Anxiolytic-like activity of pregabalin in the Vogel conflict test in α2δ-1 (R217A) and α2δ-2 (R279A) mouse mutants

J Pharmacol Exp Ther. 2011 Aug;338(2):615-21. doi: 10.1124/jpet.111.180976. Epub 2011 May 10.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / genetics
  • Animals
  • Anti-Anxiety Agents / metabolism*
  • Anti-Anxiety Agents / therapeutic use
  • Anxiety / genetics
  • Anxiety / metabolism
  • Anxiety / prevention & control
  • Arginine / genetics
  • Calcium Channels / genetics*
  • Calcium Channels / metabolism
  • Conflict, Psychological*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Point Mutation / drug effects
  • Point Mutation / genetics
  • Pregabalin
  • gamma-Aminobutyric Acid / analogs & derivatives*
  • gamma-Aminobutyric Acid / metabolism
  • gamma-Aminobutyric Acid / therapeutic use

Substances

  • Anti-Anxiety Agents
  • CACNA2D1 protein, mouse
  • Cacna2d2 protein, mouse
  • Calcium Channels
  • Pregabalin
  • gamma-Aminobutyric Acid
  • Arginine
  • Alanine