Download Our data suggests that the behavioral effects induced by

Ribeiro DE 1; Casarotto PC 1,2; Biojone C 1,2; Joca SRL 1.
¹ Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
² Neuroscience Center, University of Helsinki, Helsinki.
There is evidence pointing a potential involvement of P2X7
receptor (P2RX7) in mood disorders. In humans, P2RX7
polymorphism is associated to development of depression
(Lucae, S. et al. 2006 ). In animal models, the lack of P2RX7
seems to induce antidepressant-like behavior: P2RX7 KO
mice exhibit antidepressant-like phenotype (Basso, A.M. et
al. 2009), moreover systemic administration of a
Figure 1. Number of escapes (A: t14=2,310), avoidances (B: t14=1,922) and failures (C: t14=2,836) of rats
submitted to learned helplessness paradigm and treated with vehicle or imipramine 15 mg/Kg/day
during seven days (Student t test; *p<0.05; n=8 animals/group).
preferential P2XR antagonist induces antidepressant-like
behavior in mice (Pereira, V.S. et al. 2013 ).
The aim of this study was to investigate if the behavioral
effects induced by classical antidepressant drugs would be
associated to decreased expression of P2X7 in the dorsal
hippocampus, a brain structure which is crucial to stress
Figure 2. Number of escapes (A: t17=2,041), avoidances (B: t17=2,813) and failures (C: t17=3,155) of rats
submitted to learned helplessness paradigm and treated with vehicle or desipramine 25 mg/Kg/day
during seven days (Student t test; *p<0.05; n=9 -10 animals/group).
copying and antidepressant response.
Naive
40 inescapable footshocks 0.4mA;
10s; 60±30s intervals
Days
1st
2nd
3rd
4th
5th
6th
7th
Vehicle
Antidepressants drugs:
- Imipramine 15 mg/Kg
- Desipramine 25mg/Kg
Days
1st
2nd
3rd
4th
5th
6th
7th
Days
1st
2nd
3rd
4th
5th
6th
7th
Figure 3. Stress increased P2X7 receptor in dorsal hippocampus (*p<0.05) and the treatment with
imipramine 15mg/Kg/day (F2,18=5,466; **p<0.05), but not with desipramine 25mg/Kg/day (F2,12=4,613;
NS), reversed this effect. Statistical analysis: one way ANOVA followed by Newman-Keuls , n= 5-8
animals/group.
Our data suggests that the behavioral effects induced by
stress are associated to increased expression of P2X7
Quantification of P2X7 receptors
from dorsal hippocampus by
western blotting
30 escapable footshocks, 0.4mA; 10s;
60±30s intervals; preceded (5s) by a tone
receptors in dorsal hippocampus, and imipramine
treatment blunted both molecular and behavioral effects
of stress. On the other hand, treatment with desipramine
only partially attenuated the levels of P2X7 receptors.
P.2.a.020
Hippocampal P2X7 receptor expression is modulated by stress and antidepressant treatment in the learned
helplessness model
D. Ribeiro 1, P.C. Casarotto 2, C. Biojone 2, S.R. Joca 1
1Ribeirao Preto Medical School - University of São Pauloa Pharmacologya Ribeirão Pretoa Brazil
2University of Helsinkia Neuroscience Centera Helsinkia Finland
There is evidence pointing a potential involvement of P2X7 receptor aP2RX7) in mood disorders. In humans,
P2RX7 polymorphism is associated to development of depression [1]. In animal models, the lack of P2RX7
seems to induce antidepressant-like behavior: P2RX7 KO mice exhibit antidepressant-like phenotype [2],
moreover systemic administration of a preferential P2XR antagonist induces antidepressant-like behavior in
mice [3]. Therefore, the aim of this study was to investigate if the behavioral effects induced by classical
antidepressant drugs would be associated to decreased expression of P2X7 in the hippocampus, a brain
structure which is crucial to stress copying and antidepressant response. The learned helplessness model aLH)
was used in order to access behavioral effects of antidepressant drugs due its good predictive and face validity.
LH is a classical and widely used model of depression based on the observation that exposure to uncontrollable
stressors induces behavior deficits. Adult male rats were submitted to LH pre-test session a40 inescapable
footshocks: 0.4mA, 10s duration, 30–90s interval) and were treated with vehicle, imipramine 15mg/kg aIMI) or
desipramine 25mg/kg aDES) for seven days, and were tested 1 hour after the last injection. The test session
consisted of 30 escapable footshocks a0.4mA, 10s duration, 30–90s interval) preceded by a tone a60dB, 670Hz)
that started 5s before each shock and lasted until its end. Animals could avoid the shock during sound
presentation or interrupt its presentation by crossing to the opposite side of the chamber aescape). Absence of
one of these behaviors was considered an escape failure. An independent group of rats was submitted to LH pretest session astressed group) or habituation in the same apparatus anon-stressed group), and then the rats were
treated with vehicle, IMI or DES for seven days, and killed 1 hour after the last injection in order to have their
dorsal hippocampus dissected. P2RX7 expression in hippocampus was determined by western blotting. IMI at14 =
2.84; p<0.05) or DES at17 = 3.16; p<0.05) treatment decreased the number of escape failures of rats submitted
to the LH paradigm. Both, IMI [F 2,20=5.47; p<0.05] and DES [F 2,14=4.61; p<0.05] attenuated the stress-induced
P2RX7 expression in the dorsal hippocampus of rats submitted to PT. The post-hoc analysis indicates that IMI-,
but not DES-treated animals show significant difference from vehicle-treated groups, but both showed no
difference from naïve animals aNewman-Keuls, p<0.05). Our data suggests that the behavioral effects induced
by stress are associated to increased expression of P2RX7 in hippocampus, and imipramine treatment blunted
both molecular and behavioral effects of stress. On the other hand, treatment with desipramine only partially
attenuated the levels of P2X7R. Additional experiments are necessary to elucidate if the differential effects of
imipramine and desipramine are related to the preferential effect of this drugs upon serotonergic/noradrenergic
signaling.
1. Lucae, S. et al., 2006 P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major
depressive disorder. Human Molecular Genetics 15a16), 2438–2445.
2. Basso, A.M. et al., 2009 Behavioral profile of P2X7 receptor knockout mice in animal models of depression
and anxiety: relevance for neuropsychiatric disorders. Behavioural Brain Research 198, 83–90.
3. Pereira, V.S. et al., 2013 Antidepressant- and anticompulsive-like effects of purinergic receptor blockade:
involvement of nitric oxide. Eur Neuropsychopharmacol 23a12), 1769–1778.
Citation: Eur Neuropsychopharmacol. 2014;24aSuppl 2):S372
Keywords
Antidepressants: basic
Stress
Receptors