Nicotine-induced acute hyperactivity is mediated by dopaminergic system in a sexually dimorphic manner

- Fruit flies exhibit acute locomotor hyperactivity upon nicotine administration.
- Suppression of dopaminergic neurons or down-regulation of DopR abolishes the acute nicotine response in male flies.
- Dopaminergic neurons have potential synaptic connections with acetylcholinergic neurons in wide brain regions.
- Dopaminergic neurons are activated upon nicotine application in a sexually dimorphic manner.
- Drosophila β1 nAChR subunit plays a crucial role in mediating nicotine-induced acute locomotor hyperactivity.

Short-term exposure to nicotine induces positive effects in mice, monkeys and humans, including mild euphoria, hyperactivity, and enhanced cognition. However, the underlying neural basis and molecular mechanisms for these effects remain poorly understood. Here, using a video recording system, we find that acute nicotine administration induces locomotor hyperactivity in Drosophila, similar to observations made in higher model organisms. Suppressing dopaminergic neurons or down-regulating dopamine 1-like receptor (DopR) abolishes this acute nicotine response, but surprisingly, does so only in male flies. Using a GFP reconstitution across synaptic partners (GRASP) approach, we show that dopaminergic neurons possess potential synaptic connections with acetylcholinergic neurons in wide regions of the brain. Furthermore, dopaminergic neurons are widely activated upon nicotine perfusion in both sexes, while the response curve differs significantly between the sexes. Moreover, knockdown of the β1 nicotine acetylcholine receptor (nAChR) in dopaminergic neurons abolishes the acute nicotine response only in male flies, while panneural knock-down occurs in both sexes. Taken together, our results reveal that in fruit flies, dopaminergic neurons mediate nicotine-induced acute locomotor hyperactivity in a sexually dimorphic manner, and Drosophila β1 nAChR subunit plays a crucial role in this nicotine response. These findings provide important insights into the molecular and neural basis of acute nicotine effects, and the underlying mechanisms may play conserved roles across species.