Details

Autor(en) / Beteiligte

• Rowlett, James K
• Platt, Donna M
• Lelas, Snjezana
• Atack, John R
• Dawson, Gerard R

Titel

Different GABA sub(A) receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2005-01, Vol.102 (3), p.915-920

Erscheinungsjahr

2005

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Benzodiazepines exert their effects by binding to multiple subtypes of the GABA sub(A) receptor, the predominant subtypes in the brain being those that contain alpha sub(1)-, alpha sub(2)-, alpha sub(3)-, and alpha sub(5)-subunits. To understand the potentially different roles of these subtypes in the therapeutic and side effects of benzodiazepines, we evaluated GABA sub(A) receptor subtype-preferring compounds in nonhuman primate models predictive of anxiolytic, sedative, motor, subjective, and reinforcing effects of benzodiazepine-type drugs. These compounds included zolpidem, which shows preferential binding to GABA sub(A) receptors containing alpha sub(1)-subunits (alpha sub(1)GABA sub(A) receptors); L-838,417, which shows functional selectivity for alpha sub(2)GABA sub(A), alpha sub(3)GABA sub(A), and alpha sub(5)GABA sub(A) receptors; and nonselective conventional benzodiazepines. The results provide evidence in nonhuman primates that alpha sub(1)GABA sub(A) receptors do not play a key role in the anxiolytic and muscle-relaxant properties of benzodiazepine-type drugs; instead, these effects involve alpha sub(2)GABA sub(A), alpha sub(3)GABA sub(A), and/or alpha sub(5)GABA sub(A) subtypes. Our results also suggest that the alpha sub(1)GABA sub(A) receptor subtype might be critically involved in the subjective, sedative, and motor effects of benzodiazepine-type drugs. In contrast, stimulation of alpha sub(1)GABA sub(A) receptors is sufficient, but not necessary, for mediation of the abuse potential of these drugs.