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Projeto de investigação
INTERACTION BETWEEN ADENOSINE A2A RECEPTORS AND CANNABINOID CB1 RECEPTORS AT THE HIPPOCAMPUS: CONSEQUENCES FOR PLASTICITY AND MEMORY
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Adenosine A2A receptors facilitate synaptic NMDA currents in CA1 pyramidal neurons
Publication . Mouro, Francisco; Rombo, Diogo M.; Dias, Raquel Baptista; Ribeiro, Joaquim A.; Sebastião, Ana M
Background and purpose: NMDA receptors play a key role in both synaptic plasticity and neurodegeneration. Adenosine is an endogenous neuromodulator and through membrane receptors of the A2A subtype can influence both synaptic plasticity and neuronal death. The present work was designed to evaluate the influence of adenosine A2A receptors upon NMDA receptor activity in CA1 hippocampal neurons. We discriminated between modulation of synaptic versus extrasynaptic receptors, since extrasynaptic NMDA receptors are mostly associated with neurodegeneration while synaptic NMDA receptors are linked to plasticity phenomena.
Experimental approach: Whole-cell patch-clamp recordings were obtained to evaluate NMDA receptor actions on CA1 pyramidal neurons of young adult (5-10 weeks) male Wistar rat hippocampus.
Key results: Activation of A2A receptors with CGS 21680 (30 nM) consistently facilitated chemically-evoked NMDA receptor-currents (NMDA-PSCs) and afferent-evoked NMDA-currents (NMDA-EPSCs), an action prevented by an A2A receptor antagonist (SCH58261, 100 nM) and a PKA inhibitor, H-89 (1 μM). These actions did not reflect facilitation in glutamate release since there was no change in NMDA-EPSCs paired pulse ratio. A2A receptor actions were lost in the presence of an open-channel NMDA receptor blocker, MK-801 (10 μM), but persisted in the presence of memantine, at a concentration (10 μM) known to preferentially block extrasynaptic NMDA receptors.
Conclusion and implications: These results show that A2A receptors exert a positive postsynaptic modulatory effect over synaptic, but not extrasynaptic, NMDA receptors in CA1 neurons and, therefore, under non-pathological conditions may contribute to shift the dual role of NMDA receptors towards enhancement of synaptic plasticity.
Chronic and acute adenosine A2A receptor blockade prevents long-term episodic memory disruption caused by acute cannabinoid CB1 receptor activation
Publication . Mouro, Francisco; Batalha, Vânia; Ferreira, Diana; Coelho, Joana E; Baqi, Younis; Müller, Christa E.; Lopes, Luisa V.; Ribeiro, Joaquim A.; Sebastião, Ana M
Cannabinoid-mediated memory impairment is a concern in cannabinoid-based therapies. Caffeine exacerbates cannabinoid CB1 receptor (CB1R)-induced memory deficits through an adenosine A1 receptor-mediated mechanism. We now evaluated how chronic or acute blockade of adenosine A2A receptors (A2ARs) affects long-term episodic memory deficits induced by a single injection of a selective CB1R agonist. Long-term episodic memory was assessed by the novel object recognition (NOR) test. Mice received an intraperitoneal (i.p.) injection of the CB1/CB2 receptor agonist WIN 55,212-2 (1 mg/kg) immediately after the NOR training, being tested for novelty recognition 24 h later. Anxiety levels were assessed by the Elevated Plus Maze test, immediately after the NOR. Mice were also tested for exploratory behaviour at the Open Field. For chronic A2AR blockade, KW-6002 (istradefylline) (3 mg/kg/day) was administered orally for 30 days; acute blockade of A2ARs was assessed by i.p. injection of SCH 58261 (1 mg/kg) administered either together with WIN 55,212-2 or only 30 min before the NOR test phase. The involvement of CB1Rs was assessed by using the CB1R antagonist, AM251 (3 mg/kg, i.p.). WIN 55,212-2 caused a disruption in NOR, an action absent in mice also receiving AM251, KW-6002 or SCH 58261 during the encoding/consolidation phase; SCH 58251 was ineffective if present during retrieval only. No effects were detected in the Elevated Plus maze or Open Field Test. The finding that CB1R-mediated memory disruption is prevented by antagonism of adenosine A2ARs, highlights a possibility to prevent cognitive side effects when therapeutic application of CB1R drugs is desired.
Chronic, intermittent treatment with a cannabinoid receptor agonist impairs recognition memory and brain network functional connectivity
Publication . Mouro, Francisco; Ribeiro, Joaquim A.; Sebastião, Ana M; Dawson, Neil
Elucidating how cannabinoids affect brain function is instrumental for the development of therapeutic tools aiming to mitigate 'on target' side effects of cannabinoid-based therapies. A single treatment with the cannabinoid receptor agonist, WIN 55,212-2, disrupts recognition memory in mice. Here, we evaluate how prolonged, intermittent (30 days) exposure to WIN 55,212-2 (1 mg/kg) alters recognition memory and impacts on brain metabolism and functional connectivity. We show that chronic, intermittent treatment with WIN 55,212-2 disrupts recognition memory (Novel Object Recognition Test) without affecting locomotion and anxiety-like behaviour (Open Field and Elevated Plus Maze). Through 14 C-2-deoxyglucose functional brain imaging we show that chronic, intermittent WIN 55,212-2 exposure induces hypometabolism in the hippocampal dorsal subiculum and in the mediodorsal nucleus of the thalamus, two brain regions directly involved in recognition memory. In addition, WIN 55,212-2 exposure induces hypometabolism in the habenula with a contrasting hypermetabolism in the globus pallidus. Through the application of the Partial Least Squares Regression (PLSR) algorithm to the brain imaging data, we observed that prolonged WIN 55,212-2 administration alters functional connectivity in brain networks that underlie recognition memory, including that between the hippocampus and prefrontal cortex, the thalamus and prefrontal cortex, and between the hippocampus and the perirhinal cortex. In addition, our results support disturbed lateral habenula and serotonin system functional connectivity following WIN 55,212-2 exposure. Overall, this study provides new insight into the functional mechanisms underlying the impact of chronic cannabinoid exposure on memory and highlights the serotonin system as a particularly vulnerable target.
Interaction between adenosine A2A receptors and cannabinoid CB1 receptors at the hippocampus : consequences for memory and plasticity
Publication . Mouro, Francisco Melo Albuquerque Saraiva, 1988-; Sebastião, Ana Maria, 1958-
Adenosine is an ubiquitous neuromodulator of the central nervous system (CNS) and through receptors of the A2A subtype (A2ARs) can influence both synaptic plasticity and neuronal death. Likewise, endocannabinoids are important neuromodulators that act at the CNS, being involved in several physiological processes. Activation of the cannabinoid receptor 1 (CB1Rs) is responsible for mediating the physiological actions of endocannabinoids and the psychoactive effects of Δ9-THC. Neuromodulators of the central nervous system show the ability to modify the activity of N-methyl-D-aspartate receptors (NMDARs), known to play a key role in both synaptic plasticity and neurodegeneration. Considering the prejudicial effects upon memory associated with cannabinoid consumption and that NMDARs can induce neurodegeneration and excitotoxicity, this work was designed to understand if adenosine A2AR activity could be pharmacologically manipulated to protect neurons and synapses from insults coming from cannabinoid exposure and NMDARs hyperfunction. The results show that an adenosine A2AR agonist could selectively increase synaptic NMDAR activity, known to be related with neuroprotection. Also, it is whereby demonstrated that the activation of CB1Rs is associated with long term potentiation (LTP) impairments and disruptions in recognition memory. Simultaneous administration of an A2ARs antagonist was able to partially restore LTP and to fully cancel impairments in recognition memory. Also, it was found that chronic cannabinoid exposure modified brain metabolic activity, resulting in patterns of abnormal functional connectivity within the limbic system. These results point to dysfunctionalities in a multiplitude of brain regions involved in recognition memory. This work highlights the ability of adenosine A2ARs to act as metamodulators of synaptic transmission in the CNS. The fact that these receptors are able of increasing and decreasing, respectively, the positive outcomes of synaptic NMDAR activity and the negative consequences of CB1Rs upon recognition memory, show the potential of A2AR as therapeutic targets to tackle neuronal imbalances in psychiatric and neurologic diseases.
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Fundação para a Ciência e a Tecnologia
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SFRH/BD/89582/2012