Understanding dynorphin and dopamine dynamics during fentanyl exposure

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PROJECT SUMMARY/ABSTRACT The U.S. is currently amidst an opioid epidemic and the rise of illicitly manufactured synthetic opioids like fentanyl is largely responsible for the tripling of overdose deaths. In order to better understand illicit fentanyl use and addiction, we must develop a better understanding of endogenous opioid function. Upregulation of the kappa opioid receptor (KOR) system and its endogenous neuropeptide dynorphin is implicated in disorders of addiction and pain. Activation of KORs, specifically in brain regions enriched with dopamine (nucleus accumbens, NAc, and ventral tegmental area, VTA), produces negative affective states and decreases motivation. However, our recent work along with others has shown that the function of the dynorphin/KOR system in the NAc shell is more nuanced. We have shown that photostimulation of dynorphinergic neurons in the ventral NAc shell drives aversive-like responses and dynorphin release whereas photostimulation of dynorphinergic neurons in the dorsal NAc shell drives reward-like behavior and dynorphin release, A limited understanding of the precise role of dynorphin in drug exposure is in part due to the lack of reliable in vivo measurements of released dynorphin levels. The goal of this proposal is to determine whether dynorphin release is recruited during acute fentanyl exposure in distinct subregions of the NAc and investigate which dynorphinergic projections are critical modulators of affect and fentanyl-induced dopamine release. Dynorphin/KORs are upregulated in the NAc following compulsive drug taking, as shown by increases in mRNA and protein levels. [[However, it is not known if dynorphin is recruited following acute drug exposure and whether this translates to an increase in dynorphin release. In Aim 1, I will directly test the hypothesis that dorsal and ventral NAc shell dynorphin release is differentially activated following acute fentanyl exposure using in vivo microdialysis and voltammetry.]] Although KOR-mediated dopamine suppression is largely attributed to direct action of KORs on dopamine terminals in the NAc, KORs in the VTA also act as a key regulator of affective behaviors and neurotransmission. Still, it is unclear whether dynorphinergic projections from the NAc to the VTA have a distinct role in modulating affect and drug evoked dopamine release. [[ In Aim 2, I will test the hypothesis that distinct dynorphin-expressing neuronal projections from the NAc to the VTA transmit positive and negative valence signals while also regulating fentanyl- induced dopamine release in a biphasic manner using optogenetics, real-time place testing, and fast-scan cyclic voltammetry. Once we understand how dynorphin signaling is recruited during acute fentanyl exposure and how this recruitment modulates fentanyl evoked dopamine release, we can then begin to investigate dynorphin and dopamine dynamics during chronic contingent fentanyl exposure and identify new targets for safe and effective mitigation of illicit fentanyl use and addiction.]] The success of this multidisciplinary fellowship training plan, which incorporates activities to expand my scientific and career development, will be facilitated by the exemplary opportunities in research, collaboration, and education provided by Washington University School of Medicine.