Suppression of preoptic GABA release caused by push-pull-perfusion with sodium valproate.
The in vivo-effects of various concentrations of the anticonvulsant drug sodium valproate--within and above the therapeutic range for humans (40-100 micrograms/ml)--on the release of gamma-aminobutyric acid (GABA) were studied perfusing the preoptic area of unanaesthetized, freely moving ovarectomized rats through push-pull-cannulae at a flow rate of 20 microliters/min with a fraction period of 5 and 15 min, respectively. Local treatment with 40, 80, 100, and 200 micrograms valproate/ml perfusion medium induced a highly significant decrease in preoptic GABA release. After return to valproate-free medium this effect was reversible. A rapid onset and termination of the valproate effect within 5 min could be observed. Going higher with valproate concentrations the suppressive effect became less and at supratherapeutic valproate levels of 1600 micrograms/ml CSF an increase in GABA release could be observed in 4 out of 8 animals. This does response relationship points to a biphasic effect of valproate on the available amount of GABA in the synaptic cleft, which may be produced by at least two different dose-dependent mechanisms of action. The present results indicate that the action of therapeutic concentrations of valproate involves an alteration of GABAergic transmission different from increasing synaptic GABA release. Nevertheless, the data suggest that valproate action, at least at the level of the preoptic area, involves an enhancement of GABAergic transmission causing--via a negative feedback mechanism--the observed suppression of GABA release into the synaptic cleft.
Wolf
R
R
Max-Planck-Institut für Psychiatrie, München, Federal Republic of Germany.
Tscherne
U
U
Emrich
H M
HM
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D009043:Motor Activity / Q000187:drug effects; D010477:Perfusion; D011301:Preoptic Area / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid