Evaluation of the anxiolytic-like profile of the GABAB 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 (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.
Jacobson
Laura H
LH
Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
Cryan
John F
JF
D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy* / Q000503:physiopathology*; D001418:Baclofen / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000627:therapeutic use; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005334:Fever / Q000188:drug therapy / Q000209:etiology; D018755:GABA Agonists / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects; D010636:Phenols / Q000627:therapeutic use*; D010807:Physical Endurance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats
C438607:2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol; D014151:Anti-Anxiety Agents; D018755:GABA Agonists; D010636:Phenols; D001569:Benzodiazepines; D001418:Baclofen