Fos Immunoreactivity after Stimulation or Inhibition of Muscarinic Receptors Indicates Anatomical Specificity for Cholinergic Control of Striatal Efferent Neurons and Cortical Neurons in the Rat

Cholinergic neurons play a major role in the control of striatal activity via muscarinic receptors. The action of acetylcholine also appears to be dependent on the striosome – matrix compartmentalization of the striatum. This study was designed to find out whether modification of acetylcholine tone activates neurons in the striatum and forebrain of the rat. We looked for the appearance of immunoreactivity to Fos, a regulatory protein that is thought to convert synaptic signals into changes in gene expression. Pharmacological manipulation of muscarinic receptors was found to induce specific patterns of Fos immunoreactivity in distinct neuronal populations of the forebrain, including the striatum. Oxotremorine, a non-selective muscarinic agonist, induced Fos immunoreactivity in the striatum with a large predominance in striosomes (mostly in enkephalinergic neurons), in layers 4 and 6 of the cortex, and also in the piriform cortex and septum. The muscarinic agonist pilocarpine had an identical effect in the cortex, but the striosomal prevalence was less clear-cut than that observed after oxotremorine. Treatment with dopamine-depleting agents (6-hydroxydopamine or reserpine) and inhibitors of glutamate and opiate receptor (MK-801 and naloxone respectively) had no effect on the action of oxotremorine. This suggests that the induction of Fos provoked by oxotremorine does not involve dopamine, glutamate or opiates. Atropine, a non-specific muscarinic antagonist, also induced Fos immunoreactivity in the striatum but with matrix predominance (mostly in substance P neurons), as well as in the cingulate cortex, and the olfactory tubercle. Scopolamine, a muscarinic antagonist, induced Fos in both striosomal and matrix compartments in the striatum. No Fos immunoreactivity was observed after change in acetylcholine tone in cholinergic or somatostatinergic neurons of the striatum, or in dopaminergic neurons of the substantia nigra. Our results demonstrate that stimulation or inhibition of muscarinic receptors induces Fos activation in striatal efferent neurons with topological (striosome/matrix) and phenotypical (enkephalin/substance P) prevalence and specificity and also in cortical neurons with also topological prevalence. These data suggest that in humans, direct or indirect modifications of the cholinergic neurotransmission induced by pathological states or by drugs may lead to neuronal events in the forebrain triggered by Fos activation.