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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 (R_N) and enhance evoked discharge of spiny projection neurons in a manner similar to muscarine. Muscarinic R_N 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 M_1,4 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 R_N 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

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Copyright © 1999 Society for Neuroscience  0270-6474/99/1993629-10$05.00/0

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