Abstract
Purinergic receptors, especially P2RX, are associated to the severity of symptoms in patients suffering from depressive and bipolar disorders, and genetic deletion or pharmacological blockade of P2RX7 induces antidepressant-like effect in preclinical models. However, there is scarce evidence about the alterations in P2RX7 or P2RX4 levels and in behavioral consequences induced by previous exposure to stress, a major risk factor for depression in humans. In the present study, we evaluated the effect of imipramine (IMI) on P2RX7 and P2RX4 levels in dorsal and ventral hippocampus as well as in the frontal cortex of rats submitted to the pretest session of learned helplessness (LH) paradigm. Repeated, but not acute administration of IMI (15 mg/kg ip) reduced the levels of both P2RX7 and P2RX4 in the ventral, but not in dorsal hippocampus or frontal cortex. In addition, we tested the effect of P2RX7/P2RX4 antagonist brilliant blue G (BBG: 25 or 50 mg/kg ip) on the LH paradigm. We observed that repeated (7 days) but not acute (1 day) treatment with BBG (50 mg) reduced the number of failures to escape the shocks in the test session, a parameter mimicked by the same regimen of IMI treatment. Taken together, our data indicates that pharmacological blockade or decrease in the expression of P2RX7 is associated to the antidepressant-like behavior observed in the LH paradigm after repeated drug administration.
Highlights
Adenosine triphosphate (ATP)-mediated signaling has been recently involved in the behavioral effects of stress and neurobiology of depression (Burnstock et al, 2011; Sperlagh et al, 2012)
Experiment 1: effect of imipramine in the P2RX7 and P2RX4 levels of rats exposed to learned helplessness (LH) model One-way ANOVA indicated a significant effect of IMI treatment on P2XR7 (F(2,18) = 4.169, p = 0.0325) and P2RX4 (F(2,20) = 3.627, p = 0.0453) levels in ventral hippocampus
Experiment 2: effect of brilliant blue G (BBG) and imipramine treatment in the LH paradigm Kruskal–Wallis test showed that acute treatment with BBG altered neither the number of failures (H = 1.75, p = 0.42) nor the inter trial crossings (ITC) (H = 4.52, p = 0.10) of animals exposed to the LH model (Fig. 2A)
Summary
Adenosine triphosphate (ATP)-mediated signaling has been recently involved in the behavioral effects of stress and neurobiology of depression (Burnstock et al, 2011; Sperlagh et al, 2012). P2RX have been associated to several processes that are dysfunctional in stress response and depression neurobiology, such as neurotransmitter release, cognition, sleep, energy levels, appetite, immune and endocrine system (Burnstock et al, 2011). Clinical evidence associates a P2RX7 polymorphism that results in a mutation in the protein (Q460R), with higher severity of symptoms in patients with major depressive disorder (MDD) (Hejjas et al, 2009), which was recently confirmed by a meta-analysis study (Czamara, Müller-Myhsok & Lucae, 2018)
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