Monoamine involvement in the antidepressant-like effect induced by P2 blockade

Abstract

Depression is a common mental disorder that affects millions of individuals worldwide. Available monoaminergic antidepressants are far from ideal since they show delayed onset of action and are ineffective in approximately 40% of patients, thus indicating the need of new and more effective drugs. ATP signaling through P2 receptors seems to play an important role in neuropathological mechanisms involved in depression, since their pharmacological or genetic inactivation induce antidepressant-like effects in the forced swimming test (FST). However, the mechanisms involved in these effects are not completely understood. The present work investigated monoamine involvement in the antidepressant-like effect induced by non-specific P2 receptor antagonist (PPADS) administration. First, the effects of combining sub-effective doses of PPADS with sub-effective doses of fluoxetine (FLX, selective serotonin reuptake inhibitor) or reboxetine (RBX, selective noradrenaline reuptake inhibitor) were investigated in mice submitted to FST. Significant antidepressant-like effect was observed when subeffective doses of PPADS was combined with subeffective doses of either FLX or RBX, with no significant locomotor changes. Next, the effects of depleting serotonin and noradrenaline levels, by means of PCPA (p-Chlorophenylalanine) or DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) pretreatment, respectively, was investigated. Both, PCPA and DSP-4 pretreatment partially attenuated PPADS-induced effects in FST, without inducing relevant locomotor changes. Our results suggest that the antidepressant-like effect of PPADS involves modulation of serotonin and noradrenaline levels in the brain.

Purinergic Signaling and Related Biomarkers in Depression

“…The antidepressant phenotype related to genetic deletion of P2X7 receptors seems associated with changes in hippocampal monoaminergic transmission [66]. All these findings support the hypothesis of CNS-penetrable ATP-sensitive P2X7 receptor antagonists as novel antidepressant agents [58,59,67]. Moreover, ATP-sensitive potassium channels have been claimed to be a possible target for the treatment of depression [68][69][70].…”

“…An early study showed that erythrocyte membrane ATP activity was significantly lower during the depressive phase of patients than in the remission phase [57], suggesting that ATP may be involved in depression. The combination of non-specific P2 receptor antagonists with antidepressants has been associated with significant antidepressant-like effects in animal models [58]. It has been hypothesized that ATP released from astrocytes might trigger the development of depressive-like behaviors [59,60].…”

Antidepressant-like effect induced by Cannabidiol is dependent on brain serotonin levels

“…In this study, we used the following drugs: Cannabidiol (CBD, THC Pharma, Frankfurt, Germany): 3, 7 and 10 mg/kg (Zanelati et al, 2010); Fluoxetine (FLX, selective inhibitor of serotonin reuptake; Sigma-Aldrich, St. Louis, MO, USA): 1, 5 and 10 mg/kg (Sales and Joca, 2016); Desipramine hydrochloride (DES, tricyclic antidepressant; Sigma-Aldrich): 2.5 and 5 mg/kg (Sales and Joca, 2016); Para-Clorophenylalaninemethyl ester (PCPA, 5-HT synthesis inhibitor): 100 mg/ kg/day during 4 days (Diniz et al, 2017); -N-(2-chloroethyl)-N-ethyl-2bromobenzylamine (DSP-4, noradrenergic neurotoxin): 1 μg/μL (Diniz et al, 2017). DES was dissolved in sterile saline; CBD, FLX and PCPA were dissolved in 2% Tween 80/isotonic sterile saline.…”

Peer Review #1 of "Reduced P2X receptor levels are associated with antidepressant effect in the learned helplessness model (v0.2)"

“…In fact, the antidepressant effect induced by P2RX antagonists is dependent on the facilitatory action upon monoamine signaling in the CNS, since depletion of serotonin or noradrenaline blocked the effects induced by pyridoxalphosphate-6-azophenyl-2,4-disulphonoic acid (PPADS) (Diniz et al, 2017). Moreover, chronic blockade of P2RX7 have also shown to increase BDNF levels in mice hippocampus (Csölle et al, 2013a) as well as activate BDNF-TRKB signaling pathway in ventral hippocampus of stressed rats (Ribeiro et al, 2019), an effect that is central to the mechanism of action induced by monoaminergic drugs (Saarelainen et al, 2003;Rantamäki et al, 2007).Therefore, it is plausible to suggest that P2RX7 blockade could promote antidepressant effects as a result of monoaminergic and BDNF signaling facilitation.…”