title: Antidepressant-like properties of three new α2-adrenoceptor antagonists.
abstract: Evidence suggests that depression is associated with an increase in the high-affinity conformation of the α2-adrenoceptors in human brain. Such enhanced α2-adrenoceptor activity could explain the deficit in central noradrenergic transmission described in the aetiology of depression. Thus, administration of α2-adrenoceptor antagonists augments noradrenaline levels and provides an effective therapeutic approach for the treatment of depressive disorders. In previous studies, we have characterized three new synthesized guanidine and 2-aminoimidazoline aromatic derivatives (8b, 17b and 20b) as α2-adrenoceptor antagonists that are able to increase extracellular concentration of noradrenaline in rat brain. The purpose of the present study was to evaluate the in vivo antidepressant-like properties of these three new α2-adrenoceptor antagonists. For that aim, compounds were tested on the tail suspension test (TST) and forced swim test (FST), two classically widely-used behavioural paradigms for the evaluation of antidepressant-like activity. Compound 8b significantly reduced the immobility time at 10, 20 and 40 mg/kg doses in both TST and FST. Compound 17b reduced the immobility time at 40 mg/kg in both TST and FST. Compound 20b showed a significant decrease in the immobility time at 20 mg/kg in the TST. As drugs of reference, fluoxetine induced a significant antidepressant-like effect in both TST and FST, while mirtazapine induced a significant antidepressant-like effect only in the FST. Additionally, none of the tested compounds increased locomotor activity or displayed anxiolytic-like properties. These results suggest that these new synthesized α2-adrenoceptor antagonists may be useful as potential antidepressant drugs.
authors.affiliation: Department of Pharmacology, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Muguruza
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez
authors.forename: Isabel
authors.initials: I
authors.lastname: Rozas
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.forename: Leyre
authors.initials: L
authors.lastname: Urigüen
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D003863:Depression / Q000188:drug therapy / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D019417:Hindlimb Suspension / Q000379:methods / Q000502:physiology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000928:Antidepressive Agents