Evaluation of the anxiolytic-like profile of the GABA_B receptor positive modulator CGP7930 in rodents

There is a growing body of data to support the notion that GABA_B receptors may be a therapeutic target for anxiety disorders. However, the application of GABA_B receptor agonists in anxiety research and psychiatry is hampered by side effects that include motor in-coordination and hypothermia. Recently the GABA_B receptor positive modulator GS39783 was shown to be anxiolytic in rodent models, but was devoid of accompanying side effects characteristic of full agonists. However, it is important to test whether such anxiolytic effects generalise to another chemical class of GABA_B receptor positive modulators. We therefore aimed to investigate the anxiolytic and side-effect profile of CGP7930, the first-reported GABA_B receptor positive modulator, in rodent models of anxiety, motor coordination and hypothermia. CGP7930 (3-300 mg/kg) showed a modest, compared to the benzodiazepine chlordiazepoxide (10 mg/kg), dose-dependent anxiolytic profile in the mouse stress-induced hyperthermia (100 mg/kg), staircase (100 and 300 mg/kg) and elevated zero maze tests (3-100 mg/kg), but did not have any anxiolytic effects in the rat elevated plus maze. Similar to GS39783, CGP7930 also demonstrated a greatly reduced side-effect profile in comparison to the GABA_B receptor full agonist baclofen in the mouse rotarod and traction wire tests and did not induce hypothermia. Although the effects of CGP7930 were modest, these results represent a second, structurally distinct, class of GABA_B positive modulators showing anxiolytic activity. As such, these data support the premise that GABA_B receptor positive modulation represents a novel therapeutic strategy for the development of anxiolytic drugs with a superior side-effect profile. The generation of more potent compounds is now warranted.