Cocaine behavior: Regulation by k-opioids and serotonin

可卡因行为：k-阿片类药物和血清素的调节

• 批准号: 7495024
• 负责人: SARI IZENWASSER
• 金额: $ 17.6万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7495024
• 关键词: Accounting; Acute; Affect; Affinity; Agonist; Autoradiography; Behavior; Behavioral; Binding; Brain; Brain region; Chronic; Cocaine; Cocaine Dependence; Data; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor; Dopamine Uptake Inhibitors; Dorsal; Dose; Goals; In Vitro; Injection of therapeutic agent; Lead; Long-Term Effects; Measurement; Measures; Medial; Mediating; Mediation; Motor Activity; Narcotic Antagonists; New Avenues for the Development of Therapeutics; Numbers; Opioid; Opioid Receptor; Opioid Receptor Binding; Pharmaceutical Preparations; Play; Principal Investigator; Psychological reinforcement; Rattus; Regulation; Role; Self Administration; Serotonin; Serotonin Agonists; Serotonin Antagonists; Serotonin Uptake Inhibitors; System; Techniques; Testing; Toxin; Treatment Protocols; Tryptophan 5-monooxygenase; Up-Regulation; Withholding Treatment; day; density; dopamine transporter; kappa opioid receptors; neurochemistry; p-Chloroamphetamine; programs; radioligand; receptor; receptor binding; response; serotonin receptor; serotonin transporter; treatment duration; uptake

DESCRIPTION (provided by applicant): Many different compounds can block the behavioral effects of cocaine acutely. For example, dopamine antagonists, opioid antagonists and serotonin uptake inhibitors can all reduce cocaine self-administration. Kappa-opioid receptor agonists, which also acutely block the behavioral effects of cocaine, appear to have long-term effects as well. Days after the last of several injections of a kappa-opioid receptor agonist, the ability of cocaine to stimulate locomotor activity is still markedly reduced. This suggests that significant alterations in brain neurochemistry have occurred. Our previous studies suggest that dopaminergic changes alone cannot account for the decreased behavioral effects. Thus, it appears that other neurochemical systems are playing an important role in these long-term decreases in cocaine-stimulated activity. There are reciprocal interactions between cocaine and kappa-opioid receptors. In the other direction, chronic cocaine increases kappa-opioid receptors predominantly in serotonin rich brain regions. In addition, the upregulation of kappa-opioid receptors is not produced by selective dopamine uptake inhibitors. Together, these findings suggest that the bi-directional interactions between cocaine and kappa-opioid receptors are mediated by neurochemical systems other than dopamine, and our preliminary data all suggest that serotonin may play an important role in this regulation. The specific hypothesis of this proposal is that serotonin mediates the long-lasting regulation of cocaine-stimulated activity produced by kappa-opioid agonists, and that kappa-opioid agonist treatment produces long-term alterations in brain serotonin systems which greatly reduce the effects of cocaine on behavior. This hypothesis will be tested by studying the effects of altered serotonergic function on kappa-opioid receptor agonist regulation of cocaine-stimulated locomotor activity and cocaine self-administration. In addition, the effects of selective serotonin agonists and antagonists will be measured to determine which serotonin receptors are important in mediating this long-lasting effect. Since kappa-opioid receptor agonist treatment produces such marked effects on cocaine behaviors, and the effects continue long after the cessation of treatment, an understanding of the mechanism by which this occurs could lead to new avenues for the development of therapeutics for cocaine addiction.

描述（由申请人提供）：许多不同的化合物可以急剧阻断可卡因的行为效应。例如，多巴胺拮抗剂、阿片类拮抗剂和血清素摄取抑制剂都可以减少可卡因的自我给药。 Kappa-阿片受体激动剂也能强烈阻断可卡因的行为效应，似乎也具有长期作用。在最后几次注射κ阿片受体激动剂几天后，可卡因刺激运动活动的能力仍然明显降低。这表明大脑神经化学发生了重大变化。我们之前的研究表明，单靠多巴胺能的变化并不能解释行为影响的减少。因此，其他神经化学系统似乎在可卡因刺激活动的长期减少中发挥着重要作用。可卡因和κ阿片受体之间存在相互作用。另一方面，长期服用可卡因会增加主要位于富含血清素的大脑区域的卡帕阿片受体。此外，选择性多巴胺摄取抑制剂不会上调κ阿片受体。总之，这些发现表明可卡因和κ阿片受体之间的双向相互作用是由多巴胺以外的神经化学系统介导的，我们的初步数据都表明血清素可能在这种调节中发挥重要作用。该提案的具体假设是，血清素介导卡帕阿片激动剂产生的可卡因刺激活动的长期调节，并且卡帕阿片激动剂治疗会在大脑血清素系统中产生长期改变，从而大大减少可卡因的影响行为上。该假设将通过研究改变的血清素能功能对 kappa-阿片受体激动剂对可卡因刺激的运动活动和可卡因自我给药的调节的影响进行检验。此外，还将测量选择性血清素激动剂和拮抗剂的作用，以确定哪些血清素受体在介导这种持久作用中起重要作用。由于κ阿片受体激动剂治疗对可卡因行为产生如此显着的影响，并且这种影响在治疗停止后仍持续很长时间，因此了解这种情况发生的机制可能会为可卡因成瘾疗法的开发开辟新途径。