Nicotine Withdrawal Drives Aversive Behaviors by Recruiting Inhibitory Interpeduncular Nucleus Inputs to the Laterodorsal Tegmentum in Mice

Nicotine addiction remains a major cause of disease and premature death worldwide. Nicotine modulates neural pathways that underlie both rewarding and aversive behavioral effects, but persistent activation of brain reward circuitry drives nicotine consumption despite the negative consequences. When nicotine users attempt to quit, additional neural mechanisms are recruited to generate an aversive withdrawal state, which contributes to the remarkably high relapse rate among nicotine users. The interpeduncular nucleus (IPN) and its presynaptic inputs from the medial habenula are key mediators of aversive nicotine withdrawal symptoms, but the downstream neural targets mediating these effects are unknown. The aversive effects of acute exposure to high doses of nicotine require inhibitory IPN GABAergic projections to the laterodorsal tegmentum (LDTg), a key driver of reward-related dopamine signaling. Here we show that optogenetic inhibition of these IPN-LDTg projections reduces behavioral and physiological effects of nicotine withdrawal in male and female mice. Using fiber photometry, we found that nicotine withdrawal reduced reward-related signaling with decreases in both LDTg neuronal activity and nucleus accumbens dopamine release. These studies demonstrate a direct link between aversive and appetitive neural pathways that is active during nicotine withdrawal, providing novel targets for treating nicotine addiction. Significance Statement The likelihood of relapse to drug taking is higher for nicotine than all other addictive drugs. While the rewarding effects of the drug and strong cue associations are known to contribute to relapse, avoidance or reduction of withdrawal symptoms is a major factor driving individuals back to nicotine consumption. Indeed, one of the key features of available treatments for nicotine abuse is amelioration of withdrawal signs. Therefore, understanding the neural mechanisms underlying the symptoms of nicotine withdrawal is critical for identifying new treatment strategies. Here we provide compelling evidence that inhibitory projections from the interpeduncular nucleus to the laterodorsal tegmental nucleus is an essential mediator of the symptoms of nicotine withdrawal.