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在尖端基础研究奖(CEBRA)机制下的新R21。大多数审查药物滥用和戒毒后果的研究侧重于长期服药的影响。然而，在使用的这个阶段，大脑已经经历了重大的生理变化，通常对有效的治疗具有抵抗力。另一方面，它是 显然，天真的受试者在停用即使是单剂精神刺激剂时也会表现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避免这些行为。然而，这种急性反应背后的神经回路和生理变化尚不清楚。在药物滥用中，一种占主导地位的理论与对手-过程模型有关，在该模型中，服用与短暂的积极情绪效果相关的药物会导致一种动态平衡变化，从而以长期的负面情绪状态反对这一行为。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的多巴胺神经元的活动。我们的结果表明，抑郁症的动物模型与多巴胺神经元放电数量的减少有关，这被称为群体活动。此外，我们发现在服用安非他明18小时后也有类似的效果，与这种负面情绪状态一致。在两种抑郁症动物模型中，以及安非他明18小时后，这种多巴胺神经元活动的抑制可以通过使杏仁核失活或使用NMDA通道阻滞剂氯胺酮来逆转；氯胺酮是一种已知的快速起效的抗抑郁药物。综上所述，这些数据支持我们的中心假设：安非他明停药后的负面情绪状态，促使个人服用更多的药物，是通过杏仁核驱动的腹侧被盖区DA神经元放电的减少来调节的；此外，这种状态被氯胺酮逆转。根据这些具体目的，我们建议在急性苯丙胺给药和戒断的大鼠身上测试这一模型：1)测试急性苯丙胺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)测试杏仁核灭活或安非他明后应用心得安或氯胺酮是否能阻止腹侧被盖区多巴胺能神经元活性的下降。3)测试在安非他明后18小时测得的多巴胺神经元活动状态的下降是否与安非他明自我给药的递增比率量表的改变相关，以及普奈洛尔或氯胺酮是否能改变这一变化。这是一种非常新颖的方法，既可以提供对急性苯丙胺摄取的对手过程驱动的负面后果潜在的神经回路的洞察，也可以提供一种潜在地打破导致滥用的药物使用循环的新疗法。