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Reversing Cocaine-induced Impairments in the NAc with Controllable Stressors

用可控压力源逆转可卡因引起的 NAc 损伤

基本信息

批准号：
10475295
负责人：
Michael Saddoris
金额：
$ 34.47万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475295
关键词：
Abstinence Affect American Animal Model Animals Behavior Behavior Control Behavioral Bilateral Brain Brain region Cause of Death Centers for Disease Control and Prevention (U.S.)Cessation of life Chronic Clinical Cocaine Cognitive Cognitive deficits Country Cues Discrimination Disease Dopamine Drug Addiction Drug abuse Drug resistance Electrophysiology (science)Epidemic Exposure to Extinction (Psychology)FDA approved Family Feeling Food Food Patterns Fright Future Habits Halorhodopsins Impairment Individual Intervention Learning Link Mediating Modeling Motivation Neurons Neurophysiology - biologic function Nucleus Accumbens Occupations Optics Overdose Pathway interactions Persons Pharmaceutical Preparations Phase Play Population Predisposition Prefrontal Cortex Probability Process Property Rattus Recording of previous events Recovery Relapse Reporting Role Shock Signal Transduction Social Conditions Societies Stimulus Stress Stressful Event Structure Tail Testing Therapeutic Therapeutic Intervention Ventral Tegmental Area Vietnam Work addiction anxiety states base behavioral outcome cocaine self-administration combat conditioned fear conditioning craving dopaminergic neuron drug abstinence drug craving drug of abuse drug relapse experience experimental study in vivo insight loved ones neural circuit neurotransmission non-drug novel optogenetics predicting response prevent psychostimulant public health relevance relating to nervous system resilience severe mental illness social defeat stressor translational model

项目摘要

Project Summary / Abstract Drug addiction is a chronically relapsing disorder that often has devastating consequences for the addicted person and society as a whole. In particular, during periods of drug abstinence, drug-associated stimuli or general feelings of stress may elicit powerful feelings of craving in drug-dependent individuals. Indeed, stress is a particularly potent trigger because, unlike drug cues (e.g., paraphernalia) and contexts (i.e., places where drugs are obtained or used) which can be avoided, stress is unavoidable in non-drug contexts such as work, family, or finances. In most conditions, these stressful encounters are aversive and unavoidable, and can create a heightened anxiety state that addicted individuals attempt to alleviate by relapse to a drug-taking episode. However, in contrast to these inescapable stressors, in some situations it is possible to have control over an aversive situation. These controllable stressors, while still aversive, nonetheless have been shown to endow subjects with trans-situational resilience against future stressors. In an animal model of stressor controllability, rats can rotate a wheel to terminate an aversive tailshock (escapable shock; ES). Physically yoked animals receive the same shocks as the ES subjects, but are unable to control the experience, and thus perceive the shock as inescapable (IS). After a single ES session, rats show decreased fear reactivity in fear conditioning, conditioned social defeat compared to IS subjects and even non-stressed controls. While much is known about how uncontrollable stressors can potentiate drug-taking and relapse, little is known about whether ES experience may reverse these negative consequences. Here we report that while rats with a history of repeated cocaine self-administration display impaired neural signaling in the NAc as well as poor acquisition of higher-order associations, these deficits can be prevented or reversed by a single ES experience during the abstinence period, while also decreasing drug seeking in extinction. These control-related effects may derive from functionally overlapping set of circuits between the NAc, prefrontal cortex (PFC) and ventral tegmental area (VTA). This set of structures is known to support motivated learning and stress-induced drug relapse, and while PFC is critical for controllabilty, less is known about whether NAc or VTA also contribute to these processes. To fully characterize this phenomenon, I will first identify how neural signaling in the PFC encodes control-related information and whether this is related to recovered function in motivated learning and resistance to drug relapse. Next, we will use optogenetics to determine the necessity of PFC-to-NAc pathways in establishing the neuroprotective-like effects of control on subsequent learning and relapse. Finally, I will use TH::cre rats to determine whether dopamine signaling is critical for the acquisition and later expression of control-related benefits in motivation and relapse. These findings suggest that controllability may provide a potential therapeutic intervention with clinical implications, while also providing powerful insights into the neural circuits that support stress, addiction and resilience in both drug-experienced and drug-naïve populations.

项目摘要/摘要