Circumventing physiological consequences of drug abuse

规避药物滥用的生理后果

• 批准号: 8598969
• 负责人: ANTHONY A GRACE
• 金额: $ 18.93万
• 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/8598969
• 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NIDA尖端基础研究奖（CEBRA）机制下的新R21。审查药物滥用和戒断后果的大多数研究侧重于长期服用药物的影响。然而，在使用的这个阶段，大脑已经经历了实质性的生理变化，这些变化通常对有效治疗有抵抗力。另一方面， 很明显，幼稚的受试者在从甚至单剂量的精神兴奋剂中撤出时显示出实质性的负面情感反应，足以导致个体寻求更多的药物来抑制这些行为。然而，神经元回路和生理变化，这种急性行动的基础是未知的。药物滥用的一个主导理论与顺从过程模型有关，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稳态改变，从而以长期的消极情绪状态对抗这种行为。考虑到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。我们的研究结果表明，抑郁症的动物模型与多巴胺神经元放电的数量减少有关，称为群体活动。此外，我们发现一个类似的效果18小时后，安非他明管理，符合这种消极的情感状态。在抑郁症的动物模型和安非他明后18小时，这种多巴胺神经元活性的抑制可以通过使杏仁核失活或通过给予NMDA通道阻断剂氯胺酮来逆转;氯胺酮是一种已知的快速作用的抗抑郁药。综上所述，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，促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神经元放电减少介导的;此外，这种状态被氯胺酮给药逆转。我们建议在大鼠中使用急性安非他明给药和戒断来测试该模型，具体目的如下：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性状态的影响。2)测试杏仁核失活或安非他明后给予普萘洛尔或氯胺酮是否会防止腹侧被盖区多巴胺神经元群活性的降低。3)测试安非他明给药后18小时测量的多巴胺神经元活动状态的降低是否与安非他明自我给药的渐进比例量表的变化相关，以及普萘洛尔或氯胺酮预处理是否可以改变这一点。这是一种非常新颖的方法，既可以深入了解急性安非他明摄入的对手过程驱动的负面后果背后的神经回路，也可以提供一种新的治疗方法，可能会打破导致滥用的药物使用循环。