GABA-A RECEPTOR SUBTYPES MEDIATING SUBJECTIVE EFFECTS OF BENZODIAZEPINES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent reports suggest that the alpha-1/GABA-A receptor may play a key role in mediating the discriminative stimulus effects of conventional benzodiazepines (BZs) as well as BZ-type compounds selective for specific GABA-A subunit-containing receptors. L-838,417 is a BZ-site ligand with partial agonist efficacy at alpha-2, alpha-3, and alpha-5-subunit containing GABA-A receptors, but is an antagonist at alpha-1 subunit-containing GABA-A receptors. This subproject evaluated the discriminative stimulus effects of L-838,417 in order to determine the extent to which the alpha-2, alpha-3, and alpha-5 subunits of the GABA-A receptor contribute to the interoceptive effects of conventional BZ agonists. Squirrel monkeys were trained to discriminate L-838,417 from vehicle under a fixed-ratio schedule of food reinforcement. Under test conditions, L-838,417 engendered dose-dependent increases in drug lever responding without any effect on rates of responding. Conventional non-selective BZ agonists, e.g., triazolam, diazepam, and lorazepam, engendered full substitution for L-838,417 (80-100 per cent drug-lever responding). Surprisingly, compounds with selective affinity for alpha-1/GABA-A receptors, including zolpidem, zaleplon, and CL218872, engendered approximately 80 per cent of drug-lever responding at doses that did not alter response rates.