[Subtypes of muscarinic acetylcholine receptor following the experimental denervation of the cholinergic pathway ascending to the neocortex].

Abstract

Background: Use of an experimentally induced neurotoxic lesion of the ascending cholinergic pathway to the neocortex, in rat brain, to study the postulated selective loss of muscarinic receptor subtypes (mAChR) presynaptically located (autoreceptors).

Methods: Stereotaxic lesion of n. basalis magnocellularis was induced by 25 nmol Ibotenic acid injection in the right brain hemisphere of adult, male, Wistar rats. The contralateral hemisphere served as control. Antagonist (quinuclidinyl-benzilate) and agonist (carbachol) specific binding to mAChR receptors at equilibrium was studied 7 days post-lesion on a P2 fraction of brain cortex homogenate. Displacement of antagonist binding by carbachol was analyzed by "one-point" and "two-point" model fits.

Results: Muscarinic receptors on the control hemisphere show no sign of lesion related changes as compared to data for intact rat brain: Bmax = 0.896 pmol/mg protein and Kd = 0.25 nM. In the lesioned hemisphere a -10.3% loss of antagonist binding (not statistically significant) was observed, with an increase in receptor affinity. Heterogeneity of agonist binding was found; receptor subtype analysis showed that the proportion M2/M1 was unchanged but an increase in carbachol (M2 selective affinity) did appeared.

Conclusions: We found no evidence of a selective presynaptic localization of muscarinic receptor sub-types on terminals of the cholinergic ascending pathway to the neocortex. A receptor loss related to the intensity of the neurotoxic lesion is suggested as well as the presence of regulative mechanisms (hypersensitivity) for receptors.