Mesolimbic Dopamine Modulation of Cue-Enhanced Ventral Pallidal Activity

中脑边缘多巴胺对提示增强的腹侧苍白球活动的调节

• 批准号: 7407084
• 负责人: Jennifer L Taylor
• 金额: $ 4.96万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2010-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407084
• 关键词: Amphetamines; Animals; Brain; Brain region; Cells; Computer information processing; Condition; Control Animal; Cues; Dopamine; Fire - disasters; Globus Pallidus; Goals; Learning; Lesion; Neurons; Nucleus Accumbens; Numbers; Oxidopamine; Pathway interactions; Pattern; Pharmaceutical Preparations; Population; Process; Rate; Rattus; Recovery; Recruitment Activity; Research; Rewards; Stimulus; Sucrose; Testing; Thinking; Ventral Tegmental Area; addiction; awake; dopaminergic neuron; extracellular; insight; psychostimulant; relating to nervous system; response; size

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand how addictive drugs "hijack" brain circuits involved in the association of neutral environmental stimuli with reward. Psychostimulants such as amphetamine are thought to cause excessive dopamine release from mesolimbic neurons originating in the ventral tegmental area, which in turn would activate the nucleus accumbens to ventral pallidum reward circuit. Increased dopamine and associated circuit changes may underlie a pathological state in which reward-associated cues become overly attractive and cause excessive "wanting" of reward. Goals of the current proposal will be to identify, as well as compare and contrast, brain regions critical for mesolimbic dopamine release to enable reward-related cues to activate ventral pallidal neurons. Mesolimbic dopamine contributions to the ability of amphetamine to strengthen cue-induced increases in ventral pallidal firing rates and recruit larger responsive populations of ventral pallidal cells will also be evaluated. Dopamine neuronal projections from the ventral tegmental area to the nucleus accumbens and the ventral pallidum are hypothesized to be crucial for reward-related cues to activate ventral pallidal neurons, and for amphetamine to enhance the potency of cues on reward-related ventral pallidal firing. We will lesion dopamine neurons with 6- hydroxydopamine (6-OHDA) in the ventral tegmental area (Aim 1), nucleus accumbens (Aim 2), or ventral pallidum (Aim 3). After recovery, extracellular recordings of ventral pallidal neurons will be obtained in awake, behaving rats that are presented with previously learned reward (intraoral sucrose)-associated cues. Under vehicle and amphetamine conditions, firing rates before and after the cues and the sizes of responsive neural populations for dopamine-depleted rats will be compared to rats with sham lesions. 6- OHDA lesions of each region are expected disrupt or completely block cue-elicited activation of these neurons. Whether both pathways are necessary or if one can compensate for the loss of the other will be tested. This research will provide insight into information processing in brain circuits essential for reward, and importantly, how information reward-related neural processing might be disturbed by addictive drugs. Such information will be useful for understanding addiction and developing new therapies for treatment.

描述（由申请人提供）：本提案的长期目标是了解成瘾性药物如何“劫持”涉及中性环境刺激与奖励关联的大脑回路。安非他明等精神兴奋剂被认为会导致源自腹侧被盖区的中边缘神经元释放过量的多巴胺，从而激活伏隔核到腹侧白球的奖赏回路。多巴胺的增加和相关的电路变化可能是一种病理状态的基础，在这种状态下，与奖励相关的线索变得过于吸引人，并导致过度的“想要”奖励。目前这项研究的目标是识别、比较和对比中脑边缘多巴胺释放的关键大脑区域，以使奖励相关的线索激活腹侧苍白质神经元。中边缘多巴胺对安非他明增强线索诱导的腹侧苍白球放电率和招募更多响应性的腹侧苍白球细胞群的能力的贡献也将被评估。从腹侧被盖区到伏隔核和腹侧苍白球的多巴胺神经元投射被认为是激活腹侧苍白球神经元的奖励相关信号和安非他明增强奖励相关的腹侧苍白球放电信号效力的关键。我们将用6-羟多巴胺（6- ohda）损伤腹侧被盖区（Aim 1）、伏隔核（Aim 2）或腹侧白质（Aim 3）的多巴胺神经元。恢复后，将在清醒、行为的大鼠中获得腹侧苍白球神经元的细胞外记录，这些大鼠被给予先前习得的奖励（口服蔗糖）相关线索。在载具和安非他明条件下，将多巴胺耗竭大鼠与假性损伤大鼠在提示前后的放电率和反应神经群的大小进行比较。6-每个区域的OHDA病变预计会破坏或完全阻断这些神经元的线索引发的激活。这两种途径是否必要，或者其中一种途径能否弥补另一种途径的损失，都将受到考验。这项研究将深入了解大脑回路中对奖励至关重要的信息处理过程，更重要的是，信息奖励相关的神经处理过程是如何被成瘾药物干扰的。这些信息将有助于了解成瘾和开发新的治疗方法。