Chronic nicotine treatment enhances cognition and reduces neuroinflammation in the gp120 transgenic mouse model of neuroHIV

Rationale Antiretroviral development has improved the longevity of people with HIV (PWH), but many experience impaired cognition potentially due to neuroinflammation. PWH smoke cigarettes at higher rates than the general population, possibly for self-medication given cognitive-enhancing and anti-inflammatory properties of nicotine, the primary psychoactive ingredient cigarette smoke. We hypothesized that chronic nicotine would improve cognition in a mouse model of HIV, gp120 transgenic (Tg) mice, and reduce neuroinflammation. Methods Male and female gp120-Tg mice (n=64) and littermate controls (n=67) were operantly trained then tested for effortful motivation in the progressive ratio breakpoint task (PRBT). Mice were counter-balanced into three groups for saline or nicotine minipump implantation (0, 14 or 40 mg/kg/day) then retested 25 days later in the PRBT, probabilistic reversal learning task (PRLT – reinforcement learning and cognitive flexibility), and Iowa Gambling Task (IGT – risk-based decision-making), with a subset tested for neuroinflammation (Iba-1 levels). Results Gp120-Tg mice exhibited worse PRLT performance, attenuated by nicotine. Furthermore, nicotine selectively optimized their response strategies in the PRLT and IGT, increasing loss sensitivity, shifting animals towards “safer” responses. No motivation effects were observed. Nicotine also reduced Iba-1 expression, suggesting that its cognitive-enhancing effects may relate to reduced neuroinflammation. Conclusion Gp120-Tg mice exhibited deficits in the PRLT, which are attenuated by chronic nicotine. Furthermore, nicotine improved reinforcement learning and risky decision-making supporting its therapeutic potential for cognitive deficits in PWH, possibly via reducing neuroinflammation. With potential negative consequences of long-term nicotine use, future studies should determine its mechanism of action to develop more targeted therapeutics.