Reduced hypothalamic NOS activity and CB1 mRNA cannabinoid receptors are related to behavioral impairments in stressed rats

BERENICE BURDET; DAMIAN MAUR; ANDREA DE LAURENTIIS; RETTORI VALERIA; MA ZORRILLA ZUBILETE

San Diego, California

Congreso; Neuroscience 2013; 2013

Society for Neuroscience

Chronic stress leads to activation of the hypothalamo-pituitary-adrenal axis (HPA) and changes in different parameters in limbic areas associated with stress. The hypothalamus is the main brain structure involved in the neuroendocrine control of stress and anxiety and it has been demonstrated that nitric oxide (NO), a free radical produced by nitric oxide syntase (NOS), participates in these processes. On the other hand, there is evidence that endocannabinoid system can modulate stress responses. The aim of the present work was to study the effect of chronic restraint stress on behavioral impairments and the participation of the endocannabinoid system and NO in these effects (using a NOS inhibitor, L-NAME and a NO donor, Molsidomine). Restraint stress was applied to adult Sprague-Dawley male rats for two hours daily during 7 consecutive days (7d). Inhibitory avoidance and elevated plus maze tests, NOS activity, oxytocin and corticosterone plasma levels and cannabinoid receptor type 1 (CB1) levels in hypothalamus were evaluated. A significant decrease (p<0.001) in the activity of hypothalamic total NOS was found in stressed animals respect to control (C) animals. The expression of hypothalamic CB1 mRNA was significantly reduced (p<0.05) after restraint stress. Oxytocin and corticosterone plasma levels were significantly increased in stressed rats (p<0.01 and p<0.05 respectively). Moreover, we found a significant decrease in the latency to enter into the dark compartment in the 7d respect to C (p<0.05) as well as in 7d+Veh and C+L-NAME groups respect to C+Veh (p<0.01 and p<0.05 respectively) in the inhibitory avoidance test. Also, a significant increase in the percentage of entries and time spent in the open arms in the 7d respect to C (p<0.05) as well as in 7d+Veh and C+L-NAME groups respect to C+Veh (p<0.05) was found in the elevated plus maze test. In conclusion, our model of stress elicited anxiolytic-like behavior and a deficit in associative memory that could be related to the decrease in NO production and CB1 receptors levels in the hypothalamus. Also the increase in oxytocin plasma levels could contribute to the behavioral changes observed. (BID-PICT-2011-1015; PIP 02546)