Conclusion
It appears that doxepin exerts its effects, at least in part, through activation of the eCBs and the CB1 cannabinoid receptors play a major role in this regard.
Methods
Male Wistar rats received acute and four-week intraperitoneal injections of doxepin (3, 5, and 10 mg/kg) or its vehicle (0.9% saline). One hr after the last injection, animals were exposed to a 5 min swim stress session. In other cohorts of animals, the CB1 receptor antagonist AM251 (0.25, 0.5, and 1mg/kg) was injected 30 min before the administration of doxepin. Plasma corticosterone concentration was measured by enzyme-immunoassay at 45 min following stressing. 1, 5, and 12 hr after the last injection of doxepin, the contents of endocacannabinoids (anandamide and 2-arachidonylglycerol) within the lipid extracts of the prefrontal cortex, amygdala, hippocampus, and hypothalamus were determined using isotope-dilution liquid chromatography-mass spectrometry.
Results
Chronic treatment with doxepin (10 mg/kg) significantly reduced the secretion of corticosterone due to 5 min exposure to swim stress. Acute administration of doxepin evoked no effect. Pre-application of AM251 (1 mg/kg) abolished the ability of doxepin to reduce corticosterone secretion. Chronic administration of doxepin (10 mg/kg) led to a significant elevation of the endocannabinoids in the examined brain regions.