Sexually Dimorphic Effects of Neuromodulatory Drugs on Normal and Stress-Induced Social Behavior of Rats

Abstract

Social behavior is a complex behavior which involves different interactions between various individuals of a community. It is controlled by different neurotransmitter systems in a sexually dimorphic way. Certain environmental factors, like stress, cause various neurological disorders with associated social abnormalities in a sexually dimorphic way. Multiple drugs are commonly used in clinical settings to treat behavioral disorders. However, there is still a need to assess the sexually dimorphic effects of these drugs, particularly on social behavior. 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) in 8– 12 weeks old male and female rats under normal and stressed conditions. There were four male and four female groups, i.e., control group (no drug treatment), Risperidone (3 mg/kg/day) treated group, Donepezil (5 mg/kg/day) treated group, and Paroxetine (10 mg/kg/day) treated group, divided into two batches (batch 1 and batch 2) to perform maximum 3 behaviors on each batch. Each group received its respective drug during phase I for 21 days, followed by a 10-day break with no drug treatment. After the break, same groups received the same drugs along with tilt-cage stress for an additional 21 days during phase II. Tube dominance test, open filed test, resident intruder test, and social preference and novelty test were performed at the end of both phases (I & II), while home cage activity assessment was done once a week during both phases. In phase I in both sexes, Risperidone treatment decreased social interaction (p<0.001) and motor activity (p<0.001), particularly in male groups, compared to their respective control groups. Donepezil treatment caused an increase in motor activity (p<0.001) in females whereas reduced motor activity in males (p<0.001). Donepezil treatment also caused a reduction in Abstract xxiii social interaction (p<0.001), while Paroxetine treatment caused increased social interaction (p<0.001) and locomotion (p<0.001) in a sex-dependent manner. Social dominance (p<0.001) and aggression (p<0.001) were reduced after treatment with Risperidone and Paroxetine. In contrast, Donepezil treatment caused increased social dominance (p<0.001) and aggression (p<0.05) in both sexes. In phase II, stress led to an overall decrease in motor activity (p<0.001) and social interaction (p<0.001) of animals, while an increase in their dominance (p<0.001) and aggression (p<0.001). Treatment with Risperidone, Paroxetine, and Donepezil caused a sex specific effect on, motor activity (p<0.001), social interaction (p<0.001), social exploration (p<0.001), social dominance (p<0.001), and aggression (p<0.001). Moreover, the size of the space available for exploration, the level of crowding, and the age of the stranger rats were also found to influence the social and non-social behaviors of the animals under normal and stressed conditions. The study showed a predominant effect of Risperidone on males while there were differential effects of Donepezil and Paroxetine on both sexes. This study has paved the way for the development of more targeted and effective neuromodulatory drugs for use against various psychiatric disorders and social deficits.