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Cortical adrenoceptor expression, function and adaptation under conditions of cannabinoid receptor deletion
Journal article   Open access   Peer reviewed

Cortical adrenoceptor expression, function and adaptation under conditions of cannabinoid receptor deletion

B. A. S. Reyes, A. F. Carvalho, P. Szot, D. J. Kalamarides, Q. Wang, L. G. Kirby and E. J. Van Bockstaele
Experimental neurology, v 292, pp 179-192
01 Jun 2017
DOI: https://doi.org/10.1016/j.expneurol.2017.03.010
PMID: 28341460
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc5454488View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Life Sciences & Biomedicine Neurosciences Neurosciences & Neurology Science & Technology
A neurochemical target at which cannabinoids interact to have global effects on behavior is brain noradrenergic circuitry. Acute and repeated administration of a cannabinoid receptor synthetic agonist is capable of increasing multiple indices of noradrenergic activity. This includes cannabinoid-induced 1) increases in norepinephrine (NE) release in the medial prefrontal cortex (mPFC); 2) desensitization of cortical alpha 2-adrenoceptor-mediated effects; 3) activation of c-Fos in brainstem locus coeruleus (LC) noradrenergic neurons; and 4) increases in anxiety like behaviors. In the present study, we sought to examine adaptations in adrenoceptor expression and function under conditions of cannabinoid receptor type 1 (CB1r) deletion using knockout (KO) mice and compare these to wild type (WT) controls. Electrophysiological analysis of alpha 2-adrenoceptor-mediated responses in mPFC slices in WT mice showed a clonidine-induced a2-adrenoceptor-mediated increase in mPFC cell excitability coupled with an increase in input resistance. In contrast, CB1r KO mice showed an alpha 2-adrenoceptor-mediated decrease in mPFC cell excitability. We then examined protein expression levels of alpha 2- and beta 1-adrenoceptor subtypes in the mPFC as well as TH expression in the locus coeruleus (LC) of mice deficient in CB1r. Both alpha 2- and inadrenoceptors exhibited a significant decrease in expression levels in CB1r KO mice when compared to WT in the mPFC, while a significant increase in TH was observed in the LC. To better define whether the same cortical neurons express alpha 2A-adrenoceptor and CB1r in mPFC, we utilized high-resolution immunoelectron microscopy. We localized alpha 2A-adrenoceptors in a knock-in mouse that expressed a hemoagglutinin (HA) tag downstream of the alpha 2A-adrenoceptor promoter. Although the alpha 2A-adrenoceptor was often identifiedpre-synaptically, we observed co-localization of CB1r with alpha 2-adrenoceptors post-synaptically in the same mPFC neurons. Finally, using receptor binding, we confirmed prior results showing that alpha 2A-adrenoceptor is unchanged in mPFC following acute or chronic exposure to the synthetic cannabinoid receptor agonist, WIN 55,212-2, but is increased, following chronic treatment followed by a period of abstinence. Taken together, these data provide convergent lines of evidence indicating cannabinoid regulation of the cortical adrenergic system. (C) 2017 Elsevier Inc. All rights reserved.

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