标中，爆发之间的暂停被放置在限制或闸门之间。刺激多巴胺神经元的谷氨酸能输入引起了一阵射击，然后停了下来。这种停顿是由代谢型谷氨酸受体（MGLURS）介导的，该谷氨酸受体（MGLURS）通过从细胞内存储中释放钙来激活钙敏感的钾电导，以引起膜超极化。我们将测试急性乙醇抑制的假设，而反复暴露于乙醇暴露会增强MGLUR介导的超极化/暂停。将进行笼中化合物的共聚焦钙成像和闪光光解，以描绘介导乙醇作用的突触后靶标。 IH和IA在塑造MGLUR介导的超极化的乙醇敏感性中的作用也将得到确定。从这项研究中获得的信息将提高我们对酒精饮用行为的神经生物学过程的理解，从而有助于制定更好的酒精中毒治疗策略。