Physiology and Pharmacology of Brain Reward Circuits

大麻的主要精神活性成分是四氢大麻酚（THC）。此外，最近发现大脑中合成的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）。通过吸食或摄入大麻获得的大麻素类药物被非法使用，大概是因为它们对人类有强化或奖励作用。这些研究的目标之一是获得大麻素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效果的机制，从而维持其非法使用。本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交流的方式。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，海洛因和可卡因所改变。为了实现这些目标，我们利用从涉及处理有关愉快和不愉快环境刺激的信息的离散脑区急性获得的大鼠脑切片。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在腹侧被盖区（VTA）连接的机制。这个大脑区域及其连接与所有滥用药物的强化和奖励行为密切相关，也与介导自然环境刺激（如食物、水等）的奖励作用密切相关。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是导致成瘾、精神压力障碍、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述突触输入对不同脑区产生的VTA多巴胺神经元的相对贡献。我们目前正在研究的对VTA的皮层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，这些研究将为治疗尼古丁成瘾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）提供有用的信息。此外，由于已知PPN对设置警觉性状态和生理唤醒至关重要，因此它与焦虑和慢性应激障碍相关的皮质下脑结构密切相关。我们最近的研究检查了PPN输入到VTA的特性，关于尼古丁敏感性，以及这条通路在暴露于环境压力、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）的长期变化的能力。我们发现，对VTA的PPN输入天生就比皮层产生的谷氨酸输入弱。此外，我们还发现，如果动物暴露于压力、可卡因或四氢大麻酚中，这些PPN的输入可以得到加强，而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。这些数据表明，谷氨酸能突触在VTA多巴胺神经元上的传递强度因其来源而异，并可被常见滥用药物改变。

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.