Neural Mechanisms of Drug Seeking

描述（由申请人提供）：可卡因依赖是一种慢性复发性疾病，目前没有可用的药物。由于迫切需要抗复发药物，因此探索FDA批准的药物的潜在用途非常重要，这些药物将允许快速临床转化。最低限度，潜在的治疗应该减少药物渴望，因为渴望往往是复发的一个诱发因素。另一项不常使用的措施， 治疗的抗复发效果的表面有效性是在一段时间的戒断后恢复可卡因自我给药。在以前的资助期间，我们的研究对理解可卡因动机的神经机制做出了重大贡献，可卡因引发注射或可卡因相关线索引起可卡因的动机，这两者都会引起可卡因滥用者的渴望。在这个新的第三次竞争更新中，我们建议调查我们工作中的一个重要线索。具体来说，我们发现，尽管增加5-羟色胺（5-HT）1B受体（R）功能的操作在大鼠自我给药的维持过程中增强了可卡因的强化价值，但在长期戒断期间给予的这些相同操作降低了可卡因的强化价值，以及由可卡因相关线索或可卡因引发注射诱导的消失的可卡因寻求行为的恢复。这些发现表明，5-HT 1BR在病理性大脑回路中起着关键作用，而病理性大脑回路是戒断诱导可卡因动机增加的基础。更重要的是，研究结果表明，5-HT 1BR激动剂可能是有效的抗复发药物，这是令人兴奋的，因为有曲坦类5-HT 1BR激动剂被FDA批准用于治疗偏头痛。我们已经证明，选择性5-HT 1BR激动剂CP 94253减少了可卡因自我给药的恢复和长期禁欲后可卡因寻求行为的恢复，我们有初步数据表明，FDA批准的，但选择性较低的激动剂佐米曲坦也减少了一段时间的禁欲后可卡因的摄入。在这项提议中，我们的目的是比较CP 94253和佐米曲坦对可卡因自我管理和恢复可卡因寻求行为的影响，在维持与长期禁欲后。我们还旨在检查激动剂的抑制作用是否在长期禁欲期（60天）和每日10次治疗后仍能维持。我们计划研究我们在自我施用可卡因的雄性大鼠中观察到的CP 94253的作用是否普遍适用于雌性大鼠，并普遍适用于自我施用甲基苯丙胺的雄性大鼠。最后，我们将利用腹侧被盖区多巴胺神经元的电生理记录，研究5-HT 1BR激动剂作用方向上的禁欲诱导转换的神经机制。我们的目标具有令人兴奋的潜力，可以迅速转化为可卡因依赖的新药物，并将提供有关可卡因成瘾机制的新知识。

DESCRIPTION (provided by applicant): Cocaine dependence is a chronic relapsing disorder for which there is currently no medication available. Due to the urgent need for anti-relapse medications, it is important to explore potential uses of FDA-approved drugs that would allow for rapid clinical translation. Minimally, potential treatments should reduce drug craving, since craving is often a precipitating factor in relapse. Another measure that is not often used, but has face validity for anti-relapse effects of treatment is resumption of cocaine self-administration after a period of abstinence. During previous funding periods, our research has made significant contributions toward understanding the neural mechanisms of motivation for cocaine that is elicited by cocaine priming injections or cocaine-associated cues, both of which elicit craving in cocaine abusers. In this new 3rd competing renewal, we propose to investigate an important lead from our work. Specifically, we discovered that although manipulations that increase serotonin (5-HT) 1B receptor (R) function enhance cocaine's reinforcing value during maintenance of self-administration in rats, these same manipulations given during protracted abstinence decrease cocaine's reinforcing value, as well as reinstatement of extinguished cocaine-seeking behavior induced by cocaine-associated cues or cocaine-priming injections. These findings suggest that 5-HT1BRs play a critical role in the pathological brain circuitry that underlies abstinence-induced increases in motivation for cocaine. More importantly, the findings suggest that 5-HT1BR agonists may be effective anti-relapse medications, which is exciting given that there are triptan-class 5-HT1BR agonists that are FDA-approved for the treatment of migraines. We have shown that the selective 5-HT1BR agonist CP94253 decreases resumption of cocaine self-administration and reinstatement of cocaine seeking behaviors after protracted abstinence and we have preliminary data suggesting that the FDA-approved, but less selective agonist zolmitriptan also decreases cocaine intake after a period of abstinence. In this proposal, we aim to compare the effects of CP94253 and zolmitriptan on cocaine self-administration and reinstatement of cocaine-seeking behavior during maintenance versus after a period of protracted abstinence. We also aim to examine whether inhibitory effects of the agonists are maintained after a lengthy abstinence period (60 days) and after 10 daily treatments. We plan to investigate whether the effects that we have observed with CP94253 in male rats that have self-administered cocaine generalize to female rats and generalize to male rats that have self- administered methamphetamine. Finally, we will investigate the neural mechanisms underlying the abstinence- induced switch in the direction of 5-HT1BR agonist effects using electrophysiological recording of dopamine neurons in the VTA. Our aims have the exciting potential to rapidly translate to new medications for cocaine dependence and will provide new knowledge regarding the mechanisms of cocaine addiction.