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Agonist and Antagonist Binding to Rabbit Cortical 5-HT2A Receptors: Opposite Effects of Magnesiuma

V. J. ALOYO,b G. L. SALT, M. E. HOFFMAN, AND J. A. HARVEY

Department of Pharmacology, Division of Behavioral Neurobiology, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania 19129, USA

 

Serotonin 5-HT 2A and/or 5-HT 2C receptors have been implicated in modulating the acquisition of the classically conditioned nictitating membrane response in the rabbit.1 Thus, we have undertaken the characterization of the 5-HT 2A receptor in rabbit brain using the agonist [125I]DOI, and the antagonists [3H]ketanserin and [3H]MDL 100,907. Autoradiographic studies using both [125I]DOI and [3H]ketanserin demonstrate a high density of 5-HT 2A receptors in adult New Zealand rabbit cortex. Therefore, binding studies were performed using membranes prepared from the frontal cortex. (3H]Ketanserin (New England Nuclear) and [3H]MDL 100,907 (Amersham) binding assays were performed at 25° C in 20 mM Tris HCl pH 7.4. Nonspecific binding was defined by 1 µM methysergide and I µM spiperone [3H]ketanserin and [3H]MDL 100,907, respectively. Ketanserin binding (in the presence of 100 nM prazosin) was consistent with 2 classes of binding sites. The high affinity ketanserin site had a Kd of approximately 1 nM, which is consistent with its reported affinity at 5-HT 2A receptors. The GTP analogue, Gpp(NH)p, at concentrations up to 100 mM had no effect on ketanserin binding. In contrast, magnesium dose-dependently inhibited ketanserin binding. The IC50 for DOI displacement of bound [3H]ketanserin was decreased approximately fourfold in the presence of 5 mM MgSO4. More extensive studies were carried out with the highly selective 5-HT 2A receptor antagonist, MDL 100,907. Saturation analysis demonstrated that the binding of MDL 100,907 was consistent with a single class of sites with a Kd of approximately 0.1 nM. As for ketanserin, Gpp(NH)p at concentrations up to 100 mM had no effect, whereas magnesium dose-dependently inhibited MDL 100,907 binding. MgSO4 (5 mM) decreased the affinity of [3H]MDL 100,907 by approximately fourfold. The IC50 for DOI displacement of bound [3H]MDL 100,907 was decreased in the presence of 5 mM MgSO4. As expected, Mg++ shifts the 5HT 2A receptor toward the agonist high affinity state as demonstrated by the increased affinity of the agonist, DOI. Unexpectedly, Mg++ decreases the binding of the putative neutral antagonists ketanserin and MDL 100,907, suggesting that these compounds may actually be inverse agonists at the 5-HT 2A receptor.

REFERENCE

1. HARVEY, J. A. 1996 Behav. Brain Res 73: 47-50.


a Supported in part by USPHS MERIT Award Grant MH16841-26.
b Corresponding author Tel: 215.842,4750; Fax: 215,843,1515


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