Differential modification in neuroplasticity pathways in naive and bulbectomized animals by chronic treatment with Δ9-tetrahydrocannabinol and the SSRI fluoxetine

Abstract

Several intracellular pathways involved in cell proliferation and fate of adult hippocampal stem/progenitor cells (AHPs), such as Wnt/β-catenin, AKT/PKB and BDNF, are modulated by antidepressants: fluoxetine (SSRI) treatment has been reported to induce an increase in AKT/PKB pathway activity, cytosolic β-catenin levels and BDNF expression. On the other hand, the endogenous cannabinoid system is involved in the pathophysiology of depression: an increase of CB1 receptor density and functionality is present in animal models of depression, such as olfactory bulbectomy (OB); and increased endocannabinoid levels have been reported in frontal cortex of suicide victims. Here we have studied in rat hippocampus the modulation of the effects of fluoxetine treatment on these intracellular pathways by the coadministration of the cannabinoid agonist Δ9-tetrahydrocannabinol (THC), and the differential response in naive versus bulbectomized animals. We measured in an open-field test the number of deambulations in male Sprague Dawley rats following the chronic administration of THC (10 mg/kg/day, 21 days; i.p.), fluoxetine (10 mg/kg/day, 21 days; p.o.), or the combination of both THC+fluoxetine. The hippocampus of these animals was processed to quantify β-catenin, AKT and BDNF protein levels by western blot. The behavioural pattern of response was not significantly modified by the different treatments in naive animals, while both fluoxetine and the coadministration of fluoxetine+THC partially reversed (p<0.05) the hyperactivity present in OB rats. In naive animals, THC and THC+fluoxetine groups showed a significant decrease of β-catenin (p<0.01), AKT (p<0.001) and BDNF (p<0.001) protein levels vs vehicle. In the OB saline treated group there was also a clear but not significant reduction of β-catenin, AKT and BDNF protein levels vs vehicle treated sham animals. Both THC and fluoxetine treatments produced a significant increase of β-catenin, AKT and BDNF protein levels in hippocampal homogenates (p<0.05) from OB animals. A significantly higher effect was observed in the group corresponding to the association THC+fluoxetine (p<0.01) for these three markers. These results show a clear discrepancy between the response of naive and bulbectomized animals to THC or the coadministration of THC and fluoxetine in some proliferative markers. While THC seems to be antiproliferative in naive animals, 10 mg/kg/day of this cannabinoid clearly reverses the reduction in the expression of proliferation markers in an animal model of depression as the bulbectomized rat. This improvement in hippocampal proliferation is supported by the results of behavioural tests.