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Cocaine Potentiates Multiple 5-HT2A Receptor Signaling Pathways and Is Associated with Decreased Phosphorylation of 5-HT2A Receptors In Vivo

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Abstract

Cocaine addiction is a chronic relapsing disorder in which the underlying mechanisms are not well understood. Here, we used Sprague-Dawley rats injected with either saline (1 ml/kg) or cocaine (15 mg/kg) for 7 days (b.i.d, i.p) to study the effect of cocaine on several components of 5-HT2A receptor signaling in prefrontal cortex (PFCx). We detected enhanced activation of 5-HT2A receptor-mediated phospholipase C beta (PLCβ) and extracellular regulated kinase 1/2 activity in PFCx of cocaine-treated rats. Although we were unable to detect changes in the protein levels of several proteins associated with 5-HT2A receptor signaling such as caveolin-1, postsynaptic density protein 95, β-arrestin 2, etc., we found a significant reduction in the phosphorylation status of cortical 5-HT2A receptors. This phenomenon was associated with reduced levels of G-protein receptor kinase 5 (GRK5), but not GRK2 or RSK2, proteins. Our results suggest that decreased phosphorylation of 5-HT2A receptors could mediate, at least in part, the cocaine-induced potentiation of multiple 5-HT2A receptor signaling pathways in rat PFCx. As discussed in this manuscript, we hypothesize that preventing these neuroadaptations in 5-HT2A receptor signaling may alleviate some of the aversive withdrawal-associated symptoms that contribute to relapse to cocaine abuse.

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Acknowledgments

This study is supported by the University of Kansas Startup Funds, University of Kansas GRF no. 2301421 and NFGRF no. 2302213 Awards.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Drive, 3048B Malott Hall, Lawrence, KS, 66045, USA

    Jade M. Franklin & Gonzalo A. Carrasco

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  1. Jade M. Franklin
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  2. Gonzalo A. Carrasco
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Correspondence to Gonzalo A. Carrasco.

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Franklin, J.M., Carrasco, G.A. Cocaine Potentiates Multiple 5-HT2A Receptor Signaling Pathways and Is Associated with Decreased Phosphorylation of 5-HT2A Receptors In Vivo. J Mol Neurosci 55, 770–777 (2015). https://doi.org/10.1007/s12031-014-0419-z

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  • DOI: https://doi.org/10.1007/s12031-014-0419-z

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