Physiology and Pharmacology of Brain Reward Circuits

大麻的主要精神活性成分被称为delta 9-tetrahydrocannabinol（THC）。此外，最近还发现大脑中合成了内源性物质，可以激活大麻素受体，这些物质被称为内源性大麻素。所有天然和合成的药物，作用于这种物质的受体，统称为大麻素（CB）。通过吸食或摄入大麻获得的大麻类药物被非法使用，大概是因为它们对人类有强化或奖励作用。这些研究的目的之一是了解大麻素改变脑细胞功能的潜在机制，以及最终产生这些药物的愉悦效果的机制，这些药物维持其非法使用。该实验室的主要重点是研究滥用药物改变神经元电活动的机制，以及这些神经元通过突触连接相互通信的方式。因此，我们的目标之一是确定特定的离子通道，其活性被滥用的药物如大麻，尼古丁，海洛因和可卡因改变。为了实现这些目标，我们利用大鼠脑切片急性获得离散的大脑区域参与处理信息的愉快和不愉快的环境刺激。 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腹侧被盖区（VTA）神经元及其连接的机制。该脑区及其连接强烈地涉及所有滥用药物的强化和奖励行为，以及介导自然环境刺激（如食物、水等）的奖励效应。腹侧被盖区还涉及处理有关生理应激反应、情绪和情感以及精神警觉性的信息。 由于腹侧被盖区在这些过程中发挥着核心作用，因此它是一个导致成瘾、精神应激障碍、临床抑郁症和精神焦虑症等疾病的大脑区域。 最近的实验室研究集中在描绘突触输入的相对贡献的腹侧被盖区多巴胺神经元产生的不同的大脑区域。 我们目前正在研究的腹侧被盖区皮质下输入之一是来自脚桥核（PPN）。 这个脑核团向腹侧被盖区提供强有力的乙酰胆碱能（Ach）输入，因此可能参与调节药物尼古丁的增强和成瘾特性。 因此，这些研究将提供信息，将是有用的尼古丁成瘾的治疗，以及在预防呼吸系统疾病，如肺气肿，肺癌，尼古丁成瘾造成的。 此外，由于已知PPN对设置警觉状态和生理唤醒至关重要，因此它强烈暗示为涉及焦虑和慢性应激障碍的皮质下脑结构。 我们最近的研究检查了PPN输入到VTA的特性，关于尼古丁的敏感性，以及该途径在暴露于环境压力，可卡因或δ-9-四氢大麻酚（THC），大麻的主要精神活性成分后经历长期变化的能力，称为长期抑郁症（LTD）。 我们已经发现，PPN输入腹侧被盖区本质上弱于谷氨酸输入产生的皮层。 此外，我们发现，如果动物暴露于压力，可卡因或THC，这些PPN输入可以加强，尼古丁暴露可以改变PPN激活VTA中奖励相关多巴胺神经元的能力。 这些数据表明，腹侧被盖区多巴胺神经元上的多巴胺能突触传递的强度根据其来源而变化，并且可以被通常滥用的药物改变。 此外，在过去的报告期内，我们已经发表了正在进行的研究，证明仅在中脑多巴胺神经元上缺乏功能性NMDA受体的小鼠（通过多巴胺转运蛋白启动子驱动的NR 1亚基敲除介导）对可卡因产生了正常的致敏作用。 此外，尽管观察到将NMDA受体拮抗剂微量输注到VTA中可以阻断可卡因敏化，但仍观察到这一点。 从这一点，我们得出结论，而NMDA受体在腹侧被盖区是重要的，以支持可卡因敏化，这些受体必须驻留在非多巴胺能成分的腹侧被盖区电路。

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. Additionally, in the past reporting period, we have published ongoing studies demonstrating that mice lacking functional NMDA receptors only on midbrain dopamine neurons (mediated by knockout of the NR1 subunit driven by the dopamine transporter promoter) developed normal sensitization to cocaine. Furthermore, this was observed despite the observation that microinfusion of a NMDA receptor antagonist into the VTA could block cocaine sensitizaion. From this we conclude that whereas NMDA receptors in the VTA are important to support cocaine sensitization, these receptors must reside on non-dopaminergic components of the VTA circuitry.