Basal forebrain projections to the lateral habenula regulate ethanol and sucrose consumption

Background: The lateral habenula (LHb) receives afferent input from various basal forebrain (BF) regions known for their role in aversion-related behaviors, depression, and addiction. However, little is known about the role of this circuitry in ethanol consumption, including in the presence of aversive stimuli. Here, we assessed the role of BF input to the LHb in alcohol and sucrose consumption using a chemogenetic approach. Methods: Following long-term intermittent access to alcohol (IAA) or control conditions, male and female Long-Evans rats underwent surgery for the expression of designer receptors in BF-to-LHb projections. We then excited this pathway in rats with IAA history, or inhibited this pathway in rats with limited ethanol history, before testing consumption of ethanol and natural reward both in the presence and absence of quinine adulteration. Results: Long-term IAA elevated ethanol drinking in all rats, and enhanced ethanol preference with and without quinine adulteration in males. Chemogenetic activation of BF-to-LHb neurons in rats with IAA history produced different effects in males and females: excitation enhanced ethanol intake in females, but reduced ethanol preference in males, regardless of quinine adulteration. Activation also led to a relative insensitivity to quinine adulteration of sucrose when compared to controls, particularly in females. Chemogenetic inhibition in rats with limited ethanol history did not alter consumption of ethanol or sucrose, with or without quinine adulteration. Conclusions: Our results suggest a role for BF-to-LHb circuitry in ethanol drinking that may vary based on sex, and a potential role for this circuitry in the sensitivity to quinine when combined with natural reward.