Patterns and neurocognitive consequences of opioid-alcohol polysubstance use

Project Abstract Opioid-alcohol polysubstance use (PSU) is a clinically-relevant problem, as it worsens the trajectories and outcomes of opioid use disorder (e.g., 14-16% of opioid overdoses also involve alcohol). Both alcohol and opioid use alone are associated with significant neurobehavioral consequences, such as impaired cognition, but it is not currently known if there are additive or synergistic impairments in such domains in opioid-alcohol PSU. In order to determine the mechanisms underlying the deleterious consequences of opioid-alcohol PSU (e.g. motivation to seek drug, relapse, cognition), rodent models are necessary. Here, we propose to develop novel rodent models based on back-translated data from human opioid-alcohol polysubstance users. Thus, in this 2- phase R61/R33 proposal, we will first assess human temporal patterns of opioid and alcohol use, in terms of hour-by-hour and day-by-day use, using our novel assessment, the PolySubstance Use – Temporal Pattern Section (PSU-TPS). We will also use the Substance Abuse Module-5 (SAM-5) to determine quantity, frequency, and duration (QFD) of use and the presence of use disorders. These data will be used to define clusters of PSU patterns, based on hours/day and days/month of use, and whether use is sequential, concurrent, or simultaneous. In the same participants, cognition will be assessed at baseline and one year later. The domains of interest include working and episodic memory, impulsivity, risky decision-making, and cognitive flexibility. We will determine associations between opioid/alcohol use and cognition at both baseline and at the one year follow- up. We will also compare the adverse consequences of use between PSU clusters, with a focus on QFD of use, percent meeting DSM-V criteria for use disorder, and cognitive impairments. We will then back-translate the most prevalent PSU patterns with deleterious consequences into rodents for the assessment of intravenous opioid self-administration, motivation to seek opioids using demand curve analyses, and relapse to opioid- seeking. We will also use rodent models to directly test the role of opioid and alcohol use and polysubstance use on such cognitive impairments, using rodent tasks that have been established to assess the same domains as in humans. We will also assess whether the two patterns of PSU alter the pharmacokinetics of alcohol and opioids. This proposed 2-phase study brings together a multidisciplinary team of experts in their fields to conduct novel assessments of the patterns and consequences of real-world opioid-alcohol polysubstance use for the establishment of translational animal models that can advance the field.