Muscarinic desensitization after septal lesions in rat hippocampus: evidence for the involvement of G-proteins.

Three days after bilateral septal lesions, regional and laminar densities of the muscarinic acetylcholine receptors of the dorsal rat hippocampus were studied. The concentration of [3H]N-methylscopolamine binding sites and muscarinic M1 and M2 receptor subtypes, as well as the affinity of muscarinic receptors and their sensitivity to modulation by 5-guanylylimidodiphosphate were analysed by quantitative receptor autoradiography. The measurement of these parameters was performed with a computerized image-processing system allowing a spatial resolution down to the level of single hippocampal layers. No postlesional changes of the density of M1 receptors were detected. M2 receptors showed a remarkable decrease in concentration (less than 21%) in some hippocampal layers after septal lesions. In competition experiments the affinity of muscarinic receptors for the cholinergic agonist carbamylcholine chloride decreased significantly in all hippocampal subregions and layers of the lesioned animals. In contrast to controls, the sensitivity of muscarinic receptors of the lesioned animals could not be modulated by 5-guanylylimidodiphosphate. These findings demonstrate a desensitization of muscarinic receptors in the rat hippocampus three days after septal lesions, which is caused by changes of the coupling of guanine nucleotide-binding proteins to muscarinic receptors. Therefore, the lesion-induced alteration of the muscarinic receptor-effector complex is a major aspect of the hippocampal plasticity after cholinergic denervation.