Chronic, intermittent treatment with a cannabinoid receptor agonist impairs recognition memory
posted 10/07/2018
publication Journal of Neurochemistry, 2018; DOI: 10.1111/jnc.14549
Francisco M Mouro
Joaquim A Ribeiro
Ana M Sebastião
Neil Dawson
First published: 10 July 2018
https://doi.org/10.1111/jnc.14549
Corresponding authorAM Sebastião, Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Av. Prof Egas Moniz, 1649‐028 Lisboa, Portugal. Email: anaseb@medicina.ulisboa.pt; tel: +351‐21‐7985183
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jnc.14549
Abstract
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 (1mg/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 14C‐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.
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