Ventral tegmental area regulation of stress-induced reinstatement of cocaine-seeking behavior.

摘要

No FDA approved medications currently exist for the prevention of drug craving, drug seeking, and relapse to cocaine use. Stress is a major factor in causing relapse in cocaine dependent individuals. Cocaine use is positively correlated with stress-induced craving and relapse outcomes. Corticotropin-releasing factor (CRF) is a 41-amino acid neuropeptide that plays an important role in the stress response and in the reinstatement rodent model of stress-induced relapse. CRF is released during stress in brain regions associated with the effects of drugs of abuse, notably the ventral tegmental area (VTA). This dissertation addresses key unknown mechanisms behind drug-induced neuroplasticity and how that neuroplasticity gates the ability of stress to cause relapse. Chapter two reports that stress and intra-VTA CRF administration produces robust reinstatement in animals allowed extended long-access (LgA) but not short-access (ShA) cocaine self-administration. Moreover, LgA cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF receptor 1 (CRF-R1) dependent regulation of VTA neurocircuitry. Chapter three characterizes VTA dopamine neuron activation under conditions where stress reinstates cocaine seeking. Dopamine neuron activation was significantly increased in ShA but not LgA rats. However, when examined across groups only in rats that display relapse in response to stress is a significant increase in dopamine neuron activation observed. This suggests that stress-induced reinstatement is associated with increased activation of VTA dopamine neurons. Lastly, chapter 4 addresses the necessity of VTA glutamate and GABA receptors in footshock and intra-VTA CRF dependent reinstatement of cocaine seeking. Intra-VTA administration of NMDA, AMPA, and GABAA receptor antagonists fail to block reinstatement. In contrast, GABAB receptor antagonism blocked reinstatement by both footshock and intra-VTA CRF suggesting GABA B activation is necessary for CRF actions in the VTA. The findings from this dissertation provide much needed insight into the neuroadaptations that occur in the VTA to regulate later stressor induced relapse in cocaine addicts. The hope is that these findings will help with the understanding and eventual long-term management of stressor-induced relapse in abstinent cocaine addicts.