Dopamine cell impulse flow, reward and schizophrenia

描述（由申请人提供）：含多巴胺（DA）的神经元主要参与促进奖赏检测和传递的神经生物学过程。编码这个信号涉及瞬时放电率的变化，因此中脑DA神经元的放电模式。虽然由具有正激励值的刺激诱发的DA细胞活性的增加是由突触输入启动的，但是这些细胞的输出（即，冲动依赖性DA释放）受到几个因素的限制。这些包括细胞的内在电特性，如由其电压和配体门控离子通道的补充以及努力维持“现状”的短环和长环稳态机制所决定的。“这三个因素（传入，内在特性和稳态张力）之间的相互作用将DA神经元的活动限制在四种不同的模式之一，包括单一的尖峰和爆发活动以及由膜超极化或去极化诱导的尖峰产生机制失活（去极化阻滞）介导的两种静止状态。在正常情况下，DA细胞脉冲流的阶段性变化维持奖励适当的信号。在异常情况下，如抗精神病药物诱导的情况下，奖励适当的信号传导可能会失败。该应用的中心前提是，继发于DA D2受体功能丧失的自动调节张力的丧失将增加细胞对兴奋性（或去抑制性）输入的响应性，使其倾向于进入去极化阻滞状态（具体目标#1）。进一步推测，随后的冲动依赖性DA释放的丧失阻止了奖励信号或预测刺激的正常传输（具体目标#2）。最后，假设具有有利于内源性DA置换的受体结合特征的抗精神病药物（APD）（所谓的“快速关闭”APD）与结合更紧密的APD相比，不太可能诱导去极化阻滞，因此降低了损害奖励刺激传递的风险（具体目标#3）。为了实现这些目标，本申请提出的研究将体内电生理方法与脑刺激奖励技术相结合，研究DA细胞冲动流与奖励神经机制之间的关系。预计本申请中提出的研究将提供对神经生物学机制的深入了解，以及用于前瞻性设计抗精神病药物的框架，该抗精神病药物具有降低患者产生负面主观反应的可能性。

DESCRIPTION (provided by applicant): Dopamine (DA)-containing neurons are centrally involved in the neurobiological processes subserving the detection and transmission of reward. Encoding this signal involves changes in the instantaneous firing rate and thus the discharge pattern of mesotelencephalic DA neurons. Although increases in DA cell activity evoked by stimuli with positive motivational value are initiated by synaptic input(s), the output of these cells (i.e., impulse-dependent DA release) is constrained by several factors. These include the intrinsic electrical properties of the cell as dictated by its complement of voltage and ligand-gated ion channels and short and long-loop homeostatic mechanisms that strive to maintain the "status quo." The interaction between these three factors (afferents, intrinsic properties and homeostatic tone) constrain the activity of DA neurons to one of four distinct modes including single spike and bursting activity and two quiescence states mediated by membrane hyperpolarization or depolarization-induced inactivation of spike generating mechanisms (depolarization block). Under normal conditions, phasic changes in DA cell impulse flow maintain reward-appropriate signaling. Under abnormal conditions, such as those induced by administration of antipsychotic drugs, reward-appropriate signaling may fail. The central premise of the application is that the loss of autoregulatory tone, secondary to functional loss of DA D2 receptors, will increase the cell's responsiveness to excitatory (or disinhibitory) inputs predisposing it to enter a state of depolarization block (Specific Aim #1). It is further speculated that the ensuing loss of impulse-dependent DA release prevents normal transmission of rewarding signaling or predicting stimuli (Specific Aim #2). Finally, it is hypothesized that antipsychotic drugs (APDs) with a receptor binding profile that favors displacement by endogenous DA (so called "fast-off' APDs) will be less likely to induce depolarization block than APDs which bind more tightly and thus at reduced risk for compromising transmission of rewarding stimuli (Specific Aim #3). In order to address these aims, the research proposed in this application combines in vivo electrophysiological methods together with brain stimulation reward techniques to study the relationship between DA cell impulse flow and the neural mechanisms of reward. It is anticipated that the research proposed in this application will provide insight into neurobiological mechanisms responsible for neuroleptic dysphoria and a framework for prospectively designing antipsychotic drugs with a reduced liability for producing negative subjective responses in patients.