title: Anxiolytic-like activity of pregabalin in the Vogel conflict test in α2δ-1 (R217A) and α2δ-2 (R279A) mouse mutants.
abstract: The α(2)δ auxiliary subunits (α(2)δ-1 and α(2)δ-2) of voltage-sensitive calcium channels are thought to be the site of action of pregabalin (Lyrica), a drug that has been shown to be anxiolytic in clinical trials for generalized anxiety disorder. Pregabalin and the chemically related drug gabapentin have similar binding and pharmacology profiles, demonstrating high-affinity, in vitro binding to both α(2)δ-1 and α(2)δ-2 subunits. Two independent point mutant mouse strains were generated in which either the α(2)δ-1 subunit (arginine-to-alanine mutation at amino acid 217; R217A) or the α(2)δ-2 subunit (arginine-to-alanine mutation at amino acid 279; R279A) were rendered insensitive to gabapentin or pregabalin binding. These strains were used to characterize the activity of pregabalin in the Vogel conflict test, a measure of anxiolytic-like activity. Pregabalin showed robust anticonflict activity in wild-type littermates from each strain at a dose of 10 mg/kg but was inactive in the α(2)δ-1 (R217A) mutants up to a dose of 320 mg/kg. In contrast, pregabalin was active in the α(2)δ-2 (R279A) point mutants at 10 and 32 mg/kg. The positive control phenobarbital was active in mice carrying either mutation. These data suggest that the anxiolytic-like effects of pregabalin are mediated by binding of the drug to the α(2)δ-1 subunit.
authors.affiliation: Departments of Neuroscience, Pfizer Global Research and Development, Eastern Point Road MS 8220-4176, Groton, CT 06340, USA. susan.lotarski@pfizer.com
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lotarski
authors.forename: Sean
authors.initials: S
authors.lastname: Donevan
authors.forename: Ayman
authors.initials: A
authors.lastname: El-Kattan
authors.forename: Sarah
authors.initials: S
authors.lastname: Osgood
authors.forename: Julie
authors.initials: J
authors.lastname: Poe
authors.forename: Charles P
authors.initials: CP
authors.lastname: Taylor
authors.forename: James
authors.initials: J
authors.lastname: Offord
mesh_terms: D000409:Alanine / Q000235:genetics; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism* / Q000627:therapeutic use; D001007:Anxiety / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D001120:Arginine / Q000235:genetics; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D003220:Conflict, Psychological; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017354:Point Mutation / Q000187:drug effects / Q000235:genetics; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D014151:Anti-Anxiety Agents; C512066:CACNA2D1 protein, mouse; C486058:Cacna2d2 protein, mouse; D015220:Calcium Channels; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D001120:Arginine; D000409:Alanine