Physiology and Pharmacology of Brain Reward Circuits

大麻的主要精神活性成分是Delta9-四氢大麻酚(THC)。此外，最近还发现，大脑中合成了能激活大麻素受体的内源性物质，这些物质被称为内源性大麻素。所有作用于这种物质受体的药物，无论是天然的还是合成的，统称为大麻素(CBS)。通过吸烟或吸食大麻获得的大麻类药物被非法使用，可能是因为它们对人类有增强作用或带来回报。这些研究的目的之一是了解大麻类药物改变脑细胞功能的潜在机制，以及最终产生这些药物持续非法使用的愉悦效果的机制。这个实验室的主要重点是检查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沟通的方式。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，我们利用大鼠的脑片，这些脑片是从离散的大脑区域中获得的，这些脑片涉及处理有关愉快和不愉快的环境刺激的信息。我们利用全细胞电生理记录和细胞解剖学技术来重建我们从中记录的神经元。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。这一大脑区域及其连接与所有滥用药物的强化和奖赏行为密切相关，也参与调节自然环境刺激(如食物、水等)的奖赏效应。VTA还参与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。由于其在这些过程中的核心作用，VTA是大脑中的一个区域，它导致了诸如成瘾、精神应激障碍、临床抑郁和精神焦虑障碍等障碍。最近在实验室的研究集中在描绘突触输入对来自不同大脑区域的VTA多巴胺神经元的相对贡献。我们目前正在研究的VTA的皮质下输入之一是来自桥脚核(PPN)的输入。这个脑核向VTA提供强大的乙酰胆碱能(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，这些研究将提供有用的信息，将有助于尼古丁成瘾的治疗，以及预防由尼古丁成瘾引起的呼吸系统疾病，如肺气肿和肺癌。此外，由于PPN被认为是设定警觉状态和生理唤醒的关键，它被认为是与焦虑和慢性应激障碍有关的皮质下大脑结构。我们最近的研究考察了与尼古丁敏感性有关的VTA的PPN输入的特性，以及这一途径在暴露于环境应激、可卡因或大麻的主要精神活性成分-9-四氢大麻酚(THC)后经历长期抑郁(LTD)的能力。我们发现，VTA的PPN输入与生俱来地弱于来自皮质的谷氨酸输入。此外，我们发现，如果动物暴露在应激、可卡因或THC中，这些PPN输入可以被加强，尼古丁暴露可以改变PPN激活VTA中与奖励相关的多巴胺神经元的能力。

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.