title: In vivo potentiation of reboxetine and citalopram effect on extracellular noradrenaline in rat brain by α2-adrenoceptor antagonism.
abstract: The therapeutic activity of noradrenaline reuptake inhibitors (NaRIs) and serotonin reuptake inhibitors (SSRIs) as antidepressant is based on their ability to increase monoamine concentrations in the synaptic cleft. α(2)-Adrenoceptors inhibit noradrenaline (NA) release, which modulates antidepressant neurochemical activity. The present study assesses the influence of the addition of the selective α(2)-adrenoceptor antagonist RS79948 to the NaRI reboxetine and the SSRI citalopram on brain extracellular NA. Dual-probe microdialysis technique in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely moving rats. Acute reboxetine (3 and 5 mg/kg i.p.) promoted a dose-dependent increase of NA in LC (164 ± 15%; 243 ± 24%) and PFC (140 ± 7%; 181 ± 30%). Acute citalopram (5 mg/kg i.p.) did not change NA in LC or PFC, but at 10 mg/kg i.p. increased NA in LC (144 ± 14%) and decreased it in PFC (-42 ± 7%). An inactive dose of RS79948 (0.1mg/kg i.p.) in rats pretreated with reboxetine (3 mg/kg i.p.) or citalopram (5mg/kg i.p.) induced a significant enhancement of NA in LC (reboxetine: 462 ± 137%; citalopram: 142 ± 11%) and PFC (reboxetine: 281 ± 56%; citalopram: 130 ± 16%). The results indicate that co-administration of selective α(2)-adrenoceptor antagonist drugs might improve the effects of NaRI or SSRI antidepressants by enhancing extracellular NA concentrations in the brain.
authors.affiliation: Department of Pharmacology, University of the Basque Country (UPV/EHU), Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, 48940 Leioa, Bizkaia, Spain. jorge.ortega@ehu.es
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Ortega
authors.forename: Begoña
authors.initials: B
authors.lastname: Fernández-Pastor
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000008:administration & dosage*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D015283:Citalopram / Q000008:administration & dosage*; D004357:Drug Synergism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000008:administration & dosage*; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077593:Reboxetine
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D009025:Morpholines; D015283:Citalopram; D000077593:Reboxetine; D009638:Norepinephrine