INVOLVEMENT OF THE VENTRAL TEGMENTAL AREA – NUCLEUS ACCUMBENS AND VENTRAL TEGMENTAL AREA – BASOLATERAL AMYGDALA CIRCUITS IN THE REINFORCING EFFECTS OF NICOTINE

Nicotine, the primary psychoactive compound in tobacco, acts on nicotinic acetylcholine receptors in the ventral tegmental area (VTA) and is thought to promote addiction by increasing dopamine release in the nucleus accumbens (NAc), consistent with the classical view that drugs of abuse uniformly activate mesolimbic dopamine circuits. However, recent findings show that nicotine exerts opposing effects on distinct VTA dopamine populations: it activates VTA→NAc neurons while inhibiting VTA→amygdala (Amg) neurons. This divergence suggests that drugs of abuse influence behavior not only by enhancing reward signaling but also by suppressing circuits linked to aversion or anxiety. The aim of this project is to determine how these opposing effects on VTA→NAc and VTA→Amg pathways contribute to reinforcement and reward valuation. Using pathway-specific optogenetic and transgenic strategies combined with electrophysiology, fiber photometry, and behavioral assays, we will first characterize how nicotine and natural stimuli differentially modulate these circuits. With optogenetics, we aim to mimic the specific activation and inhibition patterns induced by drugs, compare them with patterns elicited by natural rewards and aversive stimuli, and assess how these manipulations reproduce or differ from neural responses to drugs. Finally, we will examine how the resulting imbalance between pathway activation and inhibition shapes behavioral responses that may promote the transition from controlled to compulsive drug use. By distinguishing divergent dopamine circuit responses to addictive drugs from natural stimuli, this work aims to refine understanding of circuit-level mechanisms underlying vulnerability to addiction.