The ability of reward-predictive cues to trigger reward seeking is a major facet of addiction. This ability develops through the process of Pavlovian incentive learning. Importantly, such Pavlovian incentive learning or motivation is distinct from the emotional/hedonic experience of rewards. This distinction is often referred to in the literature as """"""""wanting"""""""" versus """"""""liking"""""""". Endogenous opioid peptides have long been considered mediators of the hedonic aspects of reward. However, recent evidence also implicates endogenous opioid peptides in the motivational aspects of reward processing, including Pavlovian incentive motivation. We predict that hedonia and incentive motivation are underpinned by distinct opioid-containing elements of striatal output circuitry. To test this prediction, we will combine a measure of licking architecture with the Pavlovian-instrumental transfer task to assess both the hedonic impact of sucrose reward and the influence of conditioned cues on sucrose seeking in mice with genetic manipulations of striatal opioid-containing circuitry. Optogenetics will be employed to selectively modulate the activity of direct and indirect striatal outputs while monitoring both behavioral output and dopamine release with fast scan cyclic voltammetry or microdialysis. We will test two major hypotheses. Firstly, that the hedonic effects of opiates are mediated through mu opioid receptors in the indirect striatal output pathway while opiate facilitation of cue-induced reward seeking is mediated through mu opioid receptors in the direct pathway in a dopamine-dependent fashion. This will be addressed using genetic manipulations that either ablate mu opioid receptors from specific elements of striatal circuitry or isolate mu opioid receptor expression to those elements. The second hypothesis tested will be that enkephalin in the indirect pathway mediates palatability in the absence of exogenous drug by acting in the ventral pallidum. We speculate that this same source of enkephalin may influence cue-induced incentive motivation via collaterals to direct pathway neurons. This hypothesis will be tested using selective genetic manipulations of pro-enkephalin expression. Alongside the Pavlovian-instrumental transfer task, we will also apply advanced methodologies such as optogenetics, microdialysis and fast cyclic voltammetry to test our hypotheses.

Public Health Relevance

Addiction is often marked by excessive cue-control of behavior despite diminishing reward experience. This component assesses potential distinct roles of endogenous opioids and receptors in mediating the hedonic impact of rewards versus the invigorating effects of reward-paired signals. This research will clarify the neural mechanisms of how opiates and other addictive substances acting on brain circuitry produce addiction, and will inform future research regarding pharmacotherapies of such addictions.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Special Emphasis Panel (ZDA1-EXL-T)
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University of California Los Angeles
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