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The Journal of Neuroscience, May 1, 1999, 19(9):3629-3638
Cholinergic Modulation of Neostriatal Output: A Functional
Antagonism between Different Types of Muscarinic Receptors
Elvira
Galarraga1,
Salvador
Hernández-López1,
Arturo
Reyes3,
Isabel
Miranda2,
Federico
Bermudez-Rattoni2,
Carmen
Vilchis1, and
José
Bargas1
Departments of 1 Biophysics and
2 Neurosciences, Instituto de Fisiología Celular,
Universidad Nacional Autónoma de México,
México City DF 04510, Mexico, and 3 Escuela de
Biología, Benemérita Universidad Autónoma de
Puebla, Puebla, México
It is demonstrated that acetylcholine released from cholinergic
interneurons modulates the excitability of neostriatal projection neurons. Physostigmine and neostigmine increase input resistance (RN) and enhance evoked discharge of spiny
projection neurons in a manner similar to muscarine. Muscarinic
RN increase occurs in the whole subthreshold voltage range
( 100 to 45 mV), remains in the presence of TTX and
Cd2+, and can be blocked by the relatively selective
M1,4 muscarinic receptor antagonist pirenzepine but not by
M2 or M3 selective antagonists.
Cs+ occludes muscarinic effects at potentials more
negative than 80 mV. A Na+ reduction in the bath
occludes muscarinic effects at potentials more positive than 70 mV.
Thus, muscarinic effects involve different ionic conductances: inward
rectifying and cationic. The relatively selective M2
receptor antagonist AF-DX 116 does not block muscarinic effects
on the projection neuron but, surprisingly, has the ability to mimic
agonistic actions increasing RN and firing. Both effects are blocked by pirenzepine. HPLC measurements of acetylcholine demonstrate that AF-DX 116 but not pirenzepine greatly increases endogenous acetylcholine release in brain slices. Therefore, the effects of the M2 antagonist on the projection neurons were
attributable to autoreceptor block on cholinergic interneurons. These
experiments show distinct opposite functions of muscarinic
M1- and M2-type receptors in neostriatal
output, i.e., the firing of projection neurons. The results suggest
that the use of more selective antimuscarinics may be more profitable
for the treatment of motor deficits.
Key words:
muscarinic receptors; neuromodulation; firing patterns; neostriatum; acetylcholine; Parkinson's disease; basal ganglia
Copyright © 1999 Society for Neuroscience 0270-6474/99/1993629-10$05.00/0
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