GABAERGIC ADAPTATIONS TO ETHANOL SELF ADMINISTRATION

GABA 能对乙醇自我给药的适应

• 批准号: 2707833
• 负责人: DOUGLAS B MATTHEWS
• 金额: $ 3.02万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-28 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2707833
• 关键词: GABA receptor; alcoholism /alcohol abuse; behavioral habituation /sensitization; brain mapping; drug addiction; drug habituation; drug withdrawal; electrophysiology; immunologic assay /test; laboratory rat; self medication

Research suggests that ethanol self-administration involves GABA neurotransmission via GABAA receptors in the mesolimbic system (i.e., the nucleus accumbens [NAC], amygdala [AMG] and ventral tegmental area [VTA]). GABAA receptor modulators systematically administered or infused directly into these brain regions alter ethanol self- administration. Moreover, the effects of GABAA agonists in the amygdala differ in ethanol dependent compared to non-dependent animals. However, the role of GABAA receptor in ethanol self-administration is not known. Prolonged ethanol consumption produces dependence as seen by rebound central nervous system hyperexcitability upon the removal of ethanol. Prolonged ethanol consumption alters GABAA receptor gene expression and GABAA receptor function in the cerebral cortex and hippocampus. Consequently, alterations in NAC, AMG or VTA GABAA receptor function and gene expression may be a critical factor in the regulation of ethanol self-administration. The purpose of this proposal is to investigate if chronic ethanol self-administration 1) produces ethanol dependence, 2) alters GABAA receptor function in the NAC, AMG and VTA and 3) alters GABAA receptor gene expression in the NAC, AMG and VTA. Ethanol dependence will be determined by measuring bicuculline seizure threshold following removal of ethanol in rats that self- administer an ethanol/Polycose solution compared to control rats that self-administered a Polycose solution without ethanol. GABAA receptor function will be determined in the NAC, AMG and VTA using single-cell microinotrophoresis of GABAA and ethanol from rats that self-administer the ethanol/Polycose solution compared to control rats. GABAA receptor gene expression will be measured using semi-quantitative immuno- histochemistry from rats that self-administer an ethanol/Polycose solution compared to control rats. These studies will fill a major gap concerning the role of GABAergic mechanisms on ethanol self- administration.

研究表明，乙醇自我给药涉及GABA 通过中溶液系统中的GABAA受体的神经传递（即 伏隔核[NAC]，杏仁核[AMG]和腹侧对盖区域 [VTA]）。 GABAA受体调节剂系统地给药或 直接注入这些大脑区域改变乙醇自我 行政。 此外，加巴激动剂在 与非依赖性动物相比，杏仁核的依赖性乙醇不同。 但是，GABAA受体在乙醇自我给药中的作用是 不知道。 长时间的乙醇消耗会产生依赖性 通过反弹中枢神经系统去除后过度兴奋 乙醇。长时间的乙醇消耗改变了GABAA受体基因 大脑皮层中的表达和GABAA受体功能 海马。 因此，NAC，AMG或VTA GABAA的改变 受体功能和基因表达可能是关键因素 乙醇自我给药的调节。 该提议的目的 是为了研究慢性乙醇自我给药1）产生 乙醇依赖性，2）改变NAC中的GABAA受体功能AMG VTA和3）改变了NAC，AMG和 VTA。 乙醇依赖性将通过测量双瓜氨酸来确定 在大鼠中去除乙醇后的癫痫发作阈值 与对照大鼠相比，管理乙醇/多结溶液 没有乙醇的多源溶液自我管理。 GABAA受体 功能将在NAC，AMG和VTA中使用单细胞确定 Gabaa和乙醇的微型营养 与对照大鼠相比，乙醇/多结溶液。 GABAA受体 基因表达将使用半定量免疫 - 从自助乙醇/多卵形的大鼠的组织化学 解决方案与对照大鼠相比。 这些研究将填补主要空白 关于加巴能机制在乙醇自我上的作用 行政。