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Antagonism of the substitution of ethanol, pentobarbital, and midazolam for 1.0 and 2.0 g/kg ethanol by Ro15‐4513 and Ro15‐1788 in cynomolgus monkeys
Author(s) -
Helms Christa Marie,
Rogers Laura SM,
Grant Kathleen A
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.711.12
Subject(s) - chemistry , pharmacology , pentobarbital , potency , receptor , ethanol , antagonist , agonist , midazolam , flumazenil , gabaa receptor , medicine , biochemistry , in vitro , sedation
The GABA A receptors mediating the discriminative stimulus effects of ethanol (EtOH) were studied by comparing the potency of Ro15‐4513 and Ro15‐1788 to antagonize EtOH, pentobarbital (PB) and midazolam (MDZ) substitution for EtOH. Ro15‐4513, a GABA A partial inverse agonist, has high affinity for receptors containing α 4/6 and α 5 subunits and lower affinity for α 1 , α 2 and α 3 subunits. Ro15‐1788 is a structurally‐similar but non‐selective benzodiazepine site GABA A antagonist. Male (n = 9) and female (n = 8) monkeys were trained to discriminate EtOH (1.0 or 2.0 g/kg, i.g., 30‐min pre‐treatment) from water. EtOH, PB and MDZ dose‐dependently substituted for EtOH (≥ 80% EtOH‐appropriate responding). Ro15‐4513 (0.003‐0.56 mg/kg, i.m., 5‐min pre‐treatment) shifted the EtOH, PB and MDZ dose‐response functions rightward in 13/14, 16/16 and 11/11 monkeys tested. Ro15‐1788 (0.30‐10.0 mg/kg, i.m., 5‐min pre‐treatment) shifted the EtOH, PB and MDZ dose‐response functions rightward in 9/14, 8/10 and 7/8 monkeys, respectively. EtOH and PB substitution were more potently antagonized by Ro15‐4513 (mean ± SEM apparent pKB, 6.39 ± 0.07) compared to Ro15‐1788 (4.84 ± 0.09). MDZ substitution was antagonized with similar potency (Ro15‐4513, 7.05 ± 0.08; Ro15‐ 1788, 6.72 ± 0.14). GABA A receptors with high‐affinity for Ro15‐4513 may specifically mediate the discriminative stimulus effects of EtOH. NIH/NIAAA AA10009 and AA13860