1. ¹Department of Psychology, University of British Columbia, Vancouver, BC, Canada
2. ²Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
3. ³Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada

Correspondence: Dr BB Gorzalka, Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, BC, Canada V6T1Z4. Tel: +1 604 822 2952; Fax: +1 604 822 6923; E-mail: bgorzalka@psych.ubc.ca

Received 6 January 2006; Revised 24 March 2006; Accepted 28 March 2006; Published online 10 May 2006.

Abstract

The efficacy of antidepressants has been linked in part to their ability to reduce activity of the hypothalamic–pituitary–adrenal (HPA) axis; however, the mechanism by which antidepressants regulate the HPA axis is largely unknown. Given that recent research has demonstrated that endocannabinoids can regulate the HPA axis and exhibit antidepressant potential, we examined the hypothesis that the endocannabinoid system is regulated by long-term antidepressant treatment. Three-week administration of the tricyclic antidepressant desipramine (10 mg/kg/day) resulted in a significant increase in the density of the cannabinoid CB₁ receptor in the hippocampus and hypothalamus, without significantly altering endocannabinoid content in any brain structure examined. Furthermore, chronic desipramine treatment resulted in a reduction in both secretion of corticosterone and the induction of the immediate early gene c-fos in the medial dorsal parvocellular region of the paraventricular nucleus of the hypothalamus (PVN) following a 5 min exposure to swim stress. Acute treatment with the CB₁ receptor antagonist, AM251 (1 mg/kg), before exposure to swim stress, completely occluded the ability of desipramine to reduce both corticosterone secretion and induction of c-fos expression in the PVN. Collectively, these data demonstrate that CB₁ receptor density in the hippocampus and hypothalamus is increased by chronic tricyclic antidepressant treatment, and suggest that this upregulation could contribute to the ability of tricyclic antidepressants to suppress stress-induced activation of the HPA axis.