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

描述（由申请人提供）：本R01提案是针对PA-07-374“广泛使用的精神活性天然产物的精神药理学”而编写的。本研究的目的是研究伏隔核（NAc）中多巴胺（DA）信号的神经可塑性是否为拟精神药物salvinorin A （salvA）的奖励改变作用奠定了基础。Salvinorin A （SalvA）是致幻植物鼠尾草（Salvia divinorum）的主要活性成分，是一种有效的选择性kappa阿片受体（KOR）激动剂（Roth et al., 2002）。作为一种滥用药物，丹参在美国年轻人中迅速流行起来，但人们对丹参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），而有证据表明延迟效应包括对奖励刺激的敏感性增加（Negus, 2004; McLaughlin et al., 2006）。与此相一致的是，一次鼠尾草“旅行”通常包括一个语音障碍成分，随后是急性中毒消退后一段时间的情绪升高（Baggott, 2004; Gonzalez et al., 2006）。这些发现提出了一种可能性，即即使偶尔使用salvA也可以诱导奖励回路的可塑性，这可能会促进药物滥用和成瘾。Chartoff和他的同事们已经开始使用颅内自我刺激（ICSS）模式来研究salvA和奖励之间的时间关系，这种模式对奖励功能的增加或减少“实时”很敏感。存在双相效应：注射salvA后，维持ICSS行为所需的刺激量（阈值）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是由KORs对DA释放的抑制作用触发的（Di Chiara和Imperato， 1988），并涉及随后DA传递的神经适应。这项提议旨在测试salvA如何调节大脑的奖励功能和对高度成瘾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；和突触后camp介导的信号传导。在初步研究中，我们发现salvA对NAc的直接影响是降低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信号传导的底物。在NAc中，ERK可以激活与厌恶状态相关的转录因子CREB （Carlezon et al., 1998; Pliakas et al., 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剂，并介导salvA对奖励功能的双相作用。

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.