title: Positive allosteric modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors differentially modulates the behavioural effects of citalopram in mouse models of antidepressant and anxiolytic action.
abstract: Drugs that increase monoamine neurotransmission are effective in both anxiety and depression. The therapeutic effects of monoamine-based antidepressant drugs may involve indirect effects on neurotransmission through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR). Thus, chronic antidepressant treatment increases AMPAR-mediated neurotransmission and AMPAR-positive allosteric modulators have shown antidepressant-like efficacy in rodents. Here, the effect of enhanced AMPAR neurotransmission on the antidepressant-like and anxiolytic-like actions of the selective serotonin reuptake inhibitor citalopram (0-10 mg/kg) was investigated in mice using the AMPAR-positive allosteric modulator LY451646 (0-3 mg/kg). Antidepressant-like effects were assessed using the forced-swim test (FST), whereas anxiolytic-like effects were tested using the elevated zero maze (EZM) and the marble burying test. LY451646 (3 mg/kg) increased swim distance in the FST and a subactive dose of LY451646 (1 mg/kg) enhanced the effect of citalopram in the FST. In the EZM, LY451646 (3 mg/kg) did not show anxiogenic effects alone, but blocked the anxiolytic-like action of citalopram in the EZM, as reflected by an increase in the latency to enter the open areas and a decrease in the number of entries and time spent in the open areas in citalopram-treated mice. In the marble burying test, LY451646 (3 mg/kg) showed no effect alone, but significantly attenuated the anxiolytic-like effect of citalopram (1.25-2.5 mg/kg) by increasing the number of marbles buried in citalopram-treated mice. These results suggest that AMPAR neurotransmission plays opposite roles in anxiety and depression as AMPAR potentiation facilitated the antidepressant-like effects of citalopram while attenuating its anxiolytic-like effect. These findings have ramifications in the search for AMPAR-based novel anxiolytic and antidepressant treatments.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetparken, Copenhagen, Denmark.
authors.forename: Ciarán M
authors.initials: CM
authors.lastname: Fitzpatrick
authors.forename: Maria
authors.initials: M
authors.lastname: Larsen
authors.forename: Louise H
authors.initials: LH
authors.lastname: Madsen
authors.forename: Maitane
authors.initials: M
authors.lastname: Caballero-Puntiverio
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
authors.forename: Rasmus P
authors.initials: RP
authors.lastname: Clausen
authors.forename: Jesper T
authors.initials: JT
authors.lastname: Andreasen
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018091:Receptors, AMPA / Q000187:drug effects* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D015283:Citalopram; D018091:Receptors, AMPA; D017367:Selective Serotonin Reuptake Inhibitors; D013449:Sulfonamides; C430915:LY 404187