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: 8434863
• 负责人: ELENA H CHARTOFF
• 金额: $ 29.45万
• 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 2014-03-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434863
• 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.

描述（由申请人提供）：该R01提案是根据PA-07-374的“广泛可用的心理活性天然产品的心理药理”而编写的。该提案的目的是检查伏隔核（NAC）中多巴胺（DA）信号的神经可塑性是否构成了精神病药物salvinorin a（salva）的奖励改变作用。 Salvinorin A（salva）是致幻植物salvia divinorum的主要活性成分，是一种有效而有选择性的Kappa阿片受体（KOR）激动剂（Roth等，2002）。萨尔维亚（Salvia）在美国青年中迅速成为一种虐待药物，但对萨尔瓦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：直接反应是反对的（Shippenberg和Herz，1987; Todtenkopf等，2004; Knoll等，2007），而证据表明，延迟效应包括对奖励刺激的敏感性（Negus，2004; McLaugh et and al。，2006年）。与此一致，萨尔维亚的“跳闸”通常包括吞咽困难的成分，然后在急性中毒后的情绪升高（Baggott，2004； Gonzalez等，2006）。这些发现提出了这样的可能性，即即使偶尔使用萨尔瓦也会在奖励电路中诱导可塑性，这可能有助于滥用药物和成瘾。 Chartoff及其同事已经开始使用颅内自刺激（ICS）范式来检查萨尔瓦与奖励之间的时间关系，这对“实时的奖励功能”的增加或减少敏感。存在双相效应：维持ICSS行为所需的刺激的数量（阈值）在注射salva后立即增加（反映了奖励减少），但后来24小时下降（反映了增加的奖励）。 KOR对DA释放的抑制作用（Di Chiara and Imperato，1988年）的抑制作用可能触发salva作用的神经生物学机制，并涉及DA传播中的神经适应。该建议旨在测试萨尔瓦如何调节大脑奖励功能和对高度上瘾的滥用药物可卡因药物的敏感性。此外，该提案测试了Salva如何在三个独立但互补级别的DA信号调节：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NAC中salva的直接作用是减少的，然后在24小时后增加，增加了细胞外信号相关激酶（P-ERK）的磷酸化，这是DA受体介导的CAMP信号的底物。在NAC中，ERK可以激活CREB，这是与厌恶状态相关的转录因子（Carlezon等，1998； Pliakas等，2001）。因此，Salva介导的P-ERK可能代表NAC中CREB功能的新型上游调节剂，并介导Salva对奖励功能的双相影响。