Abstract

Antidepressant drugs have a clinical latency that correlates with the development of neuroadaptive changes, including down-regulation of β-adrenergic receptors in different brain regions. The identification of drugs that shorten this latency will have a great impact on the treatment of major depressive disorders. We report that the time required for the antidepressant imipramine to reduce the expression of β-adrenergic receptors in the hippocampus is reduced by a co-administration with centrally active ligands of type 2/3 metabotropic glutamate (mGlu2/3) receptors. Daily treatment of mice with imipramine alone (10 mg/kg, i.p.) reduced the expression of β-adrenergic receptors in the hippocampus after 21 days, but not at shorter times, as assessed by western blot analysis of β1-adrenergic receptors and by the amount of specifically bound [3H]CGP-12177, a selective β-adrenergic receptor ligand. Down-regulation of β-adrenergic receptors occurred at shorter times (i.e. after 14 days) when imipramine was combined with low doses (0.5 mg/kg, i.p.) of the selective mGlu2/3 receptor agonist LY379268, or with the preferential mGlu2/3 receptor antagonist LY341495 (1 mg/kg, i.p.). Higher doses of LY379268 (2 mg/kg, i.p.) were inactive. This intriguing finding suggests that neuroadaptation to imipramine – at least as assessed by changes in the expression of β1-adrenergic receptors – is influenced by drugs that interact with mGlu2/3 receptors and stimulates further research aimed at establishing whether any of these drugs can shorten the clinical latency of classical antidepressants