title: Cocaine potentiates multiple 5-HT2A receptor signaling pathways and is associated with decreased phosphorylation of 5-HT2A receptors in vivo.
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.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Drive, 3048B Malott Hall, Lawrence, KS, 66045, USA.
authors.forename: Jade M
authors.initials: JM
authors.lastname: Franklin
authors.forename: Gonzalo A
authors.initials: GA
authors.lastname: Carrasco
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D054799:Phospholipase C beta / Q000378:metabolism; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605257:Arrb2 protein, rat; D019390:Arrestins; D051242:Caveolin 1; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D044402:Receptor, Serotonin, 5-HT2A; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2; D054774:G-Protein-Coupled Receptor Kinase 5; C517897:Grk5 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054799:Phospholipase C beta