title: Enduring Loss of Serotonergic Control of Orbitofrontal Cortex Function Following Contingent and Noncontingent Cocaine Exposure.
abstract: Clinical descriptions of cocaine addiction include compulsive drug seeking and maladaptive decision-making despite substantial aversive consequences. Research suggests that this may result from altered orbitofrontal cortex (OFC) function and its participation in outcome-based behavior. Clinical and animal studies also implicate serotonin in the regulation of OFC function in addiction and other neuropsychiatric disorders. Here we test the hypothesis that exposure to cocaine, through self-administration (CSA) or yoked-administration (CYA), alters the regulation of OFC function by 5-HT. Using whole-cell electrophysiology in brain slices from naïve rats we find that 5-HT1A receptors generate hyperpolarizing outward currents in layer-V OFC pyramidal neurons, and that 5-HT2A receptors increase glutamate release onto these cells. Following extended withdrawal from CSA or CYA, this 5-HT regulation of OFC activity is largely lost. In-situ hybridization of 5-HT receptor transcripts reveals that 5-HT1A receptor mRNA is unaffected and 5-HT2A receptor mRNA is significantly elevated after CSA or CYA. These results demonstrate that 5-HT control of OFC neurons is disrupted for extended periods following cocaine exposure. We hypothesize that this dysregulation of 5-HT signaling leads to enduring disruptions of OFC network activity that this is involved in impaired decision-making associated with cocaine addiction.
authors.affiliation: Electrophysiology Research Section, Cellular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Wright
authors.affiliation: Electrophysiology Research Section, Cellular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Agustin
authors.initials: A
authors.lastname: Zapata
authors.affiliation: Designer Drug Research Unit, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.affiliation: Designer Drug Research Unit, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Elmore
authors.affiliation: Electrophysiology Research Section, Cellular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Hoffman
authors.affiliation: Electrophysiology Research Section, Cellular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Carl R
authors.initials: CR
authors.lastname: Lupica
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000473:pathology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D018698:Glutamic Acid / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020318:Rats, Long-Evans; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D012646:Self Administration; D012701:Serotonin / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D018698:Glutamic Acid; D003042:Cocaine
keywords: addiction; electrophysiology; prefrontal cortex; psychostimulants; self-administration