The α2δ auxiliary subunits (α2δ-1 and α2δ-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 α2δ-1 and α2δ-2 subunits. Two independent point mutant mouse strains were generated in which either the α2δ-1 subunit (arginine-to-alanine mutation at amino acid 217; R217A) or the α2δ-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 anti-conflict activity in wild-type littermates from each strain at a dose of 10 mg/kg but was inactive in the α2δ-1 (R217A) mutants up to a dose of 320 mg/kg. In contrast, pregabalin was active in the α2δ-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 α2δ-1 subunit.
- Received February 24, 2011.
- Revision received May 6, 2011.
- Accepted May 9, 2011.
- The American Society for Pharmacology and Experimental Therapeutics