Antidepressant-like effects of chronic cannabinoid agonist and antagonist treatments in the olfactory bulbectomy model of depression in rats

Maha ElBatsh, Clare Spicer, Charles Marsden, Kevin Fone, David Kendall. Institute of Neuroscience, School of Biomedical Sciences, The University of Nottingham, Nottingham, United Kingdom.

Previous studies have suggested possible therapeutic benefits of cannabinoids in depression. The situation is complicated by reports of cannabinoid receptor agonists and antagonists displaying both anxiolytic- and anxiogenic-like effects in rodent models of anxiety and depression.

The olfactory bulbectomized (OB) rat is a well-characterized animal model that exhibits a number of behavioural and neurochemical changes that have relevance to clinical depression. Hyperactivity in the open field is a robust phenotypic feature of this model which is reported to be reversed following chronic, but not acute, antidepressant treatment, simulating the clinical situation, in which mood elevation is only seen following 2-4 weeks of drug therapy (Kelly et al., 1997).

In the present study, we investigated the effects of chronic administration of Δ9tetrahydrocannabinol (THC), the principal psychoactive component of marijuana, and rimonabant (a selective CB1 receptor antagonist) on the behaviour of OB-rats in the open field test. Because brain-derived neurotrophic factor (BDNF) is considered to have a role in depression and the action of antidepressant drugs, we measured the expression of BDNF protein and its receptor tyrosine receptor kinase B (TrkB) in addition to other proteins with reported involvement in stress and depression such as cyclic adenosine monophosphate response element binding protein (CREB),phospho-CREB(pCREB), extracellular signal-regulated kinases (ERK), phospho-ERK (pERK) and glucocorticoid receptors (GR) in the hippocampus and frontal cortex.

In the open field test, the OB-rats showed the expected hyperactivity response 14 days after surgery in the form of significant increases in the total distance moved. Chronic treatment with THC (2mg/kg, ip injection every 48 h for 3 weeks, n = 10) significantly reduced the total distance moved by OB-rats. Also chronic treatment with rimonabant (5mg/kg, ip injection every 48 h for 3 weeks, n = 9) significantly reduced the total distance moved by OB-rats. There was a significant reduction in body weight of all OB groups compared to shams. There was a reduction in the adrenal gland weight in the OB rats treated with vehicle or rimonabant without changes in plasma corticosterone level. The expressions of BDNF, TrkB, CREB, pCREB, ERK, pERK and GR were not significantly affected either in the hippocampus or in the frontal cortex.

These results indicate an antidepressant-like effect of THC and rimonabant in the OB model of depression in rats. The lack of effect of THC or rimonabant on the expression of proteins integral to mitogen-activated protein (MAP) kinase and cyclic AMP signalling and CB1 receptor density suggest different mechanisms of action which requires further investigation.

Kelly JP et al. (1997). Pharmacology & Therapeutics, 74, 299-316.

This work was supported by a scholarship from the Egyptian Government to ME-B.