Anxiolytic effects of the GABAA receptor partial agonist, L-838,417: Impact of age, test context familiarity, and stress

• Anxiolytic effects of L-838,417 appear to be context-, age-, and stress-dependent.
• Adolescents are less sensitive to anxiolytic effects in an unfamiliar context.
• Reduced investigation in a familiar test may be due to motor-impairing effects.
• In both experiments, L-838,417 reduced locomotor activity at each age.

The partial α2,3,5 GABAA receptor agonist, L-838,417 has been reported to have anxiolytic effects in adult rodents. Although maturational differences exist for the GABAA receptor subunits, the anxiolytic effects of L-838,417 have not been tested in younger animals. The goal of the present experiments was to determine whether L-838,417 reverses anxiety-like behavior induced by either an unfamiliar environment (Experiment 1) or repeated restraint stress (Experiment 2) differentially in adolescent and adult, male and female Sprague–Dawley rats using a modified social interaction test. In Experiment 1, rats were injected with 0, 0.5, 1.0, 2.0, or 4.0 mg/kg L-838,417, i.p. and tested 30 min later in an unfamiliar test context for 10 min. In Experiment 2, rats were exposed to restraint stress (90 min daily for 5 days). Immediately after the last restraint session, animals were injected with L-838,417 and placed alone for 30 min in the test apparatus to familiarize them to this context prior to the 10 min social interaction test. In Experiment 1, L-838,417 produced anxiolytic effects in adults at 1.0 mg/kg, as indexed by a transformation of social avoidance into preference and an increase in social investigation. In adolescents, a dose of 2.0 mg/kg eliminated social avoidance, but had no anxiolytic effects on social investigation. Testing under familiar circumstances (Experiment 2) after repeated restraint stress eliminated age differences in sensitivity to L-838,417, with 0.5 mg/kg reversing the anxiogenic effects of prior stress regardless of age, but with doses ≥ 1 mg/kg decreasing social investigation, an effect possibly due in part to locomotor-impairing effects of this compound. Although locomotor activity was suppressed in both experiments, higher doses of L-838,417 were necessary to suppress locomotor activity in Experiment 1. Thus, anxiolytic effects of L-838,417 were found to be context-, age-, and stress-dependent.