Consequences of repeated kappa receptor activation on brain stimulation reward

描述（由申请人提供）：本B/START提案的目的是研究重复κ阿片受体（KOR）激活对脑刺激奖励的后果。压力和滥用药物如可卡因都会增加神经肽强啡肽的活性（Hurd等人，1992; Spangler等人，1993; McLaughlin等人，2003），KOR的内源性配体（Chavkin等人，1982年）。此外，压力和先前的吸毒经历已被证明会增强滥用药物的奖励效应，这在人类中可能促进成瘾的发展（Koob和Le Moal，1997; Lu等人，2003年）。KOR激动剂是烦躁不安的，并且当急性给予时减弱可卡因的运动刺激和奖励特性（Gray等人，1999; McLaughlin等人，2006年）。然而，KOR的重复激活可能会导致代偿性神经变化，随着时间的推移，KOR激活的终止可以增强可卡因的奖励作用。我们假设，反复激活的KORs可能发生在压力或药物“狂欢”期间，将烦躁不安，而先前激活的KORs的后果可能发生在压力或药物“狂欢”期间后，将增加可卡因的奖励作用。在初步研究中，我们证明了急性注射高度有效和选择性的KOR激动剂鼠尾草素A（SalvA）减少了可卡因诱导的运动活性。相反，在用SalvA重复治疗6天方案后24小时，可卡因诱导的运动活性增加。为了确定重复KOR激活对奖赏的后果，我们将使用颅内自我刺激（ICSS）来测量6天SalvA给药方案期间的脑刺激奖赏，并测量最后一次SalvA注射后24小时重复SalvA给药对可卡因增强的脑刺激奖赏的后果。此外，在对照实验中，我们将通过用KOR拮抗剂norBNI预处理大鼠来测试重复SalvA的作用是否是KOR特异性的。我们的假设预测，在重复KOR激活的整个方案中，脑刺激奖励将减少（反映在ICSS阈值的增加），而可卡因增强的脑刺激奖励将在重复KOR激活的方案后增加（反映在ICSS阈值的降低）。这些研究的数据将指导未来拨款申请的制定，我们将建议阐明重复KOR激活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.