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Cocaine inhibits 5-HT3 receptor function in neurons from transgenic mice overexpressing the receptor

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Abstract

Studies have shown that cocaine alters the function of recombinant 5-HT3 receptors and that behavioral responses to cocaine are affected by 5-HT3 receptor ligands. However, the actions of cocaine on brain 5-HT3 receptors have not been characterized because these receptors are not abundantly expressed in most neuronal populations. We examined the effect of cocaine on 5-HT3 receptor function in cultured hippocampal neurons from transgenic mice overexpressing the receptor. Cocaine competitively inhibited 5-HT3 receptors with an IC50 of ∼4 μM, indicating that brain 5-HT3 receptors are important targets for the actions of this commonly abused substance.

Introduction

5-Hydroxytryptamine type 3 (5-HT3) receptors are ligand-gated ion channels that belong to the nicotinic acetylcholine receptor superfamily. Although these receptors are expressed in the brain at relatively low densities, it is thought that they may have important presynaptic functions that modulate neurotransmitter release. The function of 5-HT3 receptors is regulated by substances of abuse, including ethanol and cocaine. Ethanol positively modulates both recombinant and native 5-HT3 receptors in vitro Lovinger, 1999, Lovinger and Zhou, 1998, Sung et al., 2000. Mice that overexpress this receptor show a decrease in ethanol consumption (Engel et al., 1998), which is probably due to enhanced ethanol sensitivity (Engel and Allan, 1999). Cocaine, on the other hand, has been shown to inhibit 5-HT3 receptor function. To date, the mechanism of the interaction between cocaine and 5-HT3 receptors has been studied mainly using non-neuronal cells, including Xenopus oocytes Fan et al., 1995, Mair et al., 1998, human embryonic kidney cells (Brown et al., 1998) and neuroblastoma cells (Lambert et al., 1989). Moreover, only one study has examined the effects of cocaine on neuronal 5-HT3 receptors. Specifically, Peters et al. (1993) found that 5-HT3 receptors expressed in sensory neurons from the rabbit nodose ganglion are inhibited by cocaine. However, we are not aware of any study of the interaction of cocaine with this receptor in neurons of the central nervous system. Since behavioral studies of the effects of cocaine on transgenic mice overexpressing the 5-HT3 receptor are currently underway, we decided to characterize the effects of this drug of abuse on currents mediated by these receptors in neurons from these animals.

Section snippets

Materials and methods

All chemicals were from Sigma or Fluka (St. Louis, MO). All animal procedures were approved by the University of New Mexico Health Sciences Center—Institutional Animal Care and Use Committee and were in accordance to National Institutes of Health guidelines. Electrophysiological studies were performed on hippocampal neuronal primary cultures that were prepared from postnatal days 3–4 homozygous or heterozygous B6SJL mice, as described previously (Costa et al., 2000). These mice were modified

Results

As shown in Fig. 1, cocaine reversibly inhibits, in a concentration-dependent manner, the current elicited by 5-HT. The cocaine IC50 concentration was 4.2 μM (95% confidence interval 3.1–5.6 μM) with a Hill slope of −1.6 (95% confidence interval −2.4 to −0.9). We then tested the effect of cocaine on the 5-HT3 receptor dose–response curve (Fig. 2A–B). We found that cocaine induces a parallel shift of the dose–response curve to the right; the EC50 concentrations were 1.8 μM (95% confidence

Discussion

The purpose of this study was to assess the effect of cocaine on native 5-HT3 receptors expressed in central nervous system neurons. In agreement with other reports, we found that cocaine inhibits 5-HT3 receptor-mediated responses in a dose-dependent manner Brown et al., 1998, Fan et al., 1995, Lambert et al., 1989, Mair et al., 1998, Peters et al., 1993. Our finding that cocaine inhibits 5-HT3 receptor-mediated responses with an IC50 of 4.2 μM is consistent with the results of a number of

Acknowledgments

C.F.V. is supported by the National Institute of Alcohol Abuse and Alcoholism and the United States Army. D.P. is supported by the National Institute of Mental Health. A.A. is supported by the United States Army.

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