Anxiogenic properties of an inverse agonist selective for α3 subunit‐containing GABAA receptors

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Abstract
1 α3IA (6‐(4‐pyridyl)‐5‐(4‐methoxyphenyl)‐3‐carbomethoxy‐1‐methyl‐1H‐pyridin‐2‐one) is a pyridone with higher binding and functional affinity and greater inverse agonist efficacy for GABAA receptors containing an α3 rather than an α1, α2 or α5 subunit. If doses are selected that minimise the occupancy at these latter subtypes, then the in vivo effects of α3IA are most probably mediated by the α3 subtype. 2 α3IA has good CNS penetration in rats and mice as measured using a [3H]Ro 15‐1788 in vivo binding assay. 3 At doses in rats that produce relatively low levels of occupancy (12%) in the cerebellum (i.e. α1‐containing receptors), α3IA (30 mg kg−1 i.p.), like the nonselective partial inverse agonist N‐methyl‐β‐carboline‐3‐carboxamide (FG 7142), not only caused behavioural disruption in an operant, chain‐pulling assay but was also anxiogenic in the elevated plus maze, an anxiogenic‐like effect that could be blocked with the benzodiazepine antagonist Ro 15‐1788 (flumazenil). 4 Neurochemically, α3IA (30 mg kg−1 i.p.) as well as FG 7142 (15 mg kg−1 i.p.) increased the concentration of the dopamine metabolite 3,4‐dihydroxyphenylacetic acid in rat medial prefrontal cortex by 74 and 68%, respectively, relative to vehicle‐treated animals, a response that mimicked that seen following immobilisation stress. 5 Taken together, these data demonstrate that an inverse agonist selective for GABAA receptors containing an α3 subunit is anxiogenic, and suggest that since α3‐containing GABAA receptors play a role in anxiety, then agonists selective for this subtype should be anxiolytic. British Journal of Pharmacology (2005) 144, 357–366. doi:10.1038/sj.bjp.0706056