title: Chronic citalopram administration desensitizes prefrontal cortex but not somatodendritic α2-adrenoceptors in rat brain.
abstract: Selective serotonin reuptake inhibitors (SSRIs) regulate brain noradrenergic neurotransmission both at somatodendritic and nerve terminal areas. Previous studies have demonstrated that noradrenaline (NA) reuptake inhibitors are able to desensitize α2-adrenoceptor-mediated responses. The present study was undertaken to elucidate the effects of repeated treatment with the SSRI citalopram on the α2-adrenoceptor sensitivity in locus coeruleus (LC) and prefrontal cortex (PFC), by using in vivo microdialysis and electrophysiological techniques, and in vitro stimulation of [35S]GTPγS binding autoradiography. Repeated, but not acute, treatment with citalopram (5 mg/kg, i.p., 14 days) increased extracellular NA concentration selectively in PFC. The α2-adrenoceptor agonist clonidine (0.3 mg/kg, i.p.), administered to saline-treated animals (1 ml/kg i.p., 14 days) induced NA decrease in LC (Emax= -44 ± 4%; p < 0.001) and in PFC (Emax= -61 ± 5%, p < 0.001). In citalopram chronically-treated rats, clonidine administration exerted a lower decrease of NA (Emax= -25 ± 7%; p < 0.001) in PFC whereas the effect in LC was not different to controls (Emax= -36 ± 4%). Clonidine administration (0.625-20 μg/kg, i.v.) evoked a dose-dependent decrease of the firing activity of LC noradrenergic neurons in both citalopram- (ED50= 3.2 ± 0.4 μg/kg) and saline-treated groups (ED50= 2.6 ± 0.5 μg/kg). No significant differences between groups were found in ED50values. The α2-adrenoceptor agonist UK14304 stimulated specific [35S]GTPγS binding in brain sections containing LC (144 ± 14%) and PFC (194 ± 32%) of saline-treated animals. In citalopram-treated animals, this increase did not differ from controls in LC (146 ± 22%) but was lower in PFC (141 ± 8%; p < 0.05). Taken together, long-term citalopram treatment induces a desensitization of α2-adrenoceptors acting as axon terminal autoreceptors in PFC without changes in somatodendritic α2-adrenoceptor sensitivity.
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Fernández-Pastor
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Spain; BioCruces Health Research Institute, Bizkaia, Spain. Electronic address: jorge.ortega@ehu.eus.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Ortega
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Grandoso
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Spain; Department of Physiology and Pharmacology, Institute of Biomedicine & Biotechnology of Cantabria (IBBTEC), University of Cantabria-CSIC-IDICAN, Santander, Cantabria, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Castro
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ugedo
authors.affiliation: Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Spain; Department of Physiology and Pharmacology, Institute of Biomedicine & Biotechnology of Cantabria (IBBTEC), University of Cantabria-CSIC-IDICAN, Santander, Cantabria, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Pazos
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Spain; BioCruces Health Research Institute, Bizkaia, Spain.
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects / Q000502:physiology; D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000068438:Brimonidine Tartrate / Q000008:administration & dosage; D015283:Citalopram / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008125:Locus Coeruleus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000068438:Brimonidine Tartrate; D015283:Citalopram; D009638:Norepinephrine; D018341:Receptors, Adrenergic, alpha-2; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Chloral hydrate (PubChem CID 2707); Citalopram; Citalopram hydrobromide (PubChem CID 77995); Clonidine hydrocloride (PubChem CID 20179); Locus coeruleus; Microdialysis; Noradrenaline; Prefrontal cortex; RX821002 (PubChem CID 108094); UK14304 (PubChem CID 2435); α(2)-adenoceptor