Zhiqiang Meng1,2,3, Lais F Berro1, Eileen K Sawyer2,4, Daniela Rüedi-Bettschen1, Jemma E Cook1, Guanguan Li5, Donna M Platt1,2, James M Cook5, James K Rowlett1,2. 1. Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA. 2. New England Primate Research Center, Harvard Medical School, Southborough, MA, USA. 3. Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, CHINA. 4. uniQure Inc., Lexington, MA USA. 5. Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
Abstract
BACKGROUND: 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. AIMS: 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. 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 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.
BACKGROUND: 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. AIMS: 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. 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 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.
Authors: James K Rowlett; Snjezana Lelas; Walter Tornatzky; Stephanie C Licata Journal: Psychopharmacology (Berl) Date: 2005-12-24 Impact factor: 4.530
Authors: Angela N Duke; Zhiqiang Meng; Donna M Platt; John R Atack; Gerard R Dawson; David S Reynolds; V V N Phani Babu Tiruveedhula; Guanguan Li; Michael Rajesh Stephen; Werner Sieghart; James M Cook; James K Rowlett Journal: J Pharmacol Exp Ther Date: 2018-05-02 Impact factor: 4.030
Authors: M Romano-Torres; E Borja-Lascurain; C Chao-Rebolledo; Y del-Río-Portilla; M Corsi-Cabrera Journal: Psychoneuroendocrinology Date: 2002-10 Impact factor: 4.905