GABAergic compounds for treating drug addiction: Preclinical models

用于治疗药物成瘾的 GABA 能化合物：临床前模型

• 批准号: 8148523
• 负责人: Eliot Gardner
• 金额: $ 29.36万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8148523
• 关键词: Drug Addiction; Pre-Clinical Model

During the period 01 Oct 09 to 30 Sept 10, significant progress was made on this research project. We had previously found that the gamma-aminobutyric acid (GABA) transaminase inhibitor gamma-vinyl-GABA (GVG, Vigabatrin) dose-dependently inhibits cocaine-triggered relapse to cocaine-seeking behavior in laboratory rats who have been pharmacologically detoxified and behaviorally extinguished from their prior cocaine-taking habits. We further found that gamma-vinyl-GABA also dose-dependently inhibits sucrose-induced reinstatement of reward-seeking behavior in rats. By using in vivo brain microdialysis, we additionally found that gamma-vinyl-GABA dose-dependently elevates extracellular GABA levels in the nucleus accumbens of the limbic forebrain. However, gamma-vinyl-GABA, when administered either systemically or locally into the nucleus accumbens, fails to inhibit either basal or cocaine-enhanced nucleus accumbens dopamine in either drug-naive rats or in cocaine-extinction rats. During the present reporting period, we additionally found that gamma-vinyl-GABA increases nonvesicular release of GABA and glutamate in the nucleus accumbens of laboratory rats via action on anion channels and on GABA transporters. This is an important discovery, as it points toward an uinderstanding of the mechanism(s) by which gamma-vinyl-GABA may exert its anti-addiction effects. This is especially timely, as gamma-vinyl-GABA has now entered human clinical trials to assess its anti-addiction efficacy at the human level. We interpret our current findings (together with our previous findings with gamma-vinyl-GABA) to suggest that: 1) gamma-vinyl-GABA appears to possess significant anti-addiction efficacy; 2) gamma-vinyl-GABA's mechanism(s) of action in the brain may differ significantly from those of other GABAmimetic compounds. This may well explain our previous findings that systemic administration of gabapentin (another putative GABAmimetic compound claimed in some previous reports from other research groups to have anti-cocaine-addiction properties) has no effect on cocaine-triggered relapse to cocaine-seeking behavior, that gabapentin also fails to alter intravenous cocaine self-administration under fixed-ratio reinforcement in laboratory rats, and that gabapentin fails to alter either basal or cocaine-enhanced dopamine levels in the nucleus accumbens as measured by in vivo brain microdialysis. When added to our previous extensive findings with gamma-vinyl-GABA in a very wide variety of addiction-related preclinical animal models, the present findings suggest that gamma-vinyl-GABA may have anti-addiction, anti-craving, and anti-relapse efficacy in human drug addiction, and that it may differ significantly from other GABAmimetic drugs with respect to mechanism(s) of action in the brain.

在09年10月1日至9月10日期间，该研究项目取得了重大进展。 我们先前已经发现，γ-氨基丁酸（GABA）转氨酶抑制剂γ-乙烯基 - 乙烯基 - 乙烯基 - 乙烯基 - 乙烯基 - 乙烯基 - 乙烯基 - GVG，Vigabatrin）剂量依赖性地抑制可卡因触发的可卡因触发的复发，以使可卡因在实验室中被药理学和行为灭绝的实验室中的可卡因辨认行为。 我们进一步发现，γ-乙烯基-GABA还依赖剂量抑制了蔗糖引起的大鼠奖励行为的恢复。 通过使用体内脑微透析，我们还发现，γ-乙烯基 - 乙烯基 - 乙烯基剂量依赖性地升高了边缘前脑伏隔核的细胞外GABA水平。 然而，γ-乙烯基 - gaba在伏伏核中施用或局部施用时，在药物 - 非洲大鼠或可卡因扩张大鼠中都无法抑制基底或可卡因增强的振帽核多巴胺。 在本报告期间，我们还发现，γ-乙烯基-GABA通过在阴离子通道和GABA转运蛋白上的作用来增加实验室大鼠伏击核中GABA和谷氨酸的无抗释放。 这是一个重要的发现，因为它指向了γ-乙烯基 - gaba可能发挥其抗添加作用的机制的震撼。 这是尤其及时的，因为伽马乙烯基-GABA现在已经进入了人类临床试验，以评估其在人类水平上的抗添加功效。 我们解释了我们当前的发现（以及我们先前与γ-乙烯基 - gaba的发现），以表明：1）γ-乙烯基 - 乙烯基 - 乙烯基 - 乙烯基 - 乙烯基 - 似乎具有显着的抗添加功效； 2）大脑作用机制的γ-乙烯基 - 乙烯基 - 智能机制可能与其他gabamimetic化合物的作用可能有显着差异。 这可能可以很好地解释我们先前的发现，即全系统地给药（在其他研究小组先前的一些报告中声称的另一种假定的gabamimetic化合物具有抗可卡因添加的特性）对可卡因触发的可卡因触发行为的复发没有影响。 gabapentin未能改变伏隔核中的基底或可卡因增强的多巴胺水平，如体内脑微透析所测量的那样。 当在我们以前与γ-乙烯基-GABA的广泛发现中添加到非常多种与成瘾相关的临床前动物模型中时，目前的发现表明，γ-乙烯基 - 乙烯基 - 乙烯基 - 乙烯基 - 乙烯基 - 乙烯基 - 乙烯基-GABA可能具有抗育，抗捕获，抗抗性，抗雷神和抗疫苗在人类药物成瘾中与其他gabamimications相关的机构（与其他gabamimics相关的机构）（S）相差很大。