Modulating the pharmacodynamics of methamphetamine and fentanyl co-use via hypocretin pathways - PROJECT SUMMARY/ABSTRACT Stimulant and opioid dependence are major public health problems and the number of people illicitly using drugs of abuse in combination is rising. In fact, opioid and opioid co-involved overdose related fatalities regrettably reached a devastating new high of more than 107,000 deaths in 2021. Co-use of stimulant and opioids, or polysubstance use, is increasingly reported in clinical survey data, highlighting the need to study the pharmacodynamics of polysubstance use. Uncovering the mechanisms and neurocircuitry underlying polysubstance use is essential to understanding and treating co-existing stimulant and opioid use disorders. Yet, current research primarily targets stimulant or opioid dependence in isolation, thereby limiting discovery of interventions for polysubstance use disorders. The hypocretin/orexin neuropeptide system has been widely implicated in mechanisms of drug addiction, across all classes of drugs and alcohol. Given the universal effect of hypocretin-receptor blockade on mitigating highly motivated drug-taking in animal models, the hypocretin system is a logical target for treatment of polysubstance use disorders in humans. Nonetheless, the role of hypocretin signaling in combined methamphetamine and fentanyl use remains to be examined. The overarching hypothesis of this proposal is that additive opioids, such as fentanyl, enhance methamphetamine self- administration, and that hypocretin signaling within stress-sensitive brain regions of the extended amygdala and the lateral habenula is a key modulator of the enhanced motivation associated with polysubstance use and dependence. Thus, this proposal aims to elucidate the pharmacodynamic nature of polysubstance use across the development and trajectory of dependence utilizing a rat model of concomitant methamphetamine and fentanyl intravenous self-administration (Aim 1) and to systematically examine the hypocretin-related neurobiological mechanisms and neurocircuitry underlying polysubstance dependence using neuropharmacological and chemogenetic DREADDs techniques (Aims 2 & 3). The data obtained from these studies will broaden our understanding of the underlying mechanisms of drug dependence and identify novel therapeutic interventions for treatment of polysubstance use disorders.
