Memory deficits induced by chronic cannabinoid exposure are prevented by adenosine A 2A R receptor antagonism.

Autor: Mouro FM; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal., Köfalvi A; CNC, Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, Portugal., André LA; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal., Baqi Y; Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie I, University of Bonn, Germany; Department of Chemistry, Faculty of Science, Sultan Qaboos University, Muscat, Oman., Müller CE; Pharma-Zentrum Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie I, University of Bonn, Germany., Ribeiro JA; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal., Sebastião AM; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal. Electronic address: anaseb@medicina.ulisboa.pt.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2019 Sep 01; Vol. 155, pp. 10-21. Date of Electronic Publication: 2019 May 16.
DOI: 10.1016/j.neuropharm.2019.05.003
Abstrakt: Patients under cannabis-based therapies are usually chronically exposed to cannabinoids. Chronic treatment with a cannabinoid receptor agonist, WIN 55,212-2, affects brain metabolism and modifies functional connectivity between brain areas responsible for memory and learning. Therefore, it is of uttermost importance to discover strategies to mitigate the negative side-effects of cannabinoid-based therapies. Previously, we showed that a single treatment with the synthetic cannabinoid WIN 55,212-2 disrupts recognition memory, an effect mediated by cannabinoid receptor 1 (CB 1 R) and cancelled by concomitant administration of adenosine A 2A receptor (A 2A R) antagonists. We herein evaluate if memory deficits induced by chronic exposure to WIN 55,212-2 can also be reverted by A 2A R antagonism, and assessed the synaptic mechanisms that could be involved in that reversal. We show that chronic administration of KW-6002 (istradefylline) (3 mg/kg/28days) reverts memory deficits (evaluated through the Novel Object Recognition Test) induced by chronic cannabinoid exposure (WIN 55,212-2, 1 mg/kg/28 days). Long Term Potentiation (LTP) of synaptic potentials recorded from the CA1 area of the hippocampus was impaired by WIN 55,212-2 (300 nM), an effect partially rescued by the A 2A R antagonist, SCH 58261 (100 nM). Chronic administration of KW-6002 or WIN 55,212-2 did not affect A 2A R or CB 1 R binding in the hippocampus and in the prefrontal cortex. These results, showing that A 2A R antagonism can still revert memory deficits after chronic administration of a cannabinoid, an effect that involves mitigation of synaptic plasticity impairment, strongly indicate that adenosine A 2A Rs are appropriate targets to tackle side-effects of putative therapies involving the activation of cannabinoid receptors.
(Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: