Abstract

There seems to be a close relationship between hippocampal N-methyl-d-aspartic acid (NMDA) and GABA(A) receptors with respect to the modulation of behavior that occurs in the CA1 region of the hippocampus. This study investigated the possible involvement of the CA1 GABA(A) receptors in anxiolytic-like effects induced by (+)-MK-801 (a noncompetitive antagonist of the NMDA subtype of the glutamate receptor). Male Wistar rats were subjected to the elevated plus-maze apparatus and open arm time (OAT), and open arm entries (OAE) for anxiety-related behaviors, and closed arm entries that correspond to the locomotor activity were assessed. An intra-CA1 injection of (+)-MK-801 (2 mu g/rat) and muscimol (0.5 mu g/rat; a GABA(A) receptor agonist) increased OAT and OAE by themselves while not altering the closed arm entries, indicating an anxiolytic-like effect of these drugs. Injection of bicuculline (0.1, 0.25, and 0.5 mu g/rat; a GABA(A) receptor antagonist) did not alter any of the anxiety-related parameters. An intra-CA1 injection of a subthreshold dose of muscimol (0.1 mu g/rat) or bicuculline (0.5 mu g/rat), 5 min before injection of subthreshold and effective doses of (+)-MK-801 (0.5, 1 and 2 mu g/rat), increased and decreased the anxiolytic-like effect of (+)-MK-801, respectively. The isobologram analysis of these findings suggested a synergistic anxiety-like effect of intra-CA1 (+)-MK-801 and muscimol. In conclusion, the CA1 GABA(A) receptors appear to be involved in anxiolytic-like behaviors induced by (+)-MK-801.