NEUROSTEROIDS MAY DIFFERENTIALLY AFFECT THE FUNCTION OF 2 NATIVE GABA(A) RECEPTOR SUBTYPES IN THE RAT-BRAIN

Hippocampal noradrenergic and cerebellar glutamatergic axon terminals are known to possess GABA(A) receptors mediating, respectively, enhanc ement of noradrenaline (NA) and glutamate release. It has been recentl y found that the hippocampal receptor is benzodiazepine-sensitive, whe reas the cerebellar receptor is insensitive to benzodiazepine agonists . We here tested the effects of neurosteroids on these two native GABA (A) receptors using superfused rat hippocampal and cerebellar synaptos omes. Allopregnanolone (3 alpha,5 alpha-P), at nanomolar concentration s, potentiated the GABA-induced [H-3]-NA release from superfused hippo campal synaptosomes; in the absence of GABA, the steroid was ineffecti ve up to 10 mu M. The enhancement by GABA of the K+-evoked [H-3]-D-asp artate release from cerebellar synaptosomes also was potentiated by na nomolar 3 alpha,5 alpha-P; in addition, at 1-10 mu M, the steroid incr eased [3H]-D-aspartate release in the absence of GABA. Both in hippoca mpus and cerebellum the potentiations of the GABA effects produced by nanomolar 3 alpha,5 alpha-P were abolished by dehydroepiandrosterone s ulphate (DHEAS). Added up to 10 mu M, DHEAS could not inhibit the effe cts of GABA alone. The enhancement of [H-3]-D-aspartate release elicit ed by 3 mu M 3 alpha,5 alpha-P in the absence of added GABA was antago nized completely by bicuculline and picrotoxin and halved by DHEAS. To conclude, 3 alpha,5 alpha-P, at nanomolar concentrations, behaves as a positive allosteric GABA modulator at both the GABA(A) receptors und er study. Low micromolar 3 alpha,5 alpha-P can directly activate the c erebellar receptor, whereas the hippocampal GABA(A) receptor is insens itive to the neurosteroid alone. DHEAS appears to be a pure antagonist at the neurosteroid allosteric sites. Along with the previously obser ved differential sensitivity to benzodiazepines, the present data stre ngthen the idea that the two receptors investigated represent native s ubtypes of the GABA(A) receptor having distinct pharmacology, neuronal localization and function.