Distinct muscarinic receptors enhance spontaneous GABA release and inhibit electrically evoked GABAergic synaptic transmission in the chick lateral spiriform nucleus.
The effects of muscarinic agonists on GABAergic synaptic transmission were examined using whole-cell patch-clamp recording in chick brain slices containing the lateral spiriform nucleus. Bath application of muscarine (10 microM) both increased the frequency of spontaneous GABAergic postsynaptic currents and reduced the amplitude of evoked GABAergic polysynaptic postsynaptic currents elicited by focal afferent fiber electrical stimulation. Both of these muscarinic actions were reversible and dose-dependent. Two M(1) antagonists, telenzepine and pirenzipine, and to a lesser extent the M(2) antagonist methoctramine, protected against muscarine's inhibition of the evoked polysynaptic currents. Other M(2) antagonists (tripitramine and gallamine) as well as the M(3) antagonist 4-DAMP mustard (4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride) and an M(4) antagonist (tropicamide) provided little or no protection against muscarine in this assay. In contrast, 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride, tropicamide and telenzepine, but not pirenzepine, methoctramine, tripitramine and gallamine, blocked muscarine's enhancement of spontaneous GABAergic currents. McN-A-343 [(4-hydroxy-2-butynyl)-1-trimethylammonium-m-chlorocarbanilate chloride] and CDD-0097 (5-propargyloxycarbonyl-1,4,5,6-tetrahydropyrimidine hydrochloride), two M(1) agonists, mimicked muscarine's inhibition of the evoked polysynaptic GABAergic currents but did not mimic muscarine's enhancement of spontaneous GABAergic currents. Both actions of muscarine persisted when slices were pretreated with pertussis toxin or N-ethylmaleimide, which inactivate G-proteins coupled to M(2) and M(4) receptors while leaving G-proteins coupled to M(1), M(3) and M(5) receptors intact. Muscarine had no significant effect on the amplitude of the direct postsynaptic current elicited by exogenous GABA in the presence of tetrodotoxin. The results demonstrate that distinct muscarinic receptors oppositely modulate GABAergic transmission in the lateral spiriform nucleus. The receptor mediating the inhibition of evoked GABAergic polysynaptic currents is pharmacologically similar to an M(1) receptor, while the enhancement of spontaneous GABAergic currents appears to be mediated by an M(3) receptor.
Guo
J
J
Department of Pharmacology, School of Medicine and Health Sciences, The George Washington University, 2300 Eye Street N.W., Washington, DC 20037, USA. phmjzg@gwumc.edu
Chiappinelli
V A
VA
D000818:Animals; D001479:Basal Ganglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002642:Chick Embryo / Q000166:cytology / Q000378:metabolism*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D009116:Muscarine / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D037342:Pertussis Toxin; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D010566:Virulence Factors, Bordetella; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D009116:Muscarine; D037342:Pertussis Toxin; D005033:Ethylmaleimide