gamma-Aminobutyric acid type A/benzodiazepine receptors regulate rat retina neurosteroidogenesis.
It has been previously shown that retinal ganglion cells have the ability to synthesize steroids including neuroactive steroids such as pregnenolone sulfate. Since ganglion cells possess GABAA/benzodiazepine (BZ) receptors and neurosteroids modulate retinal GABAA receptor function, we investigated the role of these receptors in isolated rat retina neurosteroidogenesis. Ligands for central-type BZ receptors stimulated retinal pregnenolone synthesis. Clonazepam was the most potent ligand examined acting at nanomolar concentrations. Moreover, the effective steroidogenesis stimulatory dose (ED50) for these ligands and the Ki to inhibit [3H]flunitrazepam binding showed a coefficient of correlation of r = 0.87, suggesting the involvement of the central-type BZ receptors in this event. Ro 5-4864, which preferentially binds to peripheral-type BZ receptors, was less efficacious and potent whereas PK 11195 did not affect the basal pregnenolone formation and did not antagonize the Ro 5-4864 stimulated steroid synthesis. The GABAergic agonist muscimol, stimulated neurosteroid synthesis and this effect was reversed by the GABAergic antagonists bicuculline and picrotoxinin. In addition, these antagonists decreased basal pregnenolone formation, suggesting a tonic GABAergic control of the steroidogenic pathway, and reduced clonazepam-stimulated steroidogenesis. These results, together with the reported ability of neurosteroids to modulate GABAA receptor function, suggest a novel regulatory mechanism to control the inhibitory transmission.
Guarneri
P
P
Istituto di Biologia dello Sviluppo, CNR, Palermo, Italy.
Guarneri
R
R
Cascio
C
C
Piccoli
F
F
Papadopoulos
V
V
D000818:Animals; D005445:Flunitrazepam / Q000378:metabolism / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000096:biosynthesis*; D011284:Pregnenolone / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D012160:Retina / Q000187:drug effects / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D013256:Steroids; D005445:Flunitrazepam; D011284:Pregnenolone; C037850:PK 11195