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 (10mg/kg), dose-dependent
anxiolytic profile in the mouse stress-
induced hyperthermia (100mg/kg), staircase (100 and 300 mg/kg) and elevated zero maze tests (3-100mg/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.