Serotonin and dopamine dynamics during kappa opioid mediated aversion

The National Institute on Drug Abuse awarded the University of Washington $139,812 on August 6, 2026, under the Drug Use and Addiction Research Programs (CFDA 93.279) to conduct basic research on serotonin and dopamine dynamics during kappa opioid-mediated aversion. This Project Grant (F31DA065365) funds investigation of how stress-induced activation of the dynorphin-kappa opioid receptor system modulates serotonin and dopamine signaling in the brain, with implications for understanding stress-induced vulnerability to drug reinforcement and developing therapeutics for substance use disorder and mood disorders. The research examines kappa opioid receptor activation of p38 mitogen-activated protein kinase in serotonergic neurons within the dorsal raphe nucleus and in dopaminergic neurons within the ventral tegmental area, and how this signaling leads to reduced serotonin availability in the nucleus accumbens and aversive responses to stress. Performance occurs in Seattle, Washington with an ultimate completion date of March 15, 2029. The University of Washington Office of Sponsored Programs serves as the prime recipient.

Abstract

/ narrative substance use disorder affects about 24 million people in the US due to the heightened availability of psychostimulants and synthetic opioids. Drug overdose deaths have also dramatically increased, requiring an urgent need to develop new therapeutics for this ongoing epidemic. Identifying how stress increases vulnerability to the reinforcing effects of drugs in susceptible individuals is important for developing effective strategies to treat SUD and mood disorders. Stress activates the release of the endogenous neuropeptide dynorphin (DYN) that activates GΑI/o -coupled kappa opioid receptor (KOR). Activation of KOR leads to the recruitment of the mitogen- activated protein kinase (mapk), specifically P38Α in addition to its canonical GΑI/o·GΒΓ activity. KOR activation of P38Α in serotonergic neurons (5HT) has been shown to mediate stress-induced potentiation of cocaine preference and increased serotonin transporter (sert) function in the dorsal raphe nucleus (DRN). This increase in sert activity is hypothesized to cause a hyposerotonergic state in the nucleus accumbens (NAC). In contrast, during morphine withdrawal, the hyposerotonergia is hypothesized to be a function of increased presynaptic inhibition of 5HT release by KOR. Thus, the mechanism by which KOR activation leads to hyposerotonergia remains to be resolved. Additionally, KOR activation of P38Α in the ventral tegmental area (VTA) dopamine (DA) neurons is also required for aversion in mice, and pharmacological inhibition or selective gene deletion of P38Α in VTA DA neurons blocks the aversive response to stress. Together, the DYN/KOR system remains a potent modulator of both the 5HT and DA systems that regulate the stress response. Understanding how 5HT and DA dynamics are regulated by KOR/DYN is an essential next step in the development of novel therapeutics for stress-induced mood disorders and SUD. Both aims 1 and 2 of the proposal will characterize the pharmacological and behavioral role of stress-induced activation of DYN/KOR/P38Ɑ mapk using in vivo fiber photometry with novel grab sensors and cell-specific crispr gene deletion to monitor real-time 5HT and DA tone in the NAC. These studies will be the first to offer high-resolution, simultaneous analysis of the 5HT/DA systems modulation during stress to describe 1) 5HT/DA sensitivity to P38Α during both pharmacological and behavioral modulation, 2) the mechanism by which KOR g-biased agonists and antagonists may promote stress resilience, and 3) use dual-color imaging to understand 5HT/DA together during stress. These findings will provide foundational knowledge informing stress, neuropharmacology, and opioid fields.