The absence of P2X7 receptors (P2rx7) on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice

Abstract

The purpose of this study was to explore how genetic deletion and pharmacological antagonism of the P2X7 receptor (P2rx7) alter mood-related behaviour, gene expression and stress reactivity in the brain. The forced swim test (FST), tail suspension test (TST) and amphetamine-induced hyperlocomotion (AH) tests were used in wild-type (P2rx7+/+) and P2rx7-deficient (P2rx7−/−) mice. Biogenic amine levels were analysed in the amygdala and striatum, adrenocorticotropic hormone (ACTH) and corticosterone levels were measured in the plasma and pituitary after restraint stress. Chimeric mice were generated by bone marrow transplantation. A whole genome microarray analysis with real-time polymerase chain reaction validation was performed on the amygdala. In the absence of P2rx7s decreased behavioural despair in the FST, reduced immobility in the TST and attenuated amphetamine-induced hyperactivity were detected. Basal norepinephrine levels were elevated in the amygdala, whereas stress-induced ACTH and corticosterone responses were alleviated in P2rx7−/− mice. Sub-acute treatment with the selective P2rx7 antagonist, Brilliant Blue G, reproduced the effect of genetic deletion in the TST and AH test in P2rx7+/+ but not P2rx7−/− mice. No change in behavioural phenotype was observed in chimeras lacking the P2rx7 in their haematopoietic compartment. Whole genome microarray analysis indicated a widespread up- and down-regulation of genes crucial for synaptic function and neuroplasticity by genetic deletion. Here, we present evidence that the absence of P2rx7s on non-haematopoietic cells leads to a mood-stabilizing phenotype in several behavioural models and suggest a therapeutic potential of P2rx7 antagonists for the treatment of mood disorders.

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

“…7B, doses of 3 mg/kg are SERT sparing but still high for P2X7 occupancy; as such, the efficacy observed for attenuating amphetamine hyperactivity is probably a result of P2X7 blockade. This will be the third publication indicating a role of the P2X7 pathway in amphetamine hyperactivity (Bhattacharya et al, 2013;Csölle et al, 2013). It will be an interesting avenue of science to follow to elucidate the mechanism of the interaction of amphetamine and P2X7; preliminary data indicate that the effect of P2X7 antagonists on attenuating amphetamine hyperactivity is independent of dopamine (L. Aluisio and P. Bonaventure, unpublished data).…”

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…To study the manic pole of bipolar disorder, genetic deficiency and pharmacological blockade of P2X7 receptors attenuated hyperactivity induced by amphetamine in all studies examined (Bhattacharya et al, 2013;Csolle et al, 2013a;Gubert et al, 2014;Lord et al, 2014). These findings indicate that the presence and endogenous activation of P2X7 receptors contributes to behavioral changes induced by either negative or positive challenges, and the blockade of the receptor alleviates these fluctuations.…”

“…On the other hand, amphetamine induced induction of IL-1b and oxidative stress (Gubert et al, 2014) in the striatum were reversed by a P2X7 receptor antagonist coincidently with the alleviation of amphetamine induced behavior and amphetamine induced striatal dopamine release is attenuated by the P2X7 receptor deficient genotype (Csolle et al, 2013a). The lack of local IL-1b induction and subsequent modulation of dopamine release in the absence of P2X7 receptor could explain the alleviation of amphetamine induced hyperlocomotion.…”

Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists

“…3,4 Our interest in this receptor focused on the potential relationship between certain neuroinflammatory states and mood disorders after reviewing several reports that showed that P2X7 antagonism can lead to efficacy in pre-clinical models of depression. 5,6 As such, we have been investigating the role of P2X7 in mood disorders for quite some time and toward that end we recently disclosed two novel brain penetrant P2X7 compounds (1 and 2) 7-9 and demonstrated that these compounds effectively distribute into the CNS and occupy the P2X7 receptor in rat. Both compounds are high affinity human and rodent P2X7 antagonists, which make these compounds useful tool compounds capable of probing the function of P2X7 in the CNS.…”