Involvement of the Endocannabinoid System in the Ability of Long-Term Tricyclic Antidepressant Treatment to Suppress Stress-Induced Activation of the Hypothalamic–Pituitary–Adrenal Axis

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 CB 1 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 CB 1 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 CB 1 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.

Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

“…Blenov and colleagues used mice, and alcohol was available daily. There are also studies showing that environmental stress can markedly affect endocannabinoid neurotransmission (Hill et al 2006;Patel et al 2005;Rademacher and Hillard 2007), and thus it can be speculated that different responses to the blockade of FAAH may also depend on the endogenous tone of the system at the moment of drug administration.…”

Long-Term Fluoxetine Treatment Modulates Cannabinoid Type 1 Receptor-Mediated Inhibition of Adenylyl Cyclase in the Rat Prefrontal Cortex through 5-Hydroxytryptamine1AReceptor-Dependent Mechanisms

“…Some of them suggest an enhancement of CB 1 receptor expression in brain areas with a well established role in depression (Hill et al, 2006a,b;Hill et al, 2007). Increased CB 1 receptor density in the rat PFC has been reported after long-term administration of the monoamine oxidase inhibitor tranylcypromine or with fluoxetine (Hill et al, 2008b) but not with the tricyclic desipramine (Hill et al, 2006a). Although the absence of CB 1 receptor expression modulation by fluoxetine reported here is in contrast to the findings of Hill et al (2008b), probably because of differences in the treatment regimen between both studies, our data demonstrating up-regulated CB 1 receptor coupling to G␣ i proteins/AC strengthen the idea that long-term administration of chemical antidepressants enhance CB 1 receptor activity in this brain area.…”

Endogenous cannabinoid signaling is essential for stress adaptation

“…Trunk blood collected at the same time was analyzed for corticosterone. Regions of interest included the prefrontal cortex, amygdala, thalamus, hypothalamus, and hippocampus, which were rapidly dissected and frozen on dry ice (41). Brain regions were subjected to a lipid extraction process (21), in which the contents of the two primary endocannabinoids, AEA and 2-AG, were obtained from lipid extracts in methanol using isotope-dilution, liquid chromatography−mass spectrometry as previously described (42).…”