TLR3-cholinergic interactions underly alcohol+nicotine co-use through differential effects on convergent neuroimmune signaling cascades

Project Summary/Abstract Alcohol and nicotine are two of the most commonly co-used substances. When used in combination, negative health outcomes, including rates of several cancers, increase substantially. Compounding this issue is the growing popularity of nicotine vapor products such as e-cigarettes. One area that has been receiving increased attention in recent years is the role that neuroimmune function plays in substance abuse. It has been shown that alcohol intake increases neuroimmune activation, particularly at specific subtypes of toll-like receptors (TLRs). Moreover, activation of these receptors increases alcohol self-administration, creating a feedback loop. Interestingly, nicotine in the brain has been shown to be anti-inflammatory. As such, we hypothesize that it is this modulation of neuroimmune function that may be crucial in supporting combined alcohol and nicotine dependence. That is, individuals smoke in order to combat the central negative effects of continual alcohol intake (which through this process supports itself). To do so, experiments in each Aim utilize a cutting edge, custom designed nicotine vapor + liquid alcohol delivery system, giving rats the opportunity to self-administer nicotine vapor for inhalation and liquid alcohol for oral consumption, constituting the most translational model for the use of both drugs to date. The experiments in Aim 1 will assess the effects of long-term alcohol, nicotine, and alcohol+nicotine self-administration on expression of neuroimmune markers in rat brain. Moreover, experiments in Aim 1 seek to understand the impact of individual differences and sex differences in self- administration of these drugs on their own, how preference changes when rats have co-access, and how these differences correlate with changes in neuroimmune signaling. Experiments in Aim 2 seek to understand the effects of activating the neuroimmune system in nucleus accumbens core with a TLR3 agonist or a nicotinic α7 agonist on self-administration. Finally, experiments in Aim 3 will assess the effects of genetic manipulation of prefrontal cortical projections to the nucleus accumbens core on self-administration as this PI has previously shown these projections to play an important role in nicotine+alcohol drug sensitivity. Together, these Aims will give a more complete understanding of the role that neuroimmune function, in particular the intersecting roles of TLR3 and α7 in modulating alcohol and nicotine co-use and may lead to the development of more effective therapeutics.