Evaluation of the anti-conflict, reinforcing, and sedative effects of YT-III-31, a ligand functionally selective for α3 subunit-containing GABAA receptors.

Zhiqiang Meng, Lais F Berro, Eileen K Sawyer, Daniela Rüedi-Bettschen, Jemma E Cook, Guanguan Li, Donna M Platt, James M Cook, James K Rowlett

Journal of psychopharmacology (Oxford, England) 2020 Mar

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In recent years, pharmacological strategies have implicated α3 subunit-containing GABAA (α3GABAA) receptor subtypes in the anxiety-reducing effects of benzodiazepines, whereas transgenic mouse approaches have implicated α2 or α5 subunit-containing GABAA receptors. We investigated the role of α3GABAA 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 α3GABAA receptors. 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. 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. The finding that YT-III-31 lacked anti-conflict properties is in accordance with transgenic mouse research indicating no role for α3GABAA subtypes in benzodiazepine-mediated anxiety reduction. Instead, our results raise the possibility of a role for α3GABAA receptors in the abuse potential and sedative effects of benzodiazepine-type drugs.

Citation

Zhiqiang Meng, Lais F Berro, Eileen K Sawyer, Daniela Rüedi-Bettschen, Jemma E Cook, Guanguan Li, Donna M Platt, James M Cook, James K Rowlett. Evaluation of the anti-conflict, reinforcing, and sedative effects of YT-III-31, a ligand functionally selective for α3 subunit-containing GABAA receptors. Journal of psychopharmacology (Oxford, England). 2020 Mar;34(3):348-357