BASAL FOREBRAIN CHOLINERGIC IMMUNOLESION BY 192IGG-SAPORIN - EVIDENCEFOR A PRESYNAPTIC LOCATION OF SUBPOPULATIONS OF ALPHA(2)-ADRENERGIC AND BETA-ADRENERGIC AS WELL AS 5-HT2A RECEPTORS ON CORTICAL CHOLINERGICTERMINALS

To study whether the changes in cortical noradrenergic and serotonergi c mechanisms observed in patients with Alzheimer's disease are the con sequence 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 s aporin, 192IgG-saporin) was used to produce a specific and selective l oss of cholinergic cells in rat basal forebrain nuclei. To correlate t he responses to cholinergic immunolesion in cholinoceptive cortical ta rget regions with cholinergic hypoactivity, quantitative receptor auto radiography to measure adrenoceptors and 5-hydroxytryptamine (5-HT) re ceptor subtypes, and histochemistry to estimate acetylcholinesterase a ctivity, were performed in adjacent brain sections. alpha(1)-adrenocep tor and 5-HT1A receptor binding were not affected by cholinergic immun olesion in any of the cortical and hippocampal regions studied. Howeve r, 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 acet ylcholinesterase, already detectable seven days after a single injecti on of 192IgG-saporin and persisting up to three months post lesion wit hout any significant recovery. The data suggest that at least a subpop ulation of alpha 1-and beta-adrenoceptor as well 5-HT2A receptor subty pe is present on cortical and hippocampal cholinergic terminals origin ating in the basal forebrain. The lesion-induced receptor changes sugg est that the alterations in cortical 5-HT2 receptor binding observed i n patients with Alzheimer's disease might be secondary to the choliner gic deficits.