RESUMEN
Although alcohol and nicotine are two of the most commonly co-used drugs with upwards of 90% of adults with an alcohol use disorder (AUD) in the US also smoking, we don't tend to study alcohol and nicotine use this way. The current studies sought to develop and assess a novel alcohol + nicotine co-access self-administration (SA) model in adult male and female Long-Evans rats. Further, both drugs are implicated in neuroimmune function, albeit in largely opposing ways. Chronic alcohol use increases neuroinflammation via toll-like receptors (TLRs) which in turn increases alcohol intake. By contrast, nicotine produces anti-inflammatory effects, in part, through the monomeric alpha7 receptor (ChRNa7). Following long-term co-access (6 months), rats reliably administered both drugs during daily sessions, however males generally responded for more alcohol and females for nicotine. This was reflected in plasma analysis with translationally relevant intake levels of both alcohol and nicotine, making it invaluable in studying the effects of co-use on behavior and CNS function. Moreover, male rats show sensitivity to alterations in alcohol concentration whereas females show sensitivity to alterations in nicotine concentration. Rats trained on this procedure also developed an anxiogenic phenotype. Finally, we assessed alterations in neuroimmune-related gene expression in the medial prefrontal cortex - prelimbic, (mPFC-PL), nucleus accumbens core (AcbC), and ventral tegmental area (VTA). In the AcbC, where α7 expression was increased and ß2 was decreased, markers of pro-inflammatory activity were decreased, despite increases in TLR gene expression suggesting that co-use with nicotine modulates inflammatory state downstream from the receptor level. By contrast, in mPFC-PL where α7 was not increased, both TLRs and downstream proinflammatory markers were increased. Taken together, these findings support that there are brain regional and sex differences with co-use of alcohol + nicotine SA and suggest that targeting nicotinic α7 may represent a novel strategy for treating alcohol + nicotine co-dependence.
RESUMEN
Nicotine and alcohol co-use is extremely common and their use constitutes two of the most common causes of preventable death, yet the underlying biological mechanisms are largely understudied. Activation of neuroimmune toll-like receptors (TLRs) promotes the induction of proinflammatory cascades and increases alcohol intake in rodents, which further promotes TLRs in the brain; nicotine may decrease central proinflammatory signaling. The current studies sought to determine the effects of nicotine ± alcohol (alone or in combination) on circulating blood plasma and TLR protein/gene expression in addiction-associated corticolimbic brain regions, including the prefrontal cortex-prelimbic (mPFC-PL) and nucleus accumbens core (AcbC). Adult rats were treated with alcohol (0 or 2 g/kg, IG) and exposed to nicotine vapor (0 or 30 mg/mL solution) daily for 2, 14, or 28 days. Plasma studies indicated no effects of independent exposure or coexposure in males. Coexposure decreased plasma nicotine levels versus nicotine-only treated females, yet alcohol and cotinine concentrations were unchanged. By 28 days, the anti-inflammatory cytokine IL-13 was decreased in alcohol-only females. Divergent changes in TLR3 (but not TLR4) protein occurred for independent-drug exposed males (but not coexposure), with reductions in the mPFC-PL after 14 days and increases in the AcbC by 28 days. Gene expression following chronic coexposure suggests nicotine may regionally counteract alcohol-induced inflammation, including increased AcbC-TLR3/4/7 and several downstream markers in females and increased mPFC-PL-TLR3 and -STAT3 (but not IRF3) evident in males with exposure to either drug alone. These findings give further insight into the role of sex and the neuroimmune system in independent exposure and coexposure to nicotine ± alcohol.