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）：此申请适用于NIDA的尖端基础研究奖（CEBRA）机制下的新R21。大多数研究药物滥用和戒断后果的研究集中在长期服用药物的影响上。但是，在此阶段，大脑经历了实质性的生理变化，通常对有效治疗具有抵抗力。另一方面，是 很明显，幼稚的受试者在从精神刺激剂的单一剂量中退出时会表现出很大的负面情感反应，足以使个人寻求更多药物以消除这些行为。然而，这种急性作用构成的神经元电路和生理变化尚不清楚。药物滥用中的主要理论与对手过程模型有关，其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，以长期的负面情感状态反对这一行动。鉴于多巴胺系统参与奖励和阿尼奥尼亚，我们记录了多巴胺神经元在腹侧段区域的活性。我们的结果表明，抑郁症的动物模型与多巴胺神经元射击的数量减少有关，称为种群活动。此外，我们发现苯丙胺给药18小时后的效果类似，与这种负面情感状态一致。在抑郁症的动物模型和苯丙胺后的18小时内，多巴胺神经元活性的这种抑郁症可以通过失活或通过施用NMDA通道阻滞剂氯胺酮来逆转；已知是一种迅速作用的抗抑郁药的药物。综上所述，这些数据支持我们的中心假设：苯丙胺戒断后的负面情感状态（驱动个人服用额外剂量的药物）是通过杏仁核驱动的腹侧偏段区域DA神经元射击的介导的；此外，氯胺酮给药逆转了这种状态。我们建议使用急性苯丙胺给药在大鼠中测试该模型，并根据以下特定目的戒断：1）测试急性苯丙胺给药对多巴胺神经元活性状态在给药后不同时间点测量的影响。 2）测试杏仁核灭活或苯丙胺后普萘洛尔或氯胺酮的给药是否会防止腹侧换段区域多巴胺神经元种群的减少。 3）测试原苯丙胺后18小时测量的多巴胺神经元活性状态的降低是否与苯丙胺自我给药的进行性比例量表的变化相关，并且是否可以通过普萘洛尔或氯胺酮预处理来改变这一点。这是一种高度新颖的方法，可以为急性苯丙胺摄入的对手过程驱动的负面后果以及一种可能破坏药物使用周期的新型治疗方法提供对对手过程驱动的负面后果的神经回路的见解。