CONICET | Buscador de Institutos y Recursos Humanos

Neuroendocrine response to stress is a fine tuned process that involves neurotransmitters and hormones. Endocannabinoids act as retrograde messengers in the brain that control the release of several neurotransmitters. In this manner, the endocannabinoid system functions as a neuromodulatory system to maintain the homeostasis of the brain, which is constantly challenged by physical and psychological stressors. One major neuroendocrine response to stress is the secretion of corticosterone via activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Expression of endocannabinoid components occurs at different levels controlling HPA axis function. The aim of the present study was to elucidate the role of the endocannabinoid system in the neuroendocrine response to acute neurogenic stress in adult male rats. Male adult Sprague Dawley rats were immobilized for 30 min in an acrylic cilinder. A week previous the experiment, rats were stereotaxically implanted with a cannulae in the cerebral 3rd ventricle to intracerebroventricularly (icv) administration of drugs that modify components of the endocannabinoid system. These drugs were centrally or systemic administered 15 min before stress. We determined plasma corticosterone levels by RIA. Immobilization stress significantly increased (***p<0.001) plasma corticosterone levels. Both anandamide (AEA, 50ng/5uL, icv) and FAAH enzyme inhibitor (URB597, 50ugr/5ul, icv) blocked (^^^p<0.001) the stress-induced increase in corticosterone levels. The blockade of both hypothalamic cannabinoid receptors subtypes with its selective antagonists CB1 (AM251, 500ng/5ul, icv) and CB2 (AM630, 500ng/5ul, icv) further increased plasmatic corticosterone levels in both stressed and no stressed rats. Moreover, the systemic administration of URB597 (0.3mg/kg, ip) or metha-anandamide (MetAEA, 2.5mg/kg, ip), a no hidrolizable anandamide analogue, both decreased (^^^p<0.001) the stressed-increased corticosterone levels. Previously we demonstrated the protein expression and function of CB1 cannabinoid receptors in adrenal cortex. In the present study, we confirmed the presence of CB1 mRNA by RT-PCR. Also we incubated the adrenal glands in the presence of anandamide (AEA, 10-9M) or URB597 (3uM) blocked (^^p<0.01) the stimulatory effect (***p<0.001) of ACTH (10-9M) on corticosterone secretion in vitro. In conclusion, the hypothalamic and adrenal endocannabinoid system blocked the stress-increased corticosterone plasma levels in an acute model of immobilization. Pharmacological enhancement of cannabinoid receptors activity elicits an anti-stress response in rats submitted to an acute model of stress. The ?anti-stress? effect of anandamide was elicited by both hypothalamic cannabinoid receptors. The elucidation of the complex interrelation between neuroendocrine mediators with components of the endocannabinoid system is a usefully tool for future development of therapies that reverts the deleterious stress effects by the recovery of the homeostasis with drugs that modifies the endogenous cannabinoid system. (Grant CONICET PIP 02546).