Cocaine abuse is a major public health concern in the United States, yet no FDA-approved pharmacotherapies exist. A prominent feature of cocaine abuse and dependence disorders is the frequent occurrence of relapse episodes. Because psychological distress and negative emotional affect are known to induce drug craving and promote relapse in addicted individuals, an understanding of the relationship between stress and addictive processes may help identify effective medications and/or behavioral strategies for relapse prevention. Relapse to drug use is frequently modeled in experimental animals using the reinstatement procedure. In this paradigm, animals are trained to self-administer drugs of abuse via operant responding (e.g. lever-press). Once self-administration behavior is stable, responding can be extinguished by withholding drug availability and/or drug-associated environmental stimuli. Once extinguished, responding can be """"""""reinstated"""""""" by exposing the animal to various stimuli, including stress. However, the most commonly-used stressors to reinstate cocaine- seeking behavior in animals are physical and pharmacological stressors which lack face validity as compared to psychological stressors that induce craving and promote relapse in humans. Social defeat stress occurs in both wild and laboratory rats and can be engendered by placing an """"""""intruder"""""""" rat into the home cage of a """"""""resident"""""""" territorial rat. The """"""""resident"""""""" will quickly threaten and ultimately defeat the """"""""intruder"""""""". Importantly, the psychologicl stress experienced by the intruder has been described as a valid model of the types of psychosocial stress that drug abusers experience prior to a relapse episode. However, whether social defeat stress reinstates cocaine-seeking behavior in animals has not been investigated. This research proposal therefore aims to develop and characterize a novel model of stress-induced reinstatement in rats following exposure to the ethologically-valid psychosocial stressor, social defeat. Rats will be trained to self-administer cocaine and responding will subsequently be extinguished. The first set of experiments will determine whether exposure to acute or repeated social defeat stress reinstates cocaine- seeking behavior, and if so, whether the underlying mechanisms are different from those described previously for physical and pharmacological stressors. Furthermore, as it is known that social defeat stress enhances many of the abuse-related effects of cocaine, a separate set of experiments will examine whether cocaine-primed reinstatement is potentiated in rats with a recent history of social defeat exposure. Overall, the results of these studies would be the first to describe a preclinical model of drug relapse using a rodent psychosocial stressor that closely models the types of stressors that have been found to induce craving and promote relapse in human substance abusers. With such a model available, it may be possible to subsequently identify novel pharmacotherapeutic and/or behavioral strategies to mitigate the effects of psychosocial stress and facilitate relapse prevention in individuals with substance abuse disorders.
Understanding how stress interacts with drugs of abuse, such as cocaine, is critical for developing medications and behavioral treatment programs that promote abstinence and prevent relapse. The goal of this research project is to create a new model of drug use in rats in which exposure to a psychosocial stressor causes relapse to cocaine use. This model could subsequently be used by researchers to identify systems in the brain that could be targeted by medications to prevent stress from causing relapse in human substance abusers.
|Manvich, Daniel F; Stowe, Taylor A; Godfrey, Jodi R et al. (2016) A Method for Psychosocial Stress-Induced Reinstatement of Cocaine Seeking in Rats. Biol Psychiatry 79:940-6|
|Gokhale, Avanti; Vrailas-Mortimer, Alysia; Larimore, Jennifer et al. (2015) Neuronal copper homeostasis susceptibility by genetic defects in dysbindin, a schizophrenia susceptibility factor. Hum Mol Genet 24:5512-23|
|Schmidt, Karl T; Weinshenker, David (2014) Adrenaline rush: the role of adrenergic receptors in stimulant-induced behaviors. Mol Pharmacol 85:640-50|
|Cooper, Debra A; Kimmel, Heather L; Manvich, Daniel F et al. (2014) Effects of pharmacologic dopamine ?-hydroxylase inhibition on cocaine-induced reinstatement and dopamine neurochemistry in squirrel monkeys. J Pharmacol Exp Ther 350:144-52|