Sex-specific effects of neuromodulatory drugs on normal and stress-induced social dominance and aggression in rats

Social hierarchies are important for individual’s well-being, professional and domestic growth, harmony of the society, as well as survival and morbidity. Studies have revealed sexual dimorphism in the social abilities; however, data is limited on the sex-specific effects of various drugs used to treat psychiatric disorders and social deficits. The present study aimed at evaluating the sex-dependent effects of Risperidone (antipsychotic that targets D2 dopaminergic, 5HT2A serotonergic, and α-adrenergic receptors), Donepezil (a reversible acetylcholinesterase inhibitor), and Paroxetine (a selective serotonin reuptake inhibitor) on social hierarchy in rats under normal and stressed states. 8–12 weeks old male and female Wistar rats were divided into sex-wise 4–4 groups, i.e., 1. control group, 2. Risperidone treated group (3 mg/kg/day), 3. Donepezil treated group (5 mg/kg/day), and Paroxetine treated group (10 mg/kg/day). Rats were treated with these drugs in phase I for 21 days in distilled drinking water, followed by a no (drugs) treatment break of 10 days. After the break phase II started with the administration of drugs (same as in phase I) along with tilt-cage stress for 21 days. Home cage activity assessment was performed once a week during both phases (I II), while tube dominance and resident intruder tests were performed at the end of each phase. In phase I in both sexes, Risperidone treatment decreased social interaction and motor activity while Paroxetine treatment increased these in both sexes compared to their respective control groups. Social dominance and aggression were reduced after treatment with both of these drugs. In contrast, Donepezil treatment caused an increase in motor activity in females whereas reduced motor activity in males. Furthermore, Donepezil treatment caused reduction in interaction but increased social dominance and aggression were observed in both sexes. In phase II, stress led to an overall decrease in motor activity and social interaction of animals. Treatment with Risperidone, Paroxetine, and Donepezil caused a sex-specific effect on, motor activity, social interaction, and social exploration. These results showed that Risperidone has stronger effects on male social behavior whereas Paroxetine and Donepezil differentially affect social abilities in both sexes during normal and stressed situations.