1. EFFECT OF CHRONIC MORNING VS EVENING AGOMELATINE
ADMINISTRATION ON DEPRESSIVE-LIKE BEHAVIOURS IN A
NEURODEVELOPMENTAL ANIMAL MODEL OF DEPRESSION
Coutts D1
, Möller M,1
Wegener G,3,4
Harvey BH,2
1
Division of Pharmacology, and 2
Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North West
University, Potchefstroom, South Africa and, 3
Institute for Basic Psychiatric Research, Department of Biological
Psychiatry, Skovagervej 2, DK-8240 Risskov, Denmark4
,Centre for Clinical Pharmacology, University of Aarhus, DK-
8000 Aarhus C, Denmark. Email: Brian.Harvey@nwu.ac.za
Introduction:
The etiology of depression represents a continuum of environmental, genetic and neurochemical
determinants. Early-life adversity profoundly affects brain development and behavior in adulthood,
consistent with the neurodevelopmental hypothesis of depression. Social isolation rearing (SIR) is a
neurodevelopmental animal model known to induce late-life bio-behavioral changes akin to
depression. The antidepressant action of agomelatine is mediated by re-entrainment of circadian
rhythm involving a synergy between melatonin MT1/MT2 agonism and 5HT2C antagonism. Time of
dosing is purported to be critical. We determined whether agomelatine could reverse depressive-like
behavior in SIR rats and whether efficacy is dependent on morning vs. afternoon administration.
Materials and Methods:
Male Sprague-Dawley (SD) rats (12 rats/group) were used in this study Rats were randomly
separated at weaning and exposed to either 8 weeks SIR (one rat/cage; 3 groups) or 8 weeks social
rearing (3 rats/cage; 3 groups) (Ethics number NWU-00154-14-S5). Rats received vehicle or
agomelatine (40mg/kg/day i.p. x 14 days) at either 08h00 or 16h00 each day. Depressive-like
behaviors and locomotor activity were determined on days 13 and 14 using the Forced Swim Test
(FST) and Open Field Test (OFT), respectively.
Results:
SIR significantly increased immobility in the FST vs. socially reared rats, with immobility
significantly reversed with both morning and afternoon dosing of agomelatine. Although time of
dosing did not affect serotonergic behaviors (swimming) in SIR rats, afternoon dosing significantly
increased noradrenergic behaviors (struggling). Importantly, agomelatine did not affect behavior in
socially reared rats. None of the treatments altered locomotor activity, irrespective of housing
condition.
Conclusion:
Agomelatine has antidepressant effects in a neurodevelopmental model of depression. The
antidepressant action of agomelatine is independent of morning or afternoon dosing.
However, afternoon but not morning dosing evokes noradrenergic-related behavior without
affecting that of serotonin, which corresponds with its clinical and pharmacological profile.
These data require further neurochemical validation.