Differential role of AMPA receptors in mouse tests of antidepressant and anxiolytic actionby Jesper T Andreasen, Ciaran M Fitzpatrick, Maria Larsen, Lars Skovgaard, Simon D Nielsen, Rasmus P Clausen, Karin Troelsen, Darryl S Pickering

Brain Research


Molecular Biology / Clinical Neurology / Neuroscience (all) / Developmental Biology


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Differential role of A of antidepressant an

Jesper T Andreasena,n, Ciaran

Lars Skovgaarda, Simon D Ni acolog

Medic results with both ckade. This study 6 and the AMPAR ouse forced swim g the elevated zero (NIH) tests. The rison. Due to the

I-53655 disrupted performance in the V-maze test for attention-dependent behaviour, and the social 451646 (3 mg/kg) 55 (Z5 mg/kg) had rsely, GYKI-53655 (Z2.5 mg/kg), and b r a i n r e s e a r c h 1 6 0 1 ( 2 0 1 5 ) 1 1 7 – 1 2 6E-mail address: jta@sund.ku.dk (J. Andreasen).http://dx.doi.org/10.1016/j.brainres.2015.01.001 0006-8993/& 2015 Elsevier B.V. All rights reserved.

Abbreviations: AMPA receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor; FST, forced swim test;

TST, tail suspension test; EZM, elevated zero maze; NIH, novelty-induced hypophagia; MB, marble burying; STFP, social transmission of food preference. nCorresponding author.NIH tests (Z5 mg/kg), while LY451646 (Z3 mg/kg) increased anxiety-like behaviour in the

EZM. Citalopram showed an antidepressant-like effect in the FST (Z10 mg/kg), but not

TST, an anxiolytic-like effect in the EZM (Z3 mg/kg) and MB test (Z2.5 mg/kg), and antransmission of food preference (STFP) test of long-term memory. LY showed an antidepressant-like profile in the FST and TST, and GYKI-536 a depressogenic-like effect in the TST but no effect in the FST. Conve produced marked anxiolytic-like effects in the EZM (Z2.5 mg/kg), MBTDepression



AMPA receptor


Mouse behaviour. mediated neurotransmission is beneficial in depression management, addressing AMPARs in relation to anxiety have given ambiguous anxiolytic-like and anxiogenic-like effects observed after AMPAR blo systematically compared the effects of the AMPAR potentiator LY45164 antagonist GYKI-53655 on depression-related behaviour using the m (FST) and tail suspension tests (TST), and anxiety-related behaviour usin maze (EZM), marble burying (MB) and novelty-induced hypophagia serotonin-selective antidepressant citalopram was included for compa importance of AMPARs in learning and memory we also tested if GYKKeywords:

Anxiety rotransmission, and positive allosteric modulators (PAMs) at AMPARs produced antidepressant-like effects in rodents. While this suggests that increased AMPARpreclinical studiesAccepted 1 January 2015

Available online 8 January 2015Article history: Depression and anxiety often co-occur, and conventional monoamine-facilitating antidepressants show efficacy against symptoms in both disorders. Rodent studies indicateDarryl S Pickeringa aDepartment of Drug Design and Pharm

Denmark bDepartment of Cellular and Molecular

Denmark a r t i c l e i n f oMPA receptors in mouse tests d anxiolytic action

M Fitzpatricka, Maria Larsena, elsena, Rasmus P Clausena, Karin Troelsenb, y, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, ine, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen, a b s t r a c t that antidepressant effects of monoamine-based antidepressants involve increased α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid glutamate receptor (AMPAR) neuin -ma pre

MP rge produce antidepressant-like responses in rodents (Li et al., 2001) and enhance the antidepressant-like effects of monet al., 2003) as well as the NMDAR antago easen et al., 2013).

While studies of AMPARs in relation to beneficial effects of increased AMPAR tr studies on the involvement of AMPARs in more equivocal results. Anxiety-like stat been coupled to increased AMPAR-media sion in the basolateral amygdala (Christia et al. 2007) as well as increased levels of burying (MB) and novelty-induced hypophagia (NIH) tests. We included citalopram in these tests for comparison because b r a i n r e s e a r c h 1 6 0 1 ( 2 0 1 5 ) 1 1 7 – 1 2 6118nist MK-801 (Andrdepression point to ansmission, rodent anxiety have given es in rodents have ted neurotransmission and anxiety disorders. Locomotor activity testing was included to ascertain if efficacies of LY451646 and GYKI-53655 were confounded by non-specific locomotor depression/stimulation. Finally, following a finding that GYKI-53655 generally showed an anxiolytic-like profile, and considering the important role of AMPARs in cognition (Robbins and Murphy, 2006; Sanderson et al., 2008), we tested if blockade of AMPARsoamine-based antidepressants (Andreasen et al., 2013; Li SSRI antidepressants are a first-line treatment of both depres-anxiogenic-like effect performance in the V role of AMPARs in de sant responses and A

AMPARs as a novel ta 1. Introduction

Major depression and anxiety disorders show high rates of comorbidity, and virtually all drug classes used to treat depression also reduce anxiety (Vaswani et al., 2003), reflecting an overlap in both pathophysiology and treatment. Conventional treatment with serotonin-selective or other monoamine-based antidepressants lead to remission in only about 1/3 of patients with depression or anxiety, partial response in about 1/3, and no response in the remaining 1/3 of patients (Bystritsky, 2006; Little, 2009; Rosenzweig-Lipson et al., 2007). To achieve improved therapeutic efficacy, treatment strategies may have to go beyond monoamine-based mechanisms. Research into such novel approaches will also increase the understanding of differences and similarities between depression and anxiety.

Glutamate is now recognised as a key element in the pathophysiology and treatment of affective disorders (Musazzi et al., 2013; Riaza Bermudo-Soriano et al., 2012;

Sanacora et al., 2012), and rodent studies have demonstrated that changes in glutamate transmission corresponds to some of the behavioural effects of chronic treatment with monoamine-based antidepressants (Barbon et al., 2011; MartinezTurrillas et al., 2002; Skolnick et al., 1996). Much of the research on the role of glutamate receptors in affective disorders has revolved around the ionotropic N-methyl-Daspartate glutamate receptor (NMDAR) and metabotropic glutamate receptors (mGluRs). More recently, increased transmission through the ionotropic α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) has been implicated in antidepressant efficacy.