Consequences of repeated kappa receptor activation on brain stimulation reward

描述(申请人提供)：本B/START方案的目的是研究反复激活kappa阿片受体(KOR)对脑刺激奖赏的影响。压力和滥用药物，如可卡因，都会增加强啡肽的活性(Hurd等人，1992；Spangler等人，1993；McLaughlin等人，2003)，KOR的内源性配体(Chavkin等人，1982)。此外，压力和以前的吸毒经历已被证明可以增强滥用毒品的回报效应，在人类中，滥用毒品可能会促进成瘾的发展(Koob和Le Moal，1997；Lu等人，2003)。KOR激动剂是烦躁不安和减弱的运动刺激剂和可卡因的奖赏特性，当给药时(Gray等人，1999年；McLaughlin等人，2006年)。然而，随着时间的推移，重复激活KOR可能会导致代偿性神经变化，从而终止KOR的激活可以增强可卡因的奖赏作用。我们假设，Kors的反复激活--可能发生在压力或药物“狂欢”期间--将是焦躁不安的，而先前激活Kors的结果--可能发生在压力或药物“狂欢”之后--将是可卡因回报效应的增加。在初步研究中，我们证明了急性注射高效和选择性的KOR激动剂salvinorin A(SALVA)可降低可卡因诱导的运动活动。相比之下，重复使用Salva治疗6天后24小时，可卡因诱导的运动活动增加。为了确定重复激活KOR对奖赏的影响，我们将使用颅内自我刺激(ICSS)来测量在6天的Salva给药方案中的脑刺激奖赏，并在最后一次Salva注射24小时后测量重复给药对可卡因增强的脑刺激奖赏的影响。此外，在一项对照实验中，我们将通过用KOR拮抗剂norBNI预处理大鼠来测试重复Salva的效果是否具有KOR特异性。我们的假设预测，在重复KOR激活的整个过程中，脑刺激奖赏将减少(反映为ICSS阈值的增加)，而可卡因增强的脑刺激奖赏将在重复KOR激活的方案后增加(反映为ICSS阈值的降低)。来自这些研究的数据将指导未来拨款申请的制定，在这些申请中，我们将提议阐明反复激活KOR对脑刺激奖励的影响的神经生物学机制。

DESCRIPTION (provided by applicant): The purpose of this B/START proposal is to investigate the consequences of repeated kappa opioid receptor (KOR) activation on brain stimulation reward. Both stress and drugs of abuse such as cocaine increase activity of the neuropeptide dynorphin (Hurd et al., 1992; Spangler et al., 1993; McLaughlin et al., 2003), the endogenous ligand for the KOR (Chavkin et al., 1982). Furthermore, stress and prior drug experience have been shown to enhance the rewarding effects of drugs of abuse, which-in humans-could facilitate the development of addiction (Koob and Le Moal, 1997; Lu et al., 2003). KOR agonists are dysphoric and attenuate locomotor stimulant and rewarding properties of cocaine when given acutely (Gray et al., 1999; McLaughlin et al., 2006). However, repeated activation of KOR's might lead to compensatory neural changes over time such that termination of the KOR activation could enhance the rewarding actions of cocaine. We hypothesize that repeated activation of KORs-as might occur during periods of stress or drug "binges"-will be dysphoric whereas a consequence of prior activation of KORs-as might occur after periods of stress or drug "binges"-will be an increase in the rewarding effects of cocaine. In prelimary studies we demonstrate that an acute injection of the highly potent and selective KOR agonist, Salvinorin A (SalvA) reduced cocaine- induced locomotor activity. In contrast, 24 hr after a 6-d regimen of repeated treatment with SalvA, cocaine- induced locomotor activity was increased. To determine the consequences of repeated KOR activation on reward, we will use intracranial self-stimulation (ICSS) to measure brain stimulation reward during a 6 day regimen of SalvA administration and measure the consequence of repeated SalvA administration on cocaine- enhanced brain stimulation reward 24 hr after the last SalvA injection. Additionally, in a control experiment, we will test whether the effects of repeated SalvA are KOR-specific by pre-treating rats with the KOR antagonist, norBNI. Our hypothesis predicts that brain stimulation reward will be decreased (reflected in an increase in ICSS thresholds) throughout the regimen of repeated KOR activation, whereas cocaine-enhanced brain stimulation reward will be increased (reflected in a decrease in ICSS thresholds) after the regimen of repeated KOR activation. Data from these studies will guide the formulation of future grant applications in which we will propose to elucidate the neurobiological mechanisms that underlie the effects of repeated KOR activation on brain stimulation reward.