Received for publication August 23, 2005.
Revised December 8, 2005.
Accepted for publication December 8, 2005.

Do subtype-selective GABA_A receptor modulators have a reduced propensity to induce physical dependence in mice?

Abstract

Recent evidence suggests that GABA_A receptors containing a ₁ subunit mediate the sedative effect of diazepam, whereas receptors with a ₂ subunit mediate this benzodiazepines anxiolytic effects. Thus, drugs selective for GABA_A-₂ receptors may offer advantages, i.e. lack of sedation, over current benzodiazepines. Whether such drugs would offer additional advantages over benzodiazepines is unclear. Here we address the issue of physical dependence by comparing (i) the GABA_A-₁ affinity selective drug zolpidem, (ii) the novel compounds L-838,417 and SL651498 with functional selectivity for certain non-₁ GABA_A receptors, (iii) non-selective partial agonists (bretazenil, NS2710, NS2664), and (iv) non-selective full efficacy benzodiazepines in a rapid precipitated withdrawal assay using the inverse agonist FG-7142, in a rapid precipitated withdrawal assay using the inverse agonist FG-7142. For all compounds we determined in-vitro IC₅₀ values to displace [³H]flunitrazepam from rat cortex and in-vivo ED₅₀ values for displacement of [³H]flunitrazepam from mouse forebrain (including length of in-vivo occupancy). In the precipitated withdrawal model compounds were administered at a dose giving ~80% receptor occupancy, obviating major differences in CNS bioavailability. Mice were administered compounds twice daily for 4 days and on day 5, 20h after the final dose, given a dose of FG-7142 (40 mg/kg, i.p.) that did not induce seizures in control animals. In mice treated with the three subtype selective compounds FG-7142 did not induce seizures. Moreover, there was a low propensity for FG-7142 to induce seizures in animals treated with the partial agonists, whereas seizures were clearly seen in animals treated with most benzodiazepines. Nonetheless, differences amongst the benzodiazepines themselves, similarities between the partial agonists and subtype-selective compounds, the in-vitro/in-vivo potency and in-vivo receptor exposure time data suggest a complex interaction between selectivity, efficacy, potency and receptor exposure in determining physical dependence liability of benzodiazepine site modulators in mice.

Key words: GABA_A receptor, L-838,417, SL651498, benzodiazepine, partial agonist, physical dependence