IN-VIVO ADMINISTRATION OF THE 5-HT1A RECEPTOR AGONIST 8-OH-DPAT INTERFERES WITH BRAIN GABA(A) BENZODIAZEPINE RECEPTOR COMPLEXES/

In the present study the influence of in vivo administration, or in vi tro addition, of the prototypic 5-HT1A receptor agonist 8-OH-DPAT on i n vitro characteristics of GABA(A)/benzodiazepine receptor complexes w as examined. In vivo administration of 8-OH-DPAT at a dose (32 mu g/kg , s.c. -10') that has been reported to produce anxiolytic-like effects in the elevated plus-maze doubled the K-d for in vitro binding of H-3 -flunitrazepam to rat cortical membranes (B-max was unchanged) and enh anced GABA-stimulated (3, 10, 30 and 100 mu M) Cl-36(-) influx in cort icohippocampal synaptoneurosomes. In synaptoneurosomes from vehicle tr eated rats, diazepam (1, 3 and 10 mu M) potentiated GABA-stimulated (3 mu M) Cl-36(-) influx. No such effect was observed in tissue from 8-O H-DPAT treated rats, in which the GABA-stimulated (3 mu M) Cl-36(-) in flux was similar to that caused by GABA + diazepam in tissue from vehi cle treated rats. When added in vitro, 8-OH-DPAT failed to alter basal or GABA-stimulated Cl-36(-) uptake. In vivo administration of a low ' 'anxiolytic'' dose of 8-OH-DPAT thus appears to interfere with GABA(A) /benzodiazepine receptor complexes, whereas in vitro application does not. The underlying mechanism remains to be elucidated but could invol ve in vivo release of positive modulators of GABA(A)/benzodiazepine re ceptor complexes, e.g. GABA, endozepines or neurosteroids. (C) 1997 El sevier Science Ltd.