KAPPA OPIOID AGONISTS AND COCAINE SENSITIZATION

KAPPA 阿片受体激动剂和可卡因致敏作用

• 批准号: 2608209
• 负责人: SUSAN PICKETT
• 金额: $ 18.84万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-20 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2608209
• 关键词: behavioral /social science research tag; behavioral habituation /sensitization; cocaine; dopamine; drug abuse; drug addiction antagonist; endogenous opioid; laboratory rat; limbic system; neuropharmacology; nucleus accumbens; opioid receptor; preference; psychopharmacology; receptor expression; reinforcer

DESCRIPTION: (Applicant's Abstract) The proposed studies aim to characterize the site and mechanism of action of kappa-opioid receptor agonists in preventing the sensitization or "reverse-tolerance" which develops to the rewarding effects of cocaine following its repeated administration. Our objectives are to determine whether: 1) activation of kappa-opioid receptors located in regions comprising the mesocorticolimbic dopamine (DA) system, is sufficient to prevent the sensitization which develops to the rewarding effects of cocaine; 2) the modulatory effects of systemically and intracerebrally administered kappa-agonists upon sensitization are correlated with a suppression of cocaine-induced increases in extracellular DA levels within the nucleus accumbens (NAC), a projection site of mesocorticolimbic neurons and 3) inactivation of kappa-opioid receptors exacerbates the development of the sensitization process. The conditioned place preference and intravenous self-administration paradigms, will be used to map the site of action of kappa-agonists in modulating the development of sensitization and to examine whether microinjection of a kappa-opioid receptor antagonists exacerbate the development of sensitization. The technique of microdialysis will be used to monitor extracellular DA levels within the NAC in response to the administration of cocaine and kappa-opioid receptor ligands. We hypothesize that exogenously applied kappa-opioid agonists prevent sensitization to the rewarding effects of cocaine by activating opioid receptors located within the NAC and thereby suppressing cocaine-induced increases in extracellular DA levels within this specific brain region. These studies will provide important information regarding the site of action of kappa-opioid agonists in modulating adaptive behavioral responses which occur in response to repeated cocaine administration and may contribute to the development of an effective pharmacological treatment for cocaine addiction.

描述：(申请人摘要) 建议的研究目的是确定其作用部位和作用机制。 Kappa-阿片受体激动剂在预防变态反应中的作用 “反向耐受”发展为可卡因的有益效果 在其反复管理之后。我们的目标是确定 是否：1)位于脑区的kappa-阿片受体激活 包括中皮质边缘多巴胺(DA)系统，足以 防止敏感化发展为有益的效果 可卡因；2)全身和脑内的调节作用 致敏时服用kappa激动剂与 抑制可卡因诱导的细胞外多巴胺水平升高 伏隔核(NAC)，中皮质边缘神经元的投射部位 3)kappa-阿片受体失活加剧了 敏化过程。条件性位置偏爱与静脉注射 自治范例，将用于绘制行动地点图 Kappa激动剂对敏感化发展的调控作用 微量注射Kappa-阿片受体拮抗剂是否加剧 敏化的发展。将使用微渗析技术 为了监测NAC内的细胞外DA水平 可卡因和kappa-阿片受体配体的给药。我们假设 外源性应用的kappa-阿片激动剂防止对 可卡因的奖赏效应通过激活位于脑内的阿片受体 NAC，从而抑制可卡因诱导的细胞外信号增加 这一特定大脑区域内的DA水平。这些研究将提供 关于kappa-阿片激动剂作用部位的重要信息 在调节适应性行为反应中 反复服用可卡因，可能有助于发展成 对可卡因成瘾的有效药物治疗。