Evaluation of the anti-conflict, reinforcing, and sedative effects of YT-III-31, a ligand functionally selective for alpha 3 subunit-containing GABA(A) receptors

摘要

Background: In recent years, pharmacological strategies have implicated alpha 3 subunit-containing GABA(A) (alpha 3GABA(A)) receptor subtypes in the anxiety-reducing effects of benzodiazepines, whereas transgenic mouse approaches have implicated alpha 2 or alpha 5 subunit-containing GABA(A) receptors. Aims: We investigated the role of alpha 3GABA(A) subtypes in benzodiazepine-induced behaviors by evaluating the anti-conflict, reinforcing, and sedative-motor effects of the novel compound YT-III-31, which has functional selectivity for alpha 3GABA(A) receptors. Methods: Female and male rhesus monkeys were trained under a conflict procedure (n = 3), and a progressive-ratio schedule of reinforcement with midazolam as the training drug (n = 4). Sedative-like behavior was assessed using a quantitative behavioral observation procedure (n = 4). A range of doses of YT-III-31 was administered in all tests using the i.v. route of administration. Results: In the conflict procedure, increasing doses of YT-III-31 resulted only in dose-dependent attenuation of non-suppressed responding. In the progressive-ratio model of self-administration, YT-III-31 maintained average injections/session above vehicle levels at 0.1 and 0.18 mg/kg/injection. In quantitative observation procedures, YT-III-31 engendered mild sedative effects ("rest/sleep posture"), and deep sedation at the highest dose tested (5.6 mg/kg, i.v.), along with a suppression of tactile/oral exploration and increased observable ataxia. In contrast to other benzodiazepine-like ligands, YT-III-31 uniquely engendered a biphasic dose-response function for locomotion and suppressed self-groom. Conclusions: The finding that YT-III-31 lacked anti-conflict properties is in accordance with transgenic mouse research indicating no role for alpha 3GABA(A) subtypes in benzodiazepine-mediated anxiety reduction. Instead, our results raise the possibility of a role for alpha 3GABA(A) receptors in the abuse potential and sedative effects of benzodiazepine-type drugs.