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

多巴胺信号传导在 Salvinorin A 情绪相关效应中的作用

• 批准号: 8067108
• 负责人: ELENA H CHARTOFF
• 金额: $ 30.81万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067108
• 关键词: Acute; Adenylate Cyclase; Affect; Age; Agonist; American; Behavior; Biological Assay; Biological Factors; Brain; Brain region; CREB1 gene; Chicago; Cocaine; Cyclic AMP; Dominant-Negative Mutation; Dopamine; Dopamine Receptor; Drug abuse; Emotional; Extracellular Signal Regulated Kinases; GTP-Binding Proteins; Gene Transfer; Goals; Hallucinogens; Human; Illinois; Injection of therapeutic agent; Intoxication; Laboratories; Legal; Letters; Marketing; Measurement; Measures; Mediating; Messenger RNA; Moods; Motivation; Neuronal Plasticity; Nucleus Accumbens; Pharmaceutical Preparations; Phosphorylation; Plants; Process; Property; Psychopharmacology; Rattus; Recreational Drugs; Regulation; Reporting; Rewards; Role; Salvia; Scanning; Self Stimulation; Signal Transduction; Stimulus; Synapses; System; Testing; Time; Tissues; Universities; Viral; Writing; Youth; addiction; design; drug of abuse; dysphoria; enzyme activity; extracellular; hedonic; kappa opioid receptors; neuroadaptation; neurobiological mechanism; novel; postsynaptic; presynaptic; public health relevance; receptor sensitivity; research study; response; reuptake; salvinorin A; transcription factor; transmission process

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. PUBLIC HEALTH RELEVANCE: The kappa opioid receptor agonist Salvinorin A is the main active ingredient of the hallucinogenic plant Salvia divinorum and is an increasingly popular recreational drug among youth: in 2006, 1.8 million people over the age of 12 reported having used Salvia at least once in their lifetime. In addition to its psychotomimetic properties, salvinorin A also has profound-but poorly understood-effects on hedonic state (i.e. rewarding or aversive states). The goal of the proposed studies is to determine if salvinorin A modulates brain reward systems by altering dopamine-mediated signaling in the nucleus accumbens, a brain region involved in the regulation of reward.

描述（由申请方提供）：本R 01提案是根据PA-07-374“广泛使用的精神活性天然产品的精神药理学”编写的。本研究的目的是研究拟精神病药物salvinorin A（salvA）的奖赏改变效应是否与多巴胺（DA）在中脑核（NAc）中信号传导的神经可塑性有关。鼠尾草素A（SalvA）是致幻植物鼠尾草（Salvia divinorum）的主要活性成分，并且是有效的和选择性的κ阿片样物质受体（KOR）激动剂（Roth等人，2002年）。鼠尾草作为一种滥用药物在美国青年中迅速流行，但人们对salvA影响大脑奖励功能的机制知之甚少。KOR的激活对情绪状态具有深远的影响：即时反应是厌恶的（Shippenberg和Herz，1987; Todtenkopf等人，2004; Knoll等人，2007），而证据表明延迟效应包括对奖励刺激的敏感性增加（Negus，2004; McLaughlin等人，2006年）。与此一致，鼠尾草“旅行”通常包括在急性中毒消退后的一段时间的情绪升高之后的发声障碍成分（Baggott，2004; Gonzalez等人，2006年）。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中的可塑性，这可能会促进药物滥用和成瘾的脆弱性。Chartoff及其同事已经开始使用颅内自我刺激（ICSS）范式来检查salvA和奖励之间的时间关系，该范式对“真实的时间”奖励功能的增加或减少敏感。存在双相效应：维持ICSS行为所需的刺激量（阈值）在salvA注射后立即增加（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DA传递中的后续神经适应。这项提议旨在测试salvA如何调节大脑的奖赏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;和突触后cAMP介导的信号传导。在初步研究中，我们发现salvA在NAc中的即时效应是细胞外信号相关激酶（P-ERK）（DA受体介导的cAMP信号传导的底物）磷酸化的减少，24小时后增加。在NAc中，ERK可以激活CREB，一种与厌恶状态相关的转录因子（Carlezon et al.，1998; Pliakas等人，2001年）。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对奖赏功能的双相作用。 公共卫生关系：kappa阿片受体激动剂Salvinorin A是致幻植物鼠尾草的主要活性成分，是青年中越来越受欢迎的娱乐性药物：2006年，180万12岁以上的人报告一生中至少使用过一次鼠尾草。除了其拟精神病性质之外，鼠尾草素A还对享乐状态（即奖励或厌恶状态）具有深刻但难以理解的影响。拟议研究的目标是确定salvinorin A是否通过改变多巴胺介导的神经核信号来调节大脑奖励系统，神经核是一个参与奖励调节的大脑区域。