Muscarinic receptor stimulation increases the spontaneous [3H]GABA release in the rat substantia nigra through muscarinic receptors localized on striatonigral terminals.
The effect of muscarinic agonists on the spontaneous release of [3H]GABA was investigated in vitro on rat substantia nigra slices. Acetylcholine (5 x 10(-5) M) in the presence of eserine (5 x 10(-5) M) induced a 12.3% increase of the spontaneous release of [3H]GABA. Similarly, carbachol (5 x 10(-4) M) enhanced by 9% the release of [3H]GABA. This effect was Ca(2+)-dependent, it was abolished in the presence of 0.4 mM Ca2+ and enhanced from 9 to 17% when Ca(2+)-concentration of the superfusion medium was increased from 1.3 to 2.4 mM. The carbachol effect was mediated by muscarinic receptors since it was abolished by atropine (2 x 10(-6) M). The pharmacologically M2 muscarinic receptor subtypes seems to be involved as the carbachol-induced effect was abolished by AF-DX384MS (10(-6) M), an M2 antagonist and was only partially reversed by pirenzepine (10(-5) and 10(-4) M), an M1 antagonist which at these doses also block the M2 receptors. The absence of effect of SCH23390 (10(-6) M) a D1 antagonist as well as the lack of effect of CNQX (10(-5) M) and dizocilpine maleate (10(-6) M), two glutamate antagonists, on the carbachol-induced effect indicated that neither dopamine (through D1 receptors) nor glutamate (through ionotropic receptors) were involved in the response. In addition, the persistence of the carbachol-induced effect in the presence of tetrodotoxin (2 x 10(-7) M) suggests a direct muscarinic-mediated modulation of [3H]GABA. The localization of muscarinic receptors on striatonigral fibres was confirmed by autoradiographic studies showing a decrease of [3H]pirenzepine binding in the substantia nigra after a unilateral striatal lesion induced by kainic acid injection. This latter result provides evidence of the presence of M1 receptors on striatonigral terminals as the concentration of [3H]pirenzepine used (10 nM) is M1-selective. These results indicate a cholinergic modulation of GABA release in the rat substantia nigra mediated by muscarinic receptors localized on striatonigral terminals. The involvement of the m4 muscarinic receptor subtype that have a M1/M2 pharmacology is discussed.
Kayadjanian
N
N
Laboratoire de Neurochimie-Anatomie, Institut des Neurosciences, CNRS URA 1488, Université Pierre, Paris, France.
Gioanni
H
H
Ménetrey
A
A
Besson
M J
MJ
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001552:Benzazepines / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D010890:Pirenzepine / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D001552:Benzazepines; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D005680:gamma-Aminobutyric Acid; D002217:Carbachol; D000109:Acetylcholine; D007608:Kainic Acid; D002118:Calcium; D004298:Dopamine