UC Berkeley

Decades of research implicate dopamine neurons as the brain’s center for reward, which drugs of abuse “hijack” to cause addiction. Indeed, nicotine acts on nicotinic acetylcholine receptors on ventral tegmental area dopamine neurons to increase dopamine release and consequently, feelings of reward and pleasure. However, recent research has revealed that a subset of dopamine neurons signal aversion, contrary to the popular belief that dopamine neurons solely mediate reward. At high doses, nicotine is aversive, and understanding how this dose-dependent switch in valence may lead to novel insights for treating nicotine addiction. To dissect the neural circuits that mediate nicotine’s aversive effects, I performed a detailed anatomical, electrophysiological, and behavioral investigation on VTA dopamine neurons, their inputs from the brainstem, and outputs to the nucleus accumbens. With in vivo calcium imaging, I demonstrate that a high dose of nicotine encodes aversion both by suppressing DA release in the canonical reward-signaling lateral mesolimbic pathway and by increasing DA release in the aversion-signaling medial pathway. I introduce an inhibitory input from the brainstem’s laterodorsal tegmentum (LDT) to the VTA that drives aversive behaviors when stimulated and is activated by an aversive dose of nicotine.

Importantly, when this LDT GABA population is ablated, I observed blunted DA release patterns in the nucleus accumbens in response to aversive nicotine compared to animals with an intact LDT. Together, this work provides novel insights into the circuit mechanisms of how a high dose of nicotine may induce aversion by both increasing aversion signaling and reducing reward signaling, and that an inhibitory input from the brainstem may be an important modulator of the mesolimbic pathway in the context of nicotine response.