P.2.g.001 Stimulation of D2 dopaminergic receptor corrects depression-like behaviour in prenatally stressed gonadectomised male rats

Abstract

Statement on the purpose of the study: Prenatal restraint stress (PRS) in rats is a well-documented model of early stress known to induce long-lasting neurobiological and behavioral alterations including impaired feedback mechanisms of the HPA axis, increased anxiety-/depressive-like disturbances and altered brain function of many neurotransmitter systems [1]. Several preclinical and clinical data suggest that DA, acting on D1/D2-like dopaminergic receptors, is one of the most important neuromodulators of despair behavior [2]. On the other hand, the activity of the dopaminergic neurotransmitter system is sensitive to modulation by the gonadal steroids [3]. The aim of this work was to study the effects of administration of D2 receptor agonist quinperole and D2 receptor antagonist sulpiride injected chronically for 14 days alone or in combination with low dose of testosterone propionate on depression-like behavior in adult prenatally stressed male rats. Methods: Initially, rat dams of Wistar strain were exposed to PRS during the last week of pregnancy. After delivery, prenataly stressed male offspring of 3−4 months age were subjected to gonadectomy. Two weeks after gonadectomy, prenatally stressed GDX male rats of 3−4 months age began 14 days of treatment with the vehicle, a low dose of testosterone propionate (1.0mg/kg, s.c.), D2-like dopaminergic agonist, quinpirole (0.1mg/kg, i.p.), D2-like dopaminergic antagonist, sulpiride (0.1mg/kg, i.p.), quinpirole plus testosterone propionate or sulpiride plus testosterone propionate. The animals were then tested in the forced swimming test (FST) and the open field test (OFT). The measurement of lutropine (LH) and testosterone (T) in the blood samples was performed by ELISA. Statistical processing of the received data was carried out with use of one-way ANOVA test and post-hoc test at p< 0.05. Results: The prenatally stressed GDX rats demonstrated the increased immobility time in the FST (p< 0.05). We found that quinpirole significantly decreased immobility time in the prenatally stressed GDX males. A combination of quinpeirole with a low dose of testosterone propionate induced more profound decrease of immobility time in the prenatally stressed GDX rats compared to the rats treated with quinpirole alone. On the contrary, sulpiride failed to modify depression-like behavior in the prenatally stressed GDX rats. In addition, sulpiride significantly blocked the antidepressant-like effect of testosterone propionate in prenatally stressed GDX rats. Thus, quinpirole alone or in combination with a low dose of testosterone propionate exerted antidepressant-like effect in prenatally stressed GDX rats, while the D2 receptor antagonist sulpiride produced depressant-like profile on GDX rats. Also, quinpirole in combination with low dose of testosterone propionate increased T levels, but decreased LH levels in the blood serum of GDX rats compared to the control group (p< 0.05). Conclusions: The results of this study demonstrate that quinpirole and testosterone propionate in prenatally stressed GDX rats interact to exert an antidepressant-like effect and that each of these preparations can improve action of the other drug. This study indicate that prenatal stress can be very important factor in efficacy for antidepressant treatment and limiting factor for using of antidepressants.