The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A 2A receptor (A 2A R) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A 2A R to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A 2A R in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A 2A R antagonist KW6002 (3 mg/kg, p.o.); (iii) global A 2A R deletion; and (iv) selective A 2A R deletion in forebrain neurons. Notably, A 2A R blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A 2A R antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A 2A R in the control of chronic stress-induced modifications and suggest A 2A R as candidate targets to alleviate the consequences of chronic stress on brain function.R epeated stress elicits neurochemical and morphological changes that negatively affect brain functioning (1, 2). Thus, repeated stress is a trigger or a risk factor for neuropsychiatric disorders, namely depression, in both humans and animal models (2, 3). Given the absence of effective therapeutic tools, novel strategies to manage the impact of chronic stress are needed, and analyzing particular lifestyles can provide important leads. Notably, caffeine consumption increases in stressful conditions (4) and correlates inversely with the incidence of depression (5, 6) and the risk of suicide (7,8). However, the molecular targets operated by caffeine to afford these beneficial effects have not been defined.Caffeine is the most widely consumed psychoactive drug. 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 (13-15) or from A 2A R's impact on astrocytes (16) or microglia (17). T...

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Synaptic dysfunction plays a central role in Alzheimer's disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A receptor (AR) encoding gene-ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of AR in age-related conditions. We report, for the first time, a significant overexpression of AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon AR blockade. This AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.

The function of striatal adenosine A2Areceptors (A2ARs) is well recognized because of their high expression levels and the documented antagonistic interaction between A2ARs and dopamine D2receptors in the striatum. However, the role of extrastriatal A2ARs in modulating psychomotor activity is largely unexplored because of the low level of expression and lack of tools to distinguish A2ARs in intrinsic striatal versus nonstriatal neurons. Here, we provided direct evidence for the critical role of A2ARs in extrastriatal neurons in modulating psychomotor behavior using newly developed striatum-specific A2AR knock-out (st-A2AR KO) mice in comparison with forebrain-specific A2AR KO (fb-A2AR KO) mice. In contrast to fb-A2AR KO (deleting A2ARs in the neurons of striatum as well as cerebral cortex and hippocampus), st-A2AR KO mice exhibited Cre-mediated selective deletion of the A2AR gene, mRNA, and proteins in the neurons (but not astrocytes and microglial cells) of the striatum only. Strikingly, cocaine- and phencyclidine-induced psychomotor activities were enhanced in st-A2AR KO but attenuated in fb-A2AR KO mice. Furthermore, selective inactivation of the A2ARs in extrastriatal cells by administering the A2AR antagonist KW6002 into st-A2AR KO mice attenuated cocaine effects, whereas KW6002 administration into wild-type mice enhanced cocaine effects. These results identify a critical role of A2ARs in extrastriatal neurons in providing a prominent excitatory effect on psychomotor activity. These results indicate that A2ARs in striatal and extrastriatal neurons exert an opposing modulation of psychostimulant effects and provide the first direct demonstration of a predominant facilitatory role of extrastriatal A2ARs.

Adenosine neuromodulation depends on a balanced activation of inhibitory A 1 (A 1 R) and facilitatory A 2A receptors (A 2A R). Both A 1 R and A 2A R modulate hippocampal glutamate release and NMDA-dependent long-term potentiation (LTP) but ageing affects the density of both A 1 R and A 2A R. We tested the effects of selective A 1 R and A 2A R antagonists in the modulation of synaptic transmission and plasticity in rat hippocampal slices from three age groups (young adults, 2-3 month; middle-aged adults, 6-8 months; aged, 18-20 months). The selective A 2A R antagonist SCH58261 (50 nm) attenuated LTP in all age groups, with a larger effect in aged ()63 ± 7%) than in middle-aged adults ()36 ± 9%) or young adult rats ()36 ± 9%). In contrast, the selective A 1 R antagonist DPCPX (50 nm) increased LTP magnitude in young adult rats (+42 ± 6%), but failed to affect LTP magnitude in the other age groups. Finally, in the continuous presence of DPCPX, SCH58261 caused a significantly larger inhibition of LTP amplitude in aged ()71 ± 45%) than middle-aged ()28 ± 9%) or young rats ()11 ± 2%). Accordingly, aged rats displayed an increased expression of A 2A R mRNA in the hippocampus and a higher number of glutamatergic nerve terminals equipped with A 2A R in aged (67 ± 6%) compared with middle-aged (34 ± 7%) and young rats (25 ± 5%). The results show an enhanced A 2A R-mediated modulation of LTP in aged rats, in accordance with the age-associated increased expression and density of A 2A R in glutamatergic terminals. This age-associated gain of function of A 2A R modulating synaptic plasticity may underlie the ability of A 2A R antagonists to prevent memory dysfunction in aged animals.

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Interpretation: A 2A R activity in forebrain neurons is critical to the control of motor activity, whereas brain cells other than forebrain neurons (likely glial cells) are important components for protection against acute MPTP toxicity.