Alcohol use is a leading cause of preventable disease, disability and death worldwide. Among other factors, exposure to stress or nicotine promotes drinking in humans, yet the neurobiological mechanisms mediating these interactions are unknown. Decades of research indicate that alcohol, stress hormones and nicotine act within the mesolimbic dopamine system to promote behavioral reinforcement. Based on this literature, the central hypothesis guiding my dissertation was that exposure to stress or nicotine promoted drinking via adaptations within ventral tegmental area (VTA). The findings presented in the second chapter of my thesis describe a novel adaptation within the mesolimbic dopamine system contributing to increased alcohol self-administration. Exposure to stress blunted subsequent dopamine responses to alcohol and increased alcohol consumption via VTA stress hormone receptors. These adaptations arose from excitatory GABA transmission onto VTA GABA neurons. Further investigation revealed that excitatory shifts in GABA transmission were associated with the downregulation of the chloride transporter KCC2. Pharmacological enhancement of KCC2 function within the VTA prevented stress-induced drinking, identifying a novel mechanism of stress-induced alcohol consumption. The results in the third and fourth chapters reveal that similar adaptations within the VTA may also contribute to the co-use of nicotine and alcohol. As was observed after stress, exposure to acute nicotine blunted dopamine responses to alcohol and increased alcohol self-administration. Blocking glucocorticoid receptors during nicotine normalized the dopamine signaling and drinking to control levels, indicating that nicotine recruits stress hormone receptors to influence subsequent responses to alcohol. The fourth chapter examines the effects of adolescent nicotine exposure on adult responses to alcohol, since early-life tobacco use confers a major risk for subsequent alcohol abuse. Animals treated with nicotine during adolescence show attenuated dopamine signaling and increased self-administration throughout adulthood. Pharmacological enhancement of KCC2 in adulthood prevented the elevated alcohol intake, highlighting a potential therapeutic role of this drug to reduce alcohol consumption long after the initial nicotine exposure. Taken together, this body of work suggests that exposure to stress or nicotine boosts drinking via anionic plasticity mechanisms within the VTA and implicates KCC2 activation as a potential therapeutic target in the treatment of excessive alcohol consumption.