Antidepressant-like activity of CGP 36742 and CGP 51176, selective GABAB receptor antagonists, in rodents

Background and purpose: A crucial role for the GABA(B) receptor in depression was proposed several years ago, but there are limited data to support this proposition. Therefore we decided to investigate the antidepressant-like activity of the selective GABA(B) receptor antagonists CGP 36742 and CGP 51176, and a selective agonist CGP 44532 in models of depression in rats and mice. Experimental approach: Effects of CGP 36742 and CGP 51176 as well as the agonist CGP 44532 were assessed in the forced swim test in mice. Both antagonists were also investigated in an olfactory bulbectomy (OB) model of depression in rats, while CGP 51176 was also investigated in the chronic mild stress (CMS) rat model of depression. The density of GABA(B) receptors in the mouse hippocampus after chronic administration of CGP 51176 was also investigated. Key results: The GABA(B) receptor antagonists CGP 36742 and CGP 51176 exhibited antidepressant-like activity in the forced swim test in mice. The GABA(B) receptor agonist CGP 44532 was not effective in this test, however, it counteracted the antidepressant-like effects of CGP 51176. The antagonists CGP 36742 and CGP 51176 were effective in an OB model of depression in rats. CGP 51176 was also effective in the CMS rat model of depression. Administration of CGP 51176 increased the density of GABA(B) receptors in the mouse hippocampus. Conclusions and Implications: These data suggest that selective GABA(B) receptor antagonists may be useful in treatment of depression, and support an important role for GABA-ergic transmission in this disorder.