Adenosine A2A receptor blockade reverts hippocampal stress-induced deficits and restores corticosterone circadian oscillation

Abstract

Maternal separation (MS) is an early life stress model that induces permanent changes in the central nervous system, impairing hippocampal long-term potentiation (LTP) and spatial working memory. There are compelling evidences for a role of hippocampal adenosine A(2A) receptors in stress-induced modifications related to cognition, thus opening a potential window for therapeutic intervention. Here, we submitted rats to MS and evaluated the long-lasting molecular, electrophysiological and behavioral impairments in adulthood. We then assessed the therapeutic potential of KW6002, a blocker of A(2A) receptors, in stress-impaired animals. We report that the blockade of A(2A) receptors was efficient in reverting the behavior, electrophysiological and morphological impairments induced by MS. In addition, this effect is associated with restoration of the hypothalamic-pituitary-adrenal axis (HPA-axis) activity, as both the plasma corticosterone levels and hippocampal glucocorticoid receptor expression pattern returned to physiological-like status after the treatment. These results reveal the involvement of A(2A) receptors in the stress-associated impairments and directly in the stress response system by showing that the dysfunction of the HPA-axis as well as the long-lasting synaptic and behavioral effects of MS can be reverted by targeting adenosine A(2A) receptors. These findings provide a novel evidence for the use of adenosine A(2A) receptor antagonists as potential therapy against psychopathologies.

Caffeine acts through neuronal adenosine A 2A receptors to prevent mood and memory dysfunction triggered by chronic stress

“…This A 2A R up-regulation is accompanied by an A 2A R gain of function (reviewed in ref. 33) that leads to synaptic dysfunction, as demonstrated by the ability of A 2A R antagonists to prevent synaptic plasticity dysfunction with aging (11) and maternal separation (12) and by the loss of synaptic markers in different noxious brain conditions (14,15,31), namely upon repeated restraint stress (32). How enhanced A 2A R function triggers synaptic dysfunction remains to be determined, given our current ignorance of the transducing systems operated by these pleiotropic A 2A R (34,35).…”

“…The only molecular targets for caffeine at nontoxic doses are the main adenosine receptors in the brain, namely the inhibitory A 1 receptors (A 1 R) and the facilitatory A 2A receptors (A 2A R) (9). A 2A R blockade affords robust protection against noxious brain conditions (10), an effect that might result from the ability of neuronal A 2A R to control aberrant plasticity (11,12) and synaptotoxicity (13)(14)(15) or from A 2A R's impact on astrocytes (16) or microglia (17). The protection provided by A 2A R blockade prompts the hypothesis that A 2A R antagonism may underlie the beneficial effects of caffeine on chronic stress, in accordance with the role of synaptic (18,19) or glial dysfunction (20) in mood disorders.…”

“…The protection provided by A 2A R blockade prompts the hypothesis that A 2A R antagonism may underlie the beneficial effects of caffeine on chronic stress, in accordance with the role of synaptic (18,19) or glial dysfunction (20) in mood disorders. Thus, A 2A R antagonists prolonged escape behavior in two screening tests for antidepressant activity (21)(22)(23) and prevented maternal separation-induced longterm cognitive impact (12). We combined pharmacological and tissue-selective A 2A R transgenic mice (24,25) to test if neuronal A 2A R controlled the modifications caused by chronic unpredictable stress (CUS).…”

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

“…The importance of this modulation system is best heralded by the observation that the overactivation of hippocampal A 2A Rs is necessary and sufficient to trigger spatial memory dysfunction (Li et al, 2015a;Pagnussat et al, 2015). Furthermore, conditions associated with memory deterioration trigger an upregulation of A 2A Rs in the hippocampus leading to abnormal synaptic plasticity (Costenla et al, 2011;Kaster et al, 2015), and A 2A R blockade prevent memory impairment in conditions such as stress, aging, or Alzheimer's disease (eg Batalha et al, 2013;Laurent et al, 2016;Oor et al, 2015;Prediger et al, 2005), an effect mimicked by caffeine (a nonselective adenosine receptor antagonist) both in animal models and in humans (reviewed in Cunha and Agostinho, 2010;Chen, 2014).…”

Adenosine Kinase Deficiency in the Brain Results in Maladaptive Synaptic Plasticity

“…Chemoluminescence detection was performed with an ECL-PLUS Western blot detection reagent (GE Healthcare) using X-ray films (Fujifilm). The saturation binding experiments were adapted from a previous protocol (Batalha et al, 2013).…”