Combined treatment of scopolamine and group III mGluR antagonist, CPPG, exerts antidepressant activity without affecting anxiety-related behaviors

Clinical trials have revealed that the muscarinic receptor antagonist scopolamine produces a fast and potent antidepressant response. However, the anticholinergic adverse effects and the risk of psychosis at higher doses limit the widespread clinical use of scopolamine. Combination therapy of scopolamine and other antidepressants in treating depression has been suggested. Our experiments were designed to examine the effects of the combining ineffective doses of scopolamine and a group III metabotropic glutamate receptor (mGluR) antagonist, CPPG, on depression- and anxiety-related behaviors in male NMRI mice. The forced swim test (FST) and the elevated plus maze (EPM) were selected to evaluate depression- and anxiety-related behaviors, respectively. Intraperitoneal (i.p.) administration of scopolamine (0.01-0.5 mg/kg) exerted profound antidepressive and anxiogenic effects. Intracerebroventricular (i.c.v.) administration of CPPG (12.5-50 nmol/mouse) elicited significant antidepressive and anxiolytic effects. Moreover, the ineffective dose of CPPG (12.5 nmol/mouse) plus ineffective doses of scopolamine (0.01 or 0.05 mg/kg) showed antidepressant-like effect while these combinations had no effect anxiety-related behaviors. It should be noted that none of the compounds altered locomotor activity. Results identify the combined administration of scopolamine and CPPG as a possible hopeful target in the future treatment of the depressive disorder.