Dopamine cell impulse flow, reward and schizophrenia

描述(申请人提供)：多巴胺(DA)神经元集中参与神经生物学过程，辅助检测和传递奖赏。对这一信号进行编码涉及到瞬时放电率的变化，从而改变中脑DA神经元的放电模式。尽管具有正向激励值的刺激引起的DA细胞活动的增加是由突触输入(S)启动的，但这些细胞的输出(即脉冲依赖的DA释放)受到多种因素的限制。这些包括由其电压和配基门控离子通道的补充性所决定的细胞的内在电学特性，以及努力维持“现状”的短环路和长环路内环境平衡机制。这三种因素(传入、固有特性和稳态张力)之间的相互作用将DA神经元的活动限制为四种不同的模式之一，包括单棘波和爆发式活动，以及由膜超极化或去极化导致的棘波产生机制的失活(去极化阻断)所介导的两种静止状态。在正常情况下，DA细胞冲动流的相位变化维持适当的奖赏信号。在不正常的情况下，例如服用抗精神病药物引起的情况下，适当的奖励信号可能会失败。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)输入的反应性，使其容易进入去极化阻断状态(特定目标#1)。进一步推测，随之而来的脉冲依赖的DA释放的丧失阻碍了奖励信号或预测刺激的正常传递(特定目标2)。最后，假设受体结合特征有利于内源性DA置换的抗精神病药物(APD)将不太可能导致去极化阻断，而APD结合更紧密，从而降低了损害奖赏刺激传递的风险(特定目标#3)。为了达到这些目的，本申请提出的研究将体内电生理方法与脑刺激奖赏技术相结合，以研究DA细胞冲动流与奖赏神经机制的关系。预计这项申请中提出的研究将为神经抗精神病药物焦虑症的神经生物学机制提供洞察力，并为前瞻性设计降低患者产生负面主观反应的可能性的抗精神病药物提供一个框架。

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.