Project Summary/Abstract Polysubstance use (PSU) is extremely common, with the majority of substance use treatment seekers reporting the use of multiple substances. Moreover, PSU is becoming increasingly common among adolescents and young adults, with up to 30% of individuals in this age group reporting PSU. Not only is the prevalence of PSU high, but the consequences of PSU are also thought to be worse than for individuals who use single substances. One of the most common substances to be used with any other drug of abuse is nicotine. Marijuana and nicotine co- use is particularly common, with higher overall incidence of marijuana use in the general population and up to 80% of marijuana users reporting that they also use nicotine. Recent epidemiological studies indicate that the co-use of nicotine with THC containing products is increasing, particularly in youth, and those that use both drugs at the same time have worse overall outcomes than those individuals that consume both, but on separate occasions. Thus, there is a need to increase our understanding of the interactions between nicotine and THC, including how they affect the reinforcing properties of each other, whether there are differences in neural responses relative to each substance alone, and whether co-self-administration leads to increased propensity for relapse-like behavior. Thus, in this R21 application, the labs of Drs. Mary Torregrossa and Alan Sved will collaborate to investigate in Aim 1, how nicotine influences THC self-administration. We will examine both the effect of nicotine on acquisition of THC self-administration and acute effects on established THC intake. We will also determine if nicotine alters dopamine release and neural activity in response to THC in the nucleus accumbens shell as a first step toward investigating how nicotine may alter the reinforcing effects of THC. In Aim 2, we will develop a dual catheter system to allow simultaneous intravenous self-administration of THC and nicotine, with the additional goal of making the technique available to other labs interested in PSU research of other drugs of abuse. In addition, we will begin to determine if PSU leads to different outcomes relative to mono- substance use by comparing cue-motivated, relapse-like drug seeking behavior in a cue-induced reinstatement test in rats that self-administered both THC and nicotine versus each substance alone. In both aims, we will compare adolescent and adult groups of males and females to determine if outcomes are different based on age and/or sex. In particular, we are interested in whether or not adolescents are particularly susceptible to the reinforcement-enhancing effects of nicotine/THC combinations that might explain the increased incidence of nicotine and cannabis co-use in youth. Overall, the outcomes of the project will provide the basis for future grant applications that can further probe the neural mechanisms and long-term functional outcomes of PSU and its treatm...