Blockage of 5HT<sub>2C</sub> serotonin receptors by fluoxetine (Prozac)

Laboratory of Cellular and Molecular Neurobiology, Department of Psychobiology, University of California, Irvine, CA 92697-4550

^{Present address: Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508.}

^{To whom reprint requests should be addressed.}

R. Miledi

Accepted 1996 Dec 24.

Abstract

Fluoxetine (Prozac) inhibited the membrane currents elicited by serotonin (5-hydroxytryptamine; 5HT) in Xenopus oocytes expressing either cloned 5HT_2C receptors or 5HT receptors encoded by rat cortex mRNA. Responses of 5HT_2C receptors, elicited by nM concentrations of 5HT, were rapidly and reversibly blocked by micromolar concentrations of fluoxetine. For responses elicited by 1 μM 5HT, the IC₅₀ of fluoxetine inhibition was ≈20 μM. In accord with the electrophysiological results, fluoxetine inhibited the binding of [^{H]5HT to 5HT}_2C receptors expressed in HeLa cells (K_i ≈ 65–97 nM), and the binding to 5HT receptors in rat cortex membranes was also inhibited but less efficiently (K_i ≈ 56 μM). Our results show that fluoxetine is a competitive and reversible antagonist of 5HT_2C receptors and suggest that some therapeutic effects of fluoxetine may involve blockage of 5HT receptors, in addition to its known blockage of 5HT transporters. Similar work may help to design more selective compounds for use in the treatment of brain disorders.

Keywords: membrane currents, receptor binding, Xenopus oocytes, HeLa cells

Abstract

Fluoxetine (Prozac) is widely used in the treatment of a variety of brain disorders, such as mental depression, panic disorder, obesity, and alcoholism. It is generally believed that fluoxetine exerts its therapeutic effects by enhancing serotonergic transmission, exclusively through inhibition of serotonin (5-hydroxytryptamine; 5HT) transporters with minimal or no effects on other neurotransmitter receptors (1, 2). However, it has been shown that fluoxetine inhibits 5HT binding in the choroid plexus (3), that it appears to be an agonist of 5HT_2C receptors in cultured astrocytes (4), and that it inhibits currents mediated by 5HT₃ receptors in rat nodose ganglion neurons (5), as well as the binding of 5HT to 5HT₃ and 5HT₄ receptors (6). In addition, chronic treatment of fluoxetine may cause a down-regulation of 5HT₁ receptors (2) and also alter the expression of other receptors, although the latter effects are somewhat controversial (7).

5HT_2C receptors [formerly termed 5HT_1C, (8)] are widely expressed in the brain and spinal cord, are particularly enriched in the choroid plexus (9), and appear to mediate many important effects of 5HT. For example, transgenic mice that are devoid of 5HT_2C receptors are overweight and are prone to seizure-induced death, suggesting a role for this type of receptor in the control of appetite and neuronal network excitability (10). Given fluoxetine’s multiple therapeutic effects on a variety of mental and eating disorders, it was important to study in more detail the action of fluoxetine on 5HT_2C receptors.

Acknowledgments

We thank Dr. D. J. Julius for the pSR1c, Eli Lilly Company and Dr. R. E. Purdy for the fluoxetine HCl, and Drs. L. Pulakat and G. M. Deng for preparing the bovine angiotensin II receptor mRNA. This work was supported by a grant from the National Institute of Neurological Disorders and Stroke (NS 23284).

Acknowledgments

ABBREVIATION

5HT	5-hydroxytryptamine (serotonin)

ABBREVIATION

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