Pharmacological rescue of isolation-induced social and neurochemical deficits in Drosophila melanogaster

Social isolation (ISO) is a major risk factor for mood disorders, reflected in disrupted neurochemistry and social behavior. To test whether five days of ISO induce a depression-like state in male Drosophila melanogaster, we measured brain monoamines and social interaction networks (SINs), focusing on dopamine (DA) and octopamine (OA), key regulators of motivation and reward. ISO reduced DA, OA, and tyramine (TA) while increasing acetylcholine, and produced disorganized SINs marked by weaker, shorter interactions, reduced clustering and centrality, and hyperactive, uncoordinated locomotion. To test for rescue, male flies were fed L-DOPA (L-DA), OA, or both during ISO. All treatments improved monoamine levels, with the combined supplementation normalizing or exceeding DA and OA and reducing acetylcholine to control levels. A condition-specific SINs metrics enabled consistent, quantitative comparisons across groups. SINs analyses showed that L-DA or OA alone partially restored connectivity among individuals, whereas combined supplementation most effectively rescued network cohesion, clustering, and centrality, approaching or exceeding mixed sex controls. Null-model comparisons confirmed that the restored networks reflected genuine, non-random structure rather than chance co-movement. Our findings show that five days of ISO induce neurochemical and behavioral changes in male D. melanogaster that resemble depression, and that combined L-DA+OA supplementation robustly restores monoaminergic balance and complex social organization. These results suggest a mechanistic link between brain monoamines and group-level social behavior, highlighting the neurochemical basis of social deficits and their pharmacological rescue.