Neuropharmacological Mechanisms Underlying Incentive Salience and Stress

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Doctor of Philosophy (PhD)
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Nucleus Accumbens
Neuroscience and Neurobiology
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Anhedonia, the lost of interest or pleasure in normally enjoyable activities, is a core clinical feature of major depressive disorder (MDD). Although the term encompasses both consummatory and appetitive components, empirical findings suggest that anhedonia is more closely associated with deficits in motivational processing as opposed to alterations in hedonic valuation of rewards. A growing body of evidence points to a role for the mesolimbic dopamine (DA) system in the etiology of motivational deficits. However, the neurobiological mechanisms underlying the manifestation of anhedonic behavior are still not well understood. Given the frequent presentation of anhedonia in stress-related psychiatric disorders, we hypothesized that exposure to stressors disrupts brain signaling pathways that would typically facilitate reward processing. The experiments in this thesis utilized the novelty-induced hypophagia (NIH) test, a motivational conflict paradigm, to examine the effects of stress on neural processes associated with the attribution of incentive salience to salient stimuli. Using in vivo microdialysis, we assessed the role of nucleus accumbens (NAc) DA transmission in mediating conditioned approach behavior for food reward, and established that stress exposure blunts NAc DA response to palatable food and reduces incentive salience for the reward, as defined by increased latency to approach. Pretreatment with the mixed action opioid drug buprenorphine prevented the behavioral and neurochemical effects of stress in this paradigm, implying a role for the brain opioid system in mitigating the negative effects of stress on incentive behavior. Using a combination of genetic and pharmacological tools, the role of individual opioid receptors in restoring approach behavior suppressed by stress in the NIH test was next dissected. These studies identified the mu opioid receptor as a critical mediator of approach behavior and a potential pharmacological target for alleviating prodepressive behaviors during stress. Lastly, the interaction between elevated stress hormones and treatment with the selective serotonin reuptake inhibitor fluoxetine, a commonly used antidepressant, was investigated on incentive behavior in the NIH paradigm. We found that exogenous corticosterone exposure facilitated reduced approach behavior caused by exposure to chronic fluoxetine in C57BL/6 mice. Thus, exposure to stress hormones enabled fluoxetine to produce a behavior modeling a therapeutic response in a strain of mice that are otherwise insensitive to this antidepressant drug. Collectively, these findings further expand our understanding of the mechanisms underlying stress-induced affective behavior and antidepressant drug treatments.

Irwin Lucki
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