Circumventing physiological consequences of drug abuse

规避药物滥用的生理后果

• 批准号: 8661742
• 负责人: ANTHONY A GRACE
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661742
• 关键词: Acute; Affect; Affective; Amphetamines; Amygdaloid structure; Anhedonia; Animal Model; Antidepressive Agents; Attention; Award; Basic Science; Behavior; Behavioral; Brain; Cells; Chronic; Complex; Data; Dopamine; Dose; Drug abuse; Drug usage; Emotional; Feeling; Hour; Individual; Injection of therapeutic agent; Intake; Investigation; Ketamine; Measures; Mediating; Mental Depression; Modeling; N-Methylaspartate; National Institute of Drug Abuse; Norepinephrine; Pattern; Pharmaceutical Preparations; Phase; Physiological; Population; Process; Propranolol; Rattus; Resistance; Rewards; Saline; Sampling; Self Administration; Staging; System; Testing; Time; Training; Ventral Tegmental Area; Withdrawal; analog; attenuation; channel blockers; dopamine system; dopaminergic neuron; drug abuse prevention; drug of abuse; drug withdrawal; effective therapy; insight; neural circuit; neuronal circuitry; novel; novel strategies; prevent; psychostimulant; public health relevance; relating to nervous system; response; restraint; restraint stress; stressor; theories; treatment strategy

DESCRIPTION (provided by applicant): This application is for a new R21 under the Cutting-Edge Basic Research Awards (CEBRA) mechanism from NIDA. The majority of studies that examine the consequences of drug abuse and withdrawal focus on the impact of long-term administration of drugs. However, at this stage of use the brain has undergone substantial physiological changes that are typically resistant to effective treatment. On the other hand, it is clear that naive subjects show substantial negative affective responses upon withdrawal from even single doses of a psychostimulant, sufficient to cause the individual to seek more drug to obviate these actions. However, the neuronal circuitry and the physiological changes that underlie such acute actions are unknown. A dominant theory in drug abuse relates to the opponent-process model, in which taking a drug that is associated with a brief positive emotional effect leads to a homeostatic alteration that opposes this action with a long-term negative affective state. Given the involvement of the dopamine system in reward and in anhedonia, we recorded the activity of dopamine neurons in the ventral tegmental area. Our results show that animal models of depression are associated with a decrease in the number of dopamine neurons firing, termed population activity. Moreover, we find a similar effect 18 hours following administration of amphetamine, consistent with this negative affective state. In both animal models of depression and 18 hours after amphetamine, this depression in dopamine neuron activity can be reversed by inactivating the amygdala or by administering the NMDA channel blocker ketamine; a drug that is known to be a rapidly acting antidepressant. Taken together, these data support our central hypothesis: The negative affective state following amphetamine withdrawal, which drives individuals to take additional doses of the drug, is mediated via an amygdala-driven decrease in ventral tegmental area DA neuron firing; moreover, this state is reversed by ketamine administration. We propose to test this model in a rat using acute amphetamine administration and withdrawal according to these Specific Aims: 1) Test the effects of acute amphetamine administration on dopamine neuron activity states measured at different time points after administration. 2) Test whether amygdala inactivation or administration of propranolol or ketamine after amphetamine will prevent the decrease in ventral tegmental area dopamine neuron population activity. 3) Test whether the decrease in dopamine neuron activity state measured at 18 hours post-amphetamine correlates with a change in a progressive ratio scale of amphetamine self-administration, and if this can be altered by propranolol or ketamine pre-treatment. This is a highly novel approach that can provide both insights into the neural circuits underlying the opponent process-driven negative consequences of acute amphetamine intake, as well as a novel treatment that can potentially break the cycle of drug use leading to abuse.

描述（由申请人提供）：本申请是针对 NIDA 尖端基础研究奖（CEBRA）机制下的新 R21 的申请。大多数研究药物滥用和戒断后果的研究都集中在长期用药的影响上。然而，在这个使用阶段，大脑已经发生了显着的生理变化，通常对有效的治疗产生抵抗力。另一方面，它是 很明显，幼稚的受试者在戒断单剂量的精神兴奋剂后会表现出大量的负面情感反应，足以导致个体寻求更多的药物来避免这些行为。然而，这种急性行为背后的神经回路和生理变化尚不清楚。药物滥用的一个主导理论与对手过程模型有关，在该模型中，服用与短暂的积极情绪效应相关的药物会导致体内平衡的改变，从而以长期的消极情绪状态对抗这种行为。鉴于多巴胺系统参与奖赏和快感缺乏，我们记录了腹侧被盖区多巴胺神经元的活动。我们的结果表明，抑郁症动物模型与多巴胺神经元放电数量（称为群体活动）的减少有关。此外，我们发现服用安非他明 18 小时后也出现类似的效果，与这种负面情绪状态一致。在抑郁症动物模型和安非他明服用 18 小时后，多巴胺神经元活性的抑制可以通过灭活杏仁核或服用 NMDA 通道阻滞剂氯胺酮来逆转；已知是一种快速起效的抗抑郁药。总而言之，这些数据支持我们的中心假设：安非他明戒断后的负面情感状态驱使个体服用额外剂量的药物，是通过杏仁核驱动的腹侧被盖区 DA 神经元放电减少来介导的；此外，服用氯胺酮可以逆转这种状态。我们建议根据以下具体目标，使用急性安非他明给药和戒断在大鼠中测试该模型：1）测试急性安非他明给药对给药后不同时间点测量的多巴胺神经元活动状态的影响。 2) 测试杏仁核失活或在安非他明后施用普萘洛尔或氯胺酮是否会阻止腹侧被盖区多巴胺神经元群活动的减少。 3)测试安非他明后18小时测量的多巴胺神经元活动状态的减少是否与安非他明自我给药的渐进比例量表的变化相关，以及是否可以通过普萘洛尔或氯胺酮预处理来改变这种变化。这是一种非常新颖的方法，既可以深入了解急性苯丙胺摄入的对手过程驱动的负面后果背后的神经回路，也可以提供一种可能打破药物使用导致滥用的循环的新颖治疗方法。