In:
Journal of Psychopharmacology, SAGE Publications, Vol. 34, No. 3 ( 2020-03), p. 348-357
Kurzfassung:
In recent years, pharmacological strategies have implicated α3 subunit-containing GABA A (α3GABA A ) receptor subtypes in the anxiety-reducing effects of benzodiazepines, whereas transgenic mouse approaches have implicated α2 or α5 subunit-containing GABA A receptors. Aims: We investigated the role of α3GABA 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 α3GABA 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 α3GABA A subtypes in benzodiazepine-mediated anxiety reduction. Instead, our results raise the possibility of a role for α3GABA A receptors in the abuse potential and sedative effects of benzodiazepine-type drugs.
Materialart:
Online-Ressource
ISSN:
0269-8811
,
1461-7285
DOI:
10.1177/0269881119882803
Sprache:
Englisch
Verlag:
SAGE Publications
Publikationsdatum:
2020
ZDB Id:
2028926-1
