title: Methamphetamine reduces expression of caveolin-1 in the dorsal striatum: Implication for dysregulation of neuronal function.
abstract: Role of striatal dopamine D1 receptors (D1Rs) in methamphetamine (Meth) taking and seeking is recognized from contingent Meth self-administration studies. For example, Meth increases levels of D1Rs in the dorsal striatum in animal models of Meth addiction, and blockade of striatal D1Rs decreased responding for Meth and reduced Meth priming-induced drug seeking. However, the mechanism underlying enhanced expression of striatal D1Rs in animals self-administering Meth is unknown and is hypothesized to involve maladaptive intracellular signal transduction mechanism via hyperphosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). D1Rs are predominantly localized to detergent-resistant membrane/lipid raft fractions (MLR fraction), and in vitro studies indicate that D1R signaling and recycling is regulated by the MLR-resident protein caveolin-1 (Cav-1), in an endocytotic-dependent manner. Notably, expression of Cav-1 is inversely regulated by ERK1/2 activation, suggesting a signaling interplay among D1Rs, ERK1/2 and Cav-1. We therefore evaluated the effects of extended access Meth self-administration on expression of striatal D1Rs, activated ERK1/2 and Cav-1. We first report that Cav-1 is heavily expressed in neurons located in the dorsal striatum. We also report that extended access Meth produces compulsive-like unregulated intake of the drug, and these behavioral outcomes are associated with enhanced expression of D1Rs, increased activity of ERK1/2, and reduced Cav-1 expression in the dorsal striatum. These data suggest a possible cellular mechanism that involves Cav-1 regulation of D1R expression in response to escalated Meth intake, and how this response of altered D1Rs and enhanced ERK1/2 activation to Meth self-administration contributes to contingent-related processes such as addiction.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute 10550 North Torrey Pines Road, SP30-2400, La Jolla, CA 92037, USA.
authors.forename: Sucharita S
authors.initials: SS
authors.lastname: Somkuwar
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute 10550 North Torrey Pines Road, SP30-2400, La Jolla, CA 92037, USA.
authors.forename: McKenzie J
authors.initials: MJ
authors.lastname: Fannon
authors.affiliation: Veterans Affairs San Diego Healthcare System and Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92037, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute 10550 North Torrey Pines Road, SP30-2400, La Jolla, CA 92037, USA. Electronic address: cmandyam@scripps.edu.
authors.forename: Chitra D
authors.initials: CD
authors.lastname: Mandyam
mesh_terms: D019969:Amphetamine-Related Disorders / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000633:toxicity; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage* / Q000633:toxicity; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: C495537:Cav1 protein, rat; D051242:Caveolin 1; D000697:Central Nervous System Stimulants; D017447:Receptors, Dopamine D1; D008694:Methamphetamine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: ERK; animal models; caveolin; dopamine D1 receptor; neurotoxicity; psychostimulant