Dopamine cell impulse flow, reward and schizophrenia

含多巴胺（DA）的神经元主要参与辅助检测的神经生物学过程！ 奖励的传递。对该信号进行编码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DA细胞活性的增加引起的刺激， 正激励值由突触输入启动，这些细胞的输出（即，脉冲依赖性多巴胺 释放）受到几个因素的限制。这些包括电池的固有电特性，如由 其电压和配体门控离子通道的互补以及短环和长环稳态机制， 努力维持“现状”。这三个因素之间的相互作用（传入，内在属性和 稳态张力）将DA神经元的活动限制为四种不同模式之一，包括单峰和 膜超极化或去极化诱导的爆发活动和两种静止状态 峰电位产生机制失活（去极化阻滞）。在正常情况下，DA的阶段性变化 小区脉冲流保持奖励适当的信令。在非正常条件下，例如由 抗精神病药物的管理，奖励适当的信号可能会失败。应用程序的中心前提 由于DA D2受体功能丧失，导致自身调节张力丧失， 对兴奋性（或去抑制性）输入的反应性使其进入去极化阻滞状态（特异性 目标1）。进一步推测，随之而来的冲动依赖性DA释放的丧失阻止了正常的 传递奖励信号或预测刺激（具体目标#2）。最后，假设 抗精神病药物（APD）具有有利于内源性DA（所谓的DA）置换的受体结合特征， “快速关闭”APD）将不太可能比APD诱导去极化阻滞，APD结合更紧密，因此在 降低损害奖励刺激传递的风险（具体目标#3）。为了实现这些目标， 本申请中提出的研究将体内电生理学方法与脑结合起来， 用刺激奖赏技术研究DA细胞冲动流与脑缺血的神经机制之间的关系， 奖励预计本申请中提出的研究将提供对神经生物学的深入了解。 抗精神病药物焦虑的机制和抗精神病药物前瞻性设计的框架 降低了在患者中产生负面主观反应的可能性。

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.