Drug addiction is a chronic disorder characterized by high rates of relapse, even after long periods of abstinence from drug use. Similarly, long-term success of dietary treatments is low because most individuals relapse to unhealthy eating habits within months of starting treatment. Therefore, investigations into the environmental factors and neural mechanisms that increase one's vulnerability to relapse are critical to the development of improved treatment strategies for these major public health problems. Evidence from the clinical literature suggests that relapse is often triggered by exposure to stress. Using an animal relapse model, it has been shown that acute exposure to the pharmacological stressor yohimbine induces relapse to both drug and palatable food seeking in rats. However, no systematic studies on the effects of chronic stress on relapse have been conducted. Because humans are exposed to multiple stressors, both acutely and chronically, it is important to understand the role of chronic stress in relapse vulnerability, as well as the interaction between chronic stress and acute stress during testing on reinstatement. Given that both the behavioral deficits due to acute stress and acute stress-induced relapse involve dopamine D1 receptor-mediated transmission in medial prefrontal cortex, we hypothesize that chronic exposure to stress during drug abstinence or dietary restriction increases one's vulnerability to relapse, and also that this effect is mediated by dopaminergic mechanisms. To test these hypotheses, rats will be trained to press a lever for cocaine or palatable food reinforcers, and the behavior will subsequently be extinguished. To model chronic stress, rats will be injected daily with yohimbine (0.0 or 5.0 mg/kg x 10 days;i.p.), or placed in restrainers (3 h/day x 10 days). To assess dopaminergic involvement, chronic stress will be combined with systemic or intra-medial prefrontal cortex infusions of SCH-23390 (0.0 or 10.0 ?g/kg and 0.0, 0.5, or 1.0 ?g/side, respectively), a dopamine D1-like receptor antagonist. Subsequent to chronic stress, rats will be tested for reinstatement of cocaine or food seeking triggered by acute yohimbine (0.0, 1.0, or 2.0 mg/kg;i.p.) and cocaine or food priming. Our preliminary data indicate that our approach is feasible, and that it can be used successfully as a tool for investigating the neuropharmacological mechanisms of chronic stress effects on relapse.

Public Health Relevance

The overarching goal of the proposed research is to study the effect of chronic stress on subsequent relapse to drug and food seeking. Successful completion of this project will show that chronic stress increases vulnerability to relapse and that this effet is mediated by dopamine D1-like receptors in medial prefrontal cortex. Elucidation of such mechanisms is critical to the development of improved strategies for the treatment of both drug addiction and unhealthy eating habits.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Academic Research Enhancement Awards (AREA) (R15)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Volman, Susan
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Bloomsburg University of Pennsylvania
Schools of Arts and Sciences
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Ball, Kevin T; Stone, Eric; Best, Olivia et al. (2018) Chronic restraint stress during withdrawal increases vulnerability to drug priming-induced cocaine seeking via a dopamine D1-like receptor-mediated mechanism. Drug Alcohol Depend 187:327-334
Ball, Kevin T; Best, Olivia; Luo, Jonathan et al. (2017) Chronic restraint stress causes a delayed increase in responding for palatable food cues during forced abstinence via a dopamine D1-like receptor-mediated mechanism. Behav Brain Res 319:1-8
Ball, Kevin T; Miller, Leah; Sullivan, Christopher et al. (2016) Effects of repeated yohimbine administration on reinstatement of palatable food seeking: involvement of dopamine D1 -like receptors and food-associated cues. Addict Biol 21:1140-1150
Ball, Kevin T; Jarsocrak, Hanna; Hyacinthe, Johanna et al. (2015) Yohimbine reinstates extinguished 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) seeking in rats with prior exposure to chronic yohimbine. Behav Brain Res 294:1-6
Ball, Kevin T; Slane, Mylissa (2014) Tolerance to the locomotor-activating effects of 3,4-methylenedioxymethamphetamine (MDMA) predicts escalation of MDMA self-administration and cue-induced reinstatement of MDMA seeking in rats. Behav Brain Res 274:143-8
Ball, Kevin T; Slane, Mylissa (2012) Differential involvement of prelimbic and infralimbic medial prefrontal cortex in discrete cue-induced reinstatement of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) seeking in rats. Psychopharmacology (Berl) 224:377-85
Ball, Kevin T; Klein, Jessalyn E; Plocinski, Jacob A et al. (2011) Behavioral sensitization to 3,4-methylenedioxymethamphetamine is long-lasting and modulated by the context of drug administration. Behav Pharmacol 22:847-50