Antidepressant‐like activity of CGP 36742 and CGP 51176, selective GABA_B receptor antagonists, in rodents

Abstract

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.

Depression Viewed as a GABA/Glutamate Imbalance in the Central Nervous System

“…Later on the second available antagonist, CGP51176 was shown to be active in the forced swim test (Bittiger et al, 1996;Nowak et al 2006). Similar results were observed for other antagonists such as CGP56433A and CGP55845A (Slattery et al, 2005).…”

Stress-induced inhibition of LH pulses in female rats: role of GABA in arcuate nucleus

“…On the other hand, the GABA B R antagonist, CGP-35348, is without effect on systemic stress response (Sirivelu et al 2009). Moreover, GABA B R has been reported to be involved in psychogenic disorders like anxiety and depression (Nakagawa et al 1996, Nowak et al 2006. Nevertheless, the physiological significance of the differential effects of the GABA receptor subtypes observed in the present and previous study remains to be unknown.…”

Gene Expression Profiling in Postmortem Prefrontal Cortex of Major Depressive Disorder

“…ALDH9A1, an enzyme that catalyzes the dehydrogenation of ␥-aminobutyraldehyde to GABA, was increased in depressed brain. GABA B receptor agonists have antidepressant and anxiolytic effects in rodents (Pilc and Nowak, 2005;Nowak et al, 2006). The decreased GABBR1 expression noted in our study would be expected to have a prodepressive effect.…”