Opposite effects of nicotine on distinct dopamine neurons: a specific role for VTA-Amygdala Pathway in Reinforcement – VAmPiRe

The mesocorticolimbic dopaminergic (DAergic) system originating in the ventral tegmental area (VTA) is involved in many functions such as motivation, decision-making, motor control and reinforcement. Furthermore, many diseases such as schizophrenia, ADHD, hyperactivity, and typically addiction have been linked to this system. Addictive drugs such as nicotine have been hypothesized to access the same mechanisms as reinforcement learning, leading to an overvaluation of the drug reward at the expense of other natural rewards. Nicotine is the psychoactive compound mainly responsible for tobacco addiction. It interacts with nicotinic acetylcholine receptors (nAChRs) a family of pentameric ligand-gated ion channels expressed throughout the mammalian brain, and notably in the VTA. The neuro-circuitry underlying nicotine addiction is broad, complex and disease stage-dependent. Yet, the primary action of nicotine, as of all substances of abuse, is to increase dopamine (DA) in the Nucleus accumbens (NAc). Nicotine does so by binding to somatic nAChRs and activating of VTA DA neurons. However, we recently identified in vivo a large population of DA neurons, located in the medial part of the VTA, that are inhibited by nicotine. This result contrast with the classical view that addictive drugs activate all DA neurons, without distinction, to mediate the rewarding and ultimately addictive effects. My objective is to understand the consequences of a nicotine’s effect that has so far been ignored: the inhibition VTA-amygdala DAergic pathway. Our preliminary results show that nicotine-excited neurons project primarily to the NAc while those that are inhibited project to the amygdala. Nicotine thus activates and inhibits distinct DAergic circuits that may have opposite or synergic effects on reinforcement. The rational of this project is to understand the functions of this two DAergic pathways in reinforcement, how there are modified after chronic exposure to nicotine, and if an imbalance between these two pathways can be related to addiction.

I propose to test this hypothesis by using state of the art approaches including optogenetic, chemogenetic and transgenic tools combined with electrophysiology, calcium imaging and behavioral measures. My research program will be structured around three fundamental axes:

Aim 1: I will Characterize the anatomical and cellular differences between nicotine-excited and nicotine-inhibited cells and investigate the mechanism of nicotine induced inhibition.
Aim 2: I will determine how these two opposite actions of nicotine on DA neurons impact the rewarding properties of the drug and reinforcement leading to addiction. We make the hypothesis that nicotine-induced inhibition of VTA-amygdala projecting DA neurons induces negative states that may counteract the rewarding effect of nicotine-induced activation of the VTA-NAc pathway.
Aim 3: I will examine how repeated nicotine exposure and withdrawal modify these two pathways, and how these modifications could be linked to drug intake and relapse. We will thus ask whether social stress and chronic nicotine exposure differentially affect the neurons acutely inhibited or activated by nicotine and thus impact the balance between the rewarding and negative effects of nicotine, ultimately resulting in higher drug intake.

I believe that the finding resulting from this project allow to redefine our understanding of how nicotine hijack the natural brain reward system to lead to addiction, which is of particular importance for establishing new adequate therapeutic strategies for nicotine abstinence.