Neural Mechanisms of Drug Seeking

描述(申请人提供)：可卡因依赖是一种慢性复发性障碍，目前没有治疗的药物。由于对抗复发药物的迫切需求，探索FDA批准的药物的潜在用途是重要的，这将允许快速临床翻译。最低限度，潜在的治疗方法应该减少对药物的渴望，因为渴望往往是复发的一个诱发因素。另一种不经常使用的措施，但已经 抗复发治疗的表面有效性是在戒断一段时间后恢复自我给药。在之前的资助期间，我们的研究在理解可卡因动机的神经机制方面做出了重大贡献，可卡因动机是由可卡因注射或可卡因相关线索引起的，这两者都会引起可卡因滥用者的渴望。在这次新的第三次竞争更新中，我们建议从我们的工作中调查一个重要的线索。具体地说，我们发现，尽管增加5-羟色胺(5-羟色胺)1B受体(R)功能的操作在维持大鼠自我给药期间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的操作降低了可卡因的增强价值，并恢复了由可卡因相关线索或可卡因引发的注射所诱导的消失的寻找可卡因的行为。这些发现表明，5-HT1BRs在戒断诱导的可卡因动机增加的病理性大脑回路中发挥着关键作用。更重要的是，这些发现表明5-HT1BR激动剂可能是有效的抗复发药物，这是令人兴奋的，因为有Triptan类5-HT1BR激动剂被FDA批准用于偏头痛的治疗。我们已经证明选择性5-HT1BR激动剂CP94253减少了长期戒断后可卡因自我给药的恢复和寻找可卡因行为的恢复，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戒断一段时间后的可卡因摄入量。在这项建议中，我们旨在比较CP94253和佐米曲坦在维持期间和长期戒断后对可卡因自我管理和寻求可卡因行为恢复的影响。我们的目标也是检查这些激动剂在长期禁欲(60天)和每天10次治疗后是否保持抑制效果。我们计划调查我们在自我注射可卡因的雄性大鼠身上观察到的CP94253的效果是否推广到雌性大鼠，并推广到自我注射甲基苯丙胺的雄性大鼠。最后，我们将通过电生理记录VTA中的多巴胺神经元来研究禁欲诱导的5-HT1BR激动剂效应方向的转换的神经机制。我们的目标具有迅速转化为治疗可卡因依赖的新药物的令人兴奋的潜力，并将提供关于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.