Depression results from a combination of genetic, environmental, and neurochemical factors. The document summarizes a study that examined the effects of agomelatine, a antidepressant that targets circadian rhythms and melatonergic/serotonergic receptors, on rats subjected to social isolation rearing (SIR), an animal model of depression. The study found that agomelatine reduced depressive-like behaviors in SIR rats, with effects seen regardless of whether it was administered in the morning or afternoon. However, afternoon dosing specifically increased behaviors related to noradrenergic activity without impacting serotonergic behaviors. The results suggest agomelatine has antidepressant effects in SIR rats through both monoamine-
4. Depression:
Not a single neurotransmitter disorder,
but represents a continuum of
environmental, genetic and
neurochemical determinants that
occupy a distinct role.
Many overlapping symptoms as well as
biological mechanisms characterize
mood disorders
Harvey et al., 2008; Fone & Porkess, 2008; Anderson et al., 2013; Cotton et al., 2012
5HTDA
NA
G E N E T I C S
E N V I R O N M E N T
N E U R O -
C H E M I S T R Y
I N T R O D U C T I O N
5. M O N O A M I N E S
C I R C A D I A N R H Y T H M S
O X I D A T I V E S T R E S S &
I M M U U N E -
I N F L A M M A T O R Y
D Y S F U N C T I O N
N E U R O T R O P H I C
F A C T O R S
H P A - A X I S &
C O R T I C O S T E R O N E
G A B A - G L U T A M A T E
S I G N A L I N G
H
Y
P
O
T
H
E
S
E
S
6. BDNF
Neurogenesis
Increased activity of
the HPA-axis
Production of
inflammatory
cytokines (TNF-α)
Increased
secretion of
glucocorticoids
Atrophy & death of
neurons
Circadian Rhythms
Monoamines
(5HT;NA;DA)
TNF-α; INF-γ; IL-6
Hippocampal
neurogenesis
Major
Depression
Nestler et al., 2002; Harvey et al., 2003; Savitz & Drevents, 2009; McClung, 2013
8. Early-life SIR is known to produce changes
consistent with the neurodevelopmental hypothesis
of depression.
In our hands this model demonstrated excellent
validity for modeling the neurobiology and
behavioral profile for schizophrenia.
To the best of our knowledge, the ability of
agomelatine to reverse SIR-induced bio-
behavioral changes has not been undertaken.
SIRB E H A V I O R A L L E V E L :
N e o p h o b i a
A g g r e s s i o n
C o g n i t i v e r i g i d i t y
I m p a i r e d s e n s o r i m o t o r
& s o c i a l i n t e r a c t i o n
M o n o a m i n e r g i c
D e f i c i t s
N E U R O - B I O L O G I C A L
L E V E L :
R e d u c e d P F C v o l u m e
D e c r e a s e d c o r t i c a l &
h i p p o c a m p a l s y n a p t i c
p l a s t i c i t y
13. Antidepressant efficacy is disappointing – 55-60% effective
with treatments restricted to the monoaminergic system
Circadian rhythm plays a major role to ensure optimal
functioning making it a therapeutic target in mood disorders
Agomelatine's action involves:
• resynchronizing of circadian rhythms
(via regulation of 5HT vs. melatonergic activity in SCN)
• direct effect on frontal NA/DA release (via 5HT2c antag)
• indirect action by modifying monoamine release
in brain stem (via re-entrainment of biological rhythms).
15. Male Sprague-Dawley rats (300-350g;
Vivarium, North West University)
randomly allocated to groups – 12
rats/group
PND 21 the animals was randomized
to SIR (1 animal/cage) or social
rearing (3-4 animals/cage) for 8 weeks
Animals were handled according to the
code of ethics in research (Ethics
number NWU-00154-14-S5).
A N I M A L S
We are all mice in a
giant experimental
maze, scurrying around
frantically, trying to
find our way
through…
16. G E N E R A L I N F O R M A T I O N :
1 . 1 % H E C
2 . A g o m e l a t i n e ( 4 0 m g / k g ) 0 8 H 0 0
3 . A g o m e l a t i n e ( 4 0 m g / k g ) 1 6 H 0 0
PND 21 8 Weeks Isolation Period 14 Days Treatment
Behavioral Testing
(13+14)
1 R a t / c a g e
3 - 4 R a t s / c a g e
Locomotor activity
Forced Swim Test (FST)
S T U D Y D E S I G N
17. O p e n F i e l d T e s t
( O F T )
OFT was to measure locomotor activity
which is a parameter used to test the general
ability of the animal to move and negotiate its
surrounding.
On the day of testing (Day 14), rats were
placed in the OFT arena and allowed to
explore the arena for 10min under low light.
During this time the rat was video-taped.
1 hour after locomotor activity was assessed,
a final forced swim test was done.
18. F o r c e d S w i m T e s t
( F S T )
Assessment of depressive-like symptoms:
Assessed using the forced swim test (FST) on
day 14.
24h prior to the final swim test, rats were
subjected to 15min of pre-swimming in
transparent perspex cylinders containing
30cm of clean water (25 ˚± 2C).
Immobility, climbing (NA-behaviors), diving
and swimming (5HT-behaviors),
Were recorded.
25. Agomelatine has antidepressant
effects in SIR.
Time of dosing independence.
Late afternoon dosing
evokes NA-related (struggling)
behaviors
without affecting 5HT
Morning dosing may involve
monoamine-independent actions
– neurochemical data in progress
26. People who die by suicide don’t want to end their lives,
they want to end their pain…
27. S T U D Y L E A D E R : P R O F B . H . H A R V E Y
C O - S T U D Y L E A D E R : D R . M . M Ö L L E R - W O L M A R A N S
S E R V I E R : F R É D É R I Q U E L A M O U R
C E C I L I A G A B R I E L - G A R C I A
C A R M E N M U N O Z
F U N D I N G : M R C
S E R V I E R ( D R U G S )
N R F
Acknowledgements
