Modulation of hippocampal norepinephrine release by cholinergic agonists is altered by AF64A lesion |
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Authors: | Pamela E Potter Beverly Thorne Christopher Gaughan |
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Institution: | Departments of Anesthesiology and neurosurgery, Albert Einstein College of Medicine, Montefiore Medical Center, Moses 3, 111 East 210th St., Bronx, New York 10467, USA |
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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. |
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Keywords: | Hippocampal norepinephrine release AF64A McN-A-343 Oxotremorine Nicotine Cholinergic lesion model |
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