title: Modulation of hippocampal norepinephrine release by cholinergic agonists is altered by AF64A lesion.
abstract: The effect of lesioning hippocampal cholinergic neurons with the neurotoxin AF64A on the ability of cholinergic agonists to modulate stimulation-induced release of 3H-norepinephrine (NE) from rat hippocampal slices was studied. Rats received intracerebroventricular injections of either AF64A (ethylcholine mustard aziridinium, 2 nmol) or vehicle (sham operated). Six weeks after treatment, release of 3H-NE evoked by electrical stimulation (2 Hz, 2 min) in the presence or absence of cholinergic agonists and/or antagonists was measured. Activation of M2 receptors with oxotremorine (in the presence of the M1 antagonist pirenzepine) caused a small inhibition of NE release, which was abolished in hippocampi from AF64A-treated rats. The Kd for high-affinity binding of the selective M2 ligand [3H] AF-DX 384 was increased 10-fold in lesioned tissues. The M1 selective agonist McN-A-343 produced a significant enhancement of NE release, which was unchanged by AF64A lesion. Binding studies with [3H] pirenzepine showed no change in the affinity or number of M1 receptors. Nicotine also caused a significant enhancement of evoked NE release, but this effect was markedly reduced in tissues from AF64A-treated rats. AF64A treatment caused a twofold decrease in the number of [3H] nicotine binding sites. This study suggests that long-term lesion of hippocampal cholinergic neurons with AF64A alters the function of postsynaptic muscarinic M2 and nicotinic cholinergic receptors that modulate the release of NE in the hippocampus.
authors.affiliation: Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York 10467, USA.
authors.forename: P E
authors.initials: PE
authors.lastname: Potter
authors.forename: B
authors.initials: B
authors.lastname: Thorne
authors.forename: C
authors.initials: C
authors.lastname: Gaughan
mesh_terms: D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000818:Animals; D001388:Aziridines / Q000494:pharmacology; D001665:Binding Sites; D002794:Choline / Q000031:analogs & derivatives / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology*; D018680:Cholinergic Antagonists / Q000494:pharmacology; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009538:Nicotine / Q000378:metabolism / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D010095:Oxotremorine / Q000494:pharmacology; D010890:Pirenzepine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001388:Aziridines; D018679:Cholinergic Agonists; D018680:Cholinergic Antagonists; D010890:Pirenzepine; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D010095:Oxotremorine; D009538:Nicotine; C044894:ethylcholine aziridinium; D002794:Choline; D009638:Norepinephrine