Physiology and Pharmacology of Brain Reward Circuits

大脑奖励回路的生理学和药理学

• 批准号: 8553239
• 负责人: Carl R. Lupica
• 金额: $ 51.31万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8553239
• 关键词: Acetylcholine; Affect; Animals; Anxiety; Anxiety Disorders; Area; Arousal; Brain; Brain region; Cannabinoids; Cell Nucleus; Cell physiology; Cells; Chronic stress; Cocaine; Data; Disease; Drug Addiction; Endocannabinoids; Endogenous depression; Exposure to; Food; Glutamates; Goals; Heroin; Human; Ingestion; Ion Channel; Knowledge; Laboratories; Long-Term Depression; Malignant neoplasm of lung; Marijuana; Marijuana Smoking; Mediating; Mental Depression; Mental disorders; Moods; Motivation; Neural Pathways; Neurons; Nicotine; Nicotine Dependence; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Play; Post-Traumatic Stress Disorders; Prevention; Process; Production; Property; Psyche structure; Pulmonary Emphysema; Rattus; Relative (related person); Respiration Disorders; Rewards; Role; Site; Slice; Smoking; Source; Stimulus; Stress; Structure; Synapses; Synaptic Transmission; Syndrome; Techniques; Testing; Tetrahydrocannabinol; Traumatic Stress Disorders; Ventral Tegmental Area; Water; addiction; alertness; biological adaptation to stress; brain cell; cannabinoid receptor; dopaminergic neuron; drug of abuse; endogenous cannabinoid system; information processing; insight; receptor

The main psychoactive component of marijuana is known as delta9-tetrahydrocannabinol (THC). In addition, it has recently been discovered that endogenous substances are synthesized in the brain that can activate cannabinoid receptors, and these substances are referred to as endocannabinoids. All drugs, both natural and synthetic, that act at receptors for this substance are known collectively as cannabinoids (CBs). Cannabinoid drugs obtained by the smoking or ingestion of marijuana are used illicitly presumably because they are reinforcing or rewarding to humans. One of the objectives of these studies is to gain knowledge about the underlying mechanisms through which cannabinoids alter brain cell function, and ultimately the mechanisms that produce the pleasurable effects of these drugs that sustain their illicit use. The primary focus of this laboratory is to examine the mechanisms through which abused drugs alter the electrical activity of neurons and the ways in which these neurons communicate with each other via synaptic connections. Therefore, one of our goals is to identify specific ion channels whose activity is modified by abused drugs such as marijuana, nicotine, heroin, and cocaine. To achieve these goals we utilize rat brain slices acutely obtained from discrete brain areas involved in processing information regarding pleasurable and unpleasant environmental stimuli. We utilize whole-cell electrophysiological recordings, and cellular anatomical techniques to reconstruct the neurons from which we record. In these ongoing studies we are examining the mechanisms through which these drugs affect neurons and their connections in the ventral tegmental area (VTA). This brain area and its connections are strongly implicated in the reinforcing and rewarding actions of all abused drugs, as well as in mediating the rewarding effects of natural environmental stimuli, such as food, water, etc. The VTA is also involved in processing information regarding the physiological stress responses, mood and affect, and mental alertness. Because of its central role in these processes, the VTA is a brain area that contributes to disorders such as addiction, psychiatric stress disorders, clinical depression, and psychiatric anxiety disorders. Recent studies in the laboratory have focused on delineating the relative contribution of synaptic inputs to the VTA dopamine neurons arising from distinct brain regions. One of the sub-cortical inputs to the VTA that we are currently studying is that from the pedunculopontine nucleus (PPN). This brain nucleus provides strong acetylcholinergic (Ach) input to the VTA, and therefore is likely involved in regulating the reinforcing and addictive properties of the drug nicotine. Therefore, these studies will provide information that will be useful in the treatment of nicotine addiction, as well as in the prevention of respiratory disorders, such as emphysema, and lung cancer, resulting from nicotine addiction. Moreover, since the PPN is known to be critical to setting states of alertness, and physiological arousal, it is strongly implicated as a subcortical brain structure involved in anxiety, and chronic stress disorders. Our most recent studies examine the properties of the PPN input to the VTA, with regard to nicotine sensitivity, as well as the ability of this pathway to undergo a long-term change know as long-term depression (LTD) following exposure to either environmental stress, cocaine or delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana. We have found that the PPN inputs to the VTA are inherently weaker than glutamate inputs arising from the cortex. Furthermore, we have found that these PPN inputs can be be strengthened if animals are exposed to stress, cocaine, or THC, and that nicotine exposure can alter the ability of the PPN to activate the reward-relevant dopamine neurons in the VTA. These data demonstrate that the strength of glutamatergic synaptic transmission on VTA dopamine neurons varies according to its source, and can be altered by commonly abused drugs. Additional studies are now being conducted to determine the site at which endogenous cannabinoid molecules are synthesized in brain reward circuits and where these molecules act to alter brain reward function. One hypothesis that is currently being explored is that there is a cooperation among synaptic inputs to VTA to summate and permit endocannabinoid production in VTA dopamine neurons. To test this we are activating subcortical inputs from the PPN that contain acetylcholine, just prior to the activation of glutamate inputs arising from several cortical inputs. Preliminary data suggest that the activation of multiple inputs to the same dopamine neurons is greater than additive in generating endogenous cannabinoid release from these cells. If this observation is substantiated then it suggests that some synaptic neural pathways can act as switches to control the activation of the endogenous cannabinoid system. As many studies have shown that endogenous cannabinoids play a significant role in altering the addictive potency of many abused drugs, our studies may point to critical mechanisms that can weaken the effects of these drugs on this critical component of the brain's reward pathway.

大麻的主要精神活性成分被称为delta9-tetrahydrocanbinol（THC）。此外，最近已经发现，内源性物质是可以激活大麻素受体的大脑中合成的，这些物质被称为内源性大麻素。所有天然和合成的药物都在该物质上起作用受体，统称为大麻素（CBS）。通过吸烟或摄入大麻获得的大麻素药物可能是非法使用的，因为它们正在增强或有益。这些研究的目标之一是获取有关大麻素会改变脑细胞功能的潜在机制的知识，并最终产生这些药物的愉悦作用的机制。该实验室的主要重点是检查滥用药物改变神经元的电活动以及这些神经元通过突触连接相互通信的方式的机制。因此，我们的目标之一是确定特定的离子渠道，其活动被大麻，尼古丁，海洛因和可卡因等滥用药物所修饰。为了实现这些目标，我们利用大鼠脑切片从涉及处理有关愉悦和不愉快的环境刺激的信息的离散大脑区域敏锐地获得。 我们利用全细胞电生理记录和细胞解剖技术来重建我们记录的神经元。在这些正在进行的研究中，我们正在研究这些药物影响神经元及其连接在腹侧段区域（VTA）的机制。该大脑区域及其联系极大地牵涉到所有受滥用药物的加强和有益的作用，以及介导自然环境刺激的有意义的效果，例如食物，水等。VTA还参与了处理有关生理压力反应，情绪和情感和心理和精神警觉和精神警觉的处理信息。 由于其在这些过程中的核心作用，VTA是一个大脑区域，会导致诸如成瘾，精神胁迫障碍，临床抑郁症和精神焦虑症等疾病。 实验室的最新研究集中在描述突触输入对由不同大脑区域引起的VTA多巴胺神经元的相对贡献。 我们目前正在研究的VTA的亚皮质输入之一是来自Pedunculopontine核（PPN）。 该脑核为VTA提供了强大的乙酰胆碱能（ACH）输入，因此很可能参与调节药物尼古丁的增强和成瘾性。 因此，这些研究将提供有关尼古丁成瘾的治疗以及预防呼吸系统疾病（例如肺气肿和肺癌）的信息。 此外，由于已知PPN对于设定机敏状态和生理唤醒至关重要，因此它被强烈牵涉到与焦虑症和慢性应激障碍有关的皮层下大脑结构。 我们最近的研究研究了尼古丁敏感性PPN输入对VTA的特性，以及在暴露于环境压力，可卡因或Delta-9-9-9-tetrahydrahydrocannabinol（thc）之后，这种长期变化的途径经历长期变化的能力，是原始的精神构成。 我们发现，对VTA的PPN输入本质上比由皮质引起的谷氨酸输入弱弱。 此外，我们发现，如果动物暴露于压力，可卡因或THC，可以加强这些PPN输入，并且尼古丁暴露可以改变PPN激活VTA中奖励相关的多巴胺神经元的能力。 这些数据表明，VTA多巴胺神经元上谷氨酸能突触传播的强度根据其来源而变化，并且可以通过普遍滥用的药物改变。 现在正在进行其他研究，以确定内源性大麻素分子在大脑奖励电路中合成的位置，以及这些分子作用以改变大脑奖励功能。 目前正在探索的一个假设是，与VTA的突触输入之间存在合作，以总结并允许VTA多巴胺神经元中的内源性大麻素产生。 为了测试这一点，我们正在激活含有乙酰胆碱的PPN的皮质下输入，就在激活谷氨酸输入之前，我们是由多个皮质输入引起的。 初步数据表明，在从这些细胞中产生内源性大麻素释放时，多种输入对同一多巴胺神经元的激活大于添加剂。 如果证实了该观察结果，则表明某些突触神经途径可以作为控制内源性大麻素系统激活的转换。 由于许多研究表明，内源性大麻素在改变许多滥用药物的上瘾效力中起着重要作用，我们的研究可能指出了关键机制，这些机制可以削弱这些药物对大脑奖励途径的关键成分的影响。