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）：该申请是NIDA前沿基础研究奖（CEBRA）机制下的新R21。大多数检查药物滥用和停药后果的研究都集中在长期服用药物的影响上。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的治疗有抵抗力。另一方面，它是