The effects of HIV-1 regulatory Tat expression on nicotine dependence in mice

HIV-1 affects nearly 40 million people worldwide, with people living with HIV disproportionately impacted by tobacco and nicotine use. Despite the high smoking prevalence in this population, the mechanisms underlying nicotine dependence in this context remain poorly understood. Using an HIV-1 Tat transgenic mouse model, we investigated the effects of Tat expression on nicotine intake, preference, and withdrawal-related behaviors. Male and female Tat(+)/Tat(-) mice received chronic nicotine or saline via osmotic minipumps for 14 days and spontaneous withdrawal was evaluated. Withdrawal signs of anxiety-like behavior, somatic signs, thermal hyperalgesia, and anhedonia-like behavior were assessed after short- or long-term Tat expression. Nicotine intake and preference were evaluated using a two-bottle choice (2BC) paradigm. Acute nicotinic behavioral responses were also assessed. Brain and plasma nicotine/cotinine levels were quantified using HPLC-MS/MS to determine pharmacokinetic variables. Short-term Tat expression increased somatic signs of nicotine withdrawal without affecting affective behaviors. However, long-term Tat expression exacerbated somatic and affective symptoms, with somatic signs persisting seven days post-withdrawal. Doxycycline alone did not influence withdrawal. Tat expression did not alter plasma or brain nicotine/cotinine levels, nor did it change acute pharmacological responses to nicotine. In the 2BC paradigm, long-term Tat expression reduced nicotine intake and preference at higher concentrations. In summary, our findings demonstrate that chronic HIV-1 Tat expression exacerbates nicotine withdrawal, producing heightened somatic and affective symptoms, while concurrently reducing nicotine intake and preference.