Progesterone and allopregnanolone enhance the miniature synaptic release of glycine in the rat hypoglossal nucleus.
It is well known that progesterone is synthesised and metabolised within the nervous system, and that one of its metabolites, allopregnanolone, potentiates the activity of GABA receptor anionic channels and modulates GABAergic neurotransmission. Progesterone is now under clinical trial for its neuroprotective properties, but its possible effects on neurotransmission have not yet been fully explored. The present study investigated acute effects of progesterone on the other major type of synaptic inhibition, glycinergic neurotransmission. Spontaneous glycinergic miniature currents were recorded in hypoglossal motoneurons, using the whole-cell patch-clamp technique in rat brainstem slices. A 20-min superfusion with progesterone (1 mum) triggered an increase in the frequency of glycinergic miniatures, whereas no effect of progesterone was observed after block with finasteride (5 mum) of 5alpha -reductase, the first enzymatic step leading from progesterone to allopregnanolone. The effect of progesterone could be mimicked by superfusion with allopregnanolone (0.3 mum), whereas no effect was induced by epiallopregnanolone. Thus, progesterone can increase the synaptic miniature release of glycine and this effect appears to be indirect, resulting from its metabolism into 5alpha-reduced derivatives, in particular into allopregnanolone. A low concentration of an exogenous GABA(A) agonist can also increase the frequency of inhibitory miniature currents in hypoglossal motoneurons. Thus, the effects of progesterone and allopregnanolone on glycine release can be at least partly explained by the potentiation of the activity of depolarizing presynaptic GABA receptor channels. The increase in the tonic synaptic release of a major inhibitory neurotransmitter should reduce the excitability of the neurons and contribute to their protection against excitotoxicity.
Chesnoy-Marchais
Dominique
D
UMR 788 INSERM-University Paris-Sud 11 Steroids, neuroprotection and neuroregeneration, Bâtiment Grégory Pincus, 80 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cedex, France. dominique.chesnoy@inserm.fr
D000200:Action Potentials / Q000187:drug effects; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D004558:Electric Stimulation; D018755:GABA Agonists / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism* / Q000494:pharmacology; D007002:Hypoglossal Nerve / Q000502:physiology; D007555:Isoxazoles / Q000494:pharmacology; D008526:Medulla Oblongata / Q000166:cytology*; D009046:Motor Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011280:Pregnanolone / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects
D000777:Anesthetics; D018755:GABA Agonists; D007555:Isoxazoles; D011372:Progestins; D011374:Progesterone; D011280:Pregnanolone; C015542:gaboxadol; D005998:Glycine