Role of dopamine signaling in the mood-related effects of salvinorin A

描述(由申请人提供)：本R01建议书是为响应PA-07-374《广泛存在的精神活性天然产品的精神药理学》而撰写的。本研究的目的是研究伏隔核(NAC)多巴胺(DA)信号的神经可塑性是否支持拟精神病药物salvinorin A(Salva)的奖赏改变效应。Salvinorin A(Salva)是致幻植物丹参的主要活性成分，是一种有效和选择性的kappa阿片受体(KOR)激动剂(Roth等人，2002年)。丹参作为一种滥用药物在美国年轻人中迅速流行起来，但人们对Salva影响大脑奖励功能的机制知之甚少。Kors的激活对情绪状态有深远的影响：即时反应是厌恶的(Shippenberg and Herz，1987；Todtenkopf et al.，2004；Knoll et al.，2007)，而证据表明，延迟效应包括对奖赏刺激的敏感性增加(Negus，2004；McLaughlin et al.，2006)。与此一致的是，丹参“旅行”通常包括发音困难的成分，然后是急性中毒消退后一段时间的情绪高涨(Baggot，2004；Gonzalez等人，2006)。这些发现提出了一种可能性，即即使偶尔使用Salva，也可以在奖励回路中诱导可塑性，这可能会促进药物滥用和成瘾。Chartoff和他的同事已经开始使用颅内自我刺激(ICSS)范式来研究Salva和奖励之间的时间关系，该范式对奖励功能的增加或减少非常敏感。有两个阶段的影响：维持ICSS行为所需的刺激量(阈值)在注射Salva后立即增加(反映奖励减少)，但在24小时后减少(反映奖励增加)。Salva作用的神经生物学机制可能由Kors对DA释放的抑制作用触发(Di Chiara和Imperato，1988)，并涉及随后的DA传递中的神经适应。这项提议旨在测试Salva如何调节大脑奖励功能和对高度成瘾的滥用药物可卡因的敏感性。此外，该提案还测试了Salva如何在三个独立但互补的水平上调节DA信号：突触前DA释放；突触后DA受体敏感性；以及突触后cAMP介导的信号。在初步研究中，我们发现Salva在NAC的直接作用是减少细胞外信号相关激酶(P-ERK)的磷酸化，24小时后增加，P-ERK是DA受体介导的cAMP信号转导的底物。在NAC中，ERK可以激活CREB，这是一种与厌恶状态相关的转录因子(Carlezon等人，1998；Pliakas等人，2001)。因此，Salva介导的P-ERK可能代表了NAC中CREB功能的一种新的上游调节器，并介导了Salva对奖赏功能的双相效应。

DESCRIPTION (provided by applicant): This R01 proposal was written in response to PA-07-374, "Psychopharmacology of widely available psychoactive natural products". The purpose of this proposal is to examine whether neuroplasticity of dopamine (DA) signaling in the nucleus accumbens (NAc) underlies the reward-altering effects of the psychotomimetic drug salvinorin A (salvA). Salvinorin A (SalvA) is the main active ingredient of the hallucinogenic plant Salvia divinorum and is a potent and selective kappa opioid receptor (KOR) agonist (Roth et al., 2002). Salvia is rapidly gaining in popularity among American youth as a drug of abuse, but little is known about the mechanisms through which salvA impacts brain reward function. Activation of KORs has profound effects on emotional states: immediate responses are aversive (Shippenberg and Herz, 1987; Todtenkopf et al., 2004; Knoll et al., 2007), whereas evidence suggests that delayed effects include increased sensitivity to rewarding stimuli (Negus, 2004; McLaughlin et al., 2006). Consistent with this, a Salvia "trip" often includes a dysphonic component followed by a period of elevated mood after acute intoxication has subsided (Baggott, 2004; Gonzalez et al., 2006). These findings raise the possibility that even occasional use of salvA can induce plasticity within reward circuits, which might facilitate drug abuse and vulnerability to addiction. Chartoff and colleagues have begun to examine the temporal relationship between salvA and reward using the intracranial self-stimulation (ICSS) paradigm, which is sensitive to increases or decreases in reward function "in real time". There are biphasic effects: the amount (threshold) of stimulation required to sustain ICSS behavior is increased (reflects decreased reward) immediately after an injection of salvA, but decreased (reflects increased reward) 24 hr later. The neurobiological mechanisms underlying the effects of salvA may be triggered by the inhibitory actions of KORs on DA release (Di Chiara and Imperato, 1988) and involve subsequent neuroadaptations in DA transmission. This proposal is designed to test how salvA modulates brain reward function and sensitivity to the highly addictive drug of abuse, cocaine. Also, the proposal tests how salvA modulates DA signaling at three independent but complementary levels: presynaptic DA release; postsynaptic DA receptor sensitivity; and postsynaptic cAMP-mediated signaling. In preliminary studies, we found that an immediate effect of salvA in the NAc is a decrease, followed 24 hr later by an increase, in the phosphorylation of extracellular signal-related kinase (P-ERK), a substrate for DA receptor-mediated cAMP signaling. In the NAc, ERK can activate CREB, a transcription factor associated with aversive states (Carlezon et al., 1998; Pliakas et al., 2001). Thus, salvA-mediated P-ERK might represent a novel upstream modulator of CREB function in the NAc and mediate the biphasic effects of salvA on reward function.