Mechanisms of nicotine toxicity and addiction-like behavior in Drosophila melanogaster: The role of α7 & β2 nicotinic acetylcholine receptor subunits in sensory valence and cellular stress.

Nicotine addiction and toxicity are complex neurobiological conditions that exerts both toxicological and rewarding effects through nicotinic acetylcholine receptors (nAChRs), which are conventionally treated as separable phenomena, yet the relationship and shared overlapping neurobiological effects remains incompletely understood. This study combined biochemical profiling, transcriptomics, genetics, and olfactory conditioning to examine the mechanisms underlying nicotine's systemic toxicity, cellular stress responses, and addiction-like behavior in Drosophila melanogaster, with a focus on α7 and β2 nAChR subunits. Chronic dietary nicotine exposure (0.15, 0.25, and 0.35 mg/mL for 5 days) reduced survival and locomotor performance, increased reactive oxygen species levels, depleted total thiols, and suppressed acetylcholinesterase (AChE) and monoamine oxidase (MAO) enzymatic activities in control flies; these effects were attenuated innAChRα7-/- and nAChRβ2-/- In addition, transcriptomic re-analysis of a publicly available microarray dataset revealed a coordinated cellular stress response in nicotine-exposed flies, including the altered expression of detoxification genes, odorant-binding protein Obp56h and mechanosensory genes. Behaviorally, nicotine exposure during conditioning altered the innate odor valence and resulted in a persistent punishment-resistant odor preference, defined here as addiction-like behavior; this nicotine-induced reassignment was not observed in mutant flies. Collectively, these data suggest that α7- and β2-nAChR subunits function are mediators of nicotine's toxicological and behavioral effects, and support the use of Drosophila as a model the investigation of nicotinic effects, while recognizing that direct equivalence with mammalian addiction circuitry should not be assumed.