Basal forebrain cholinergic immunolesion by 192IgG-saporin: Evidence for a presynaptic location of subpopulations of alpha(2)- and beta-adrenergic as well as 5-HT2A receptors on cortical cholinergic terminals

To study whether the changes in cortical noradrenergic and serotonergic mechanisms observed in patients with Alzheimer's disease are the consequence of reduced cortical cholinergic activity, a navel cholinergic immunotoxin (conjugate of the monoclonal antibody 192IgG against the low-affinity nerve growth factor receptor with the cytotoxic protein saporin, 192IgG-saporin) was used to produce a specific and selective loss of cholinergic cells in rat basal forebrain nuclei. To correlate the responses to cholinergic immunolesion in cholinoceptive cortical target regions with cholinergic hypoactivity, quantitative receptor autoradiography to measure adrenoceptors and 5-hydroxytryptamine (5-HT) receptor subtypes, and histochemistry to estimate acetylcholinesterase activity, were performed in adjacent brain sections. alpha(1)-adrenoceptor and 5-HT1A receptor binding were not affected by cholinergic immunolesion in any of the cortical and hippocampal regions studied. However, cholinergic immunolesion resulted in significantly reduced alpha(2)-and beta-adrenoceptor as well as 5-HT2A receptor binding in a number cortical and hippocampal regions displaying a reduced activity of acetylcholinesterase, already detectable seven days after a single injection of 192IgG-saporin and persisting up to three months post lesion without any significant recovery. The data suggest that at least a subpopulation of alpha 1-and beta-adrenoceptor as well 5-HT2A receptor subtype is present on cortical and hippocampal cholinergic terminals originating in the basal forebrain. The lesion-induced receptor changes suggest that the alterations in cortical 5-HT2 receptor binding observed in patients with Alzheimer's disease might be secondary to the cholinergic deficits.