An inhibitory brainstem input to dopamine neurons encodes nicotine aversion

Nicotine stimulates the dopamine (DA) system, which is essential for its rewarding effect. Nicotine is also aversive at high doses; yet, our knowledge about nicotine's dose-dependent effects on DA circuits remains limited. Here, we demonstrate that high doses of nicotine, which induce aversion-related behavior in mice, cause biphasic inhibitory and excitatory responses in VTA DA neurons that can be dissociated by distinct projections to lateral and medial nucleus accumben subregions, respectively. Guided by computational modeling, we performed a pharmacological investigation to establish that inhibitory effects of aversive nicotine involve desensitization of a4b2 and activation of a7 nicotinic acetylcholine receptors. We identify a7-dependent activation of upstream GABA neurons in the laterodorsal tegmentum (LDT) as a key regulator of heterogeneous DA release following aversive nicotine. Finally, inhibition of LDT GABA terminals in VTA pre-vents nicotine aversion. Together, our findings provide a mechanistic circuit-level understanding of nicotine's dose-dependent effects on reward and aversion.

Automated summary

Nicotine stimulates the dopamine system and has aversive effects at high doses. This study found that high doses of nicotine cause inhibitory and excitatory responses in VTA DA neurons, which can be separated by projections to different subregions. The aversive effects involve desensitization of a4b2 receptors and activation of a7 receptors, as well as the activation of upstream GABA neurons in the LDT. Inhibiting these GABA neurons prevents nicotine aversion.