CB1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal.
Biological Psychiatry. 2017-04-01; 81(7): 625-634
DOI: 10.1016/j.biopsych.2016.07.007
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1. Biol Psychiatry. 2017 Apr 1;81(7):625-634. doi: 10.1016/j.biopsych.2016.07.007.
Epub 2016 Jul 16.
CB1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity
Changes During Nicotine Withdrawal.
Saravia R(1), Flores Á(1), Plaza-Zabala A(1), Busquets-Garcia A(1), Pastor A(2),
de la Torre R(2), Di Marzo V(3), Marsicano G(4), Ozaita A(1), Maldonado R(1),
Berrendero F(5).
Author information:
(1)Laboratory of Neuropharmacology, Department of Experimental and Health
Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
(2)Integrative Pharmacology and Systems Neuroscience, IMIM-Hospital del Mar
Medical Research Institute, Barcelona, Spain; CIBER Fisiopatología Obesidad y
Nutrición (AP, RdlT), Instituto Salud Carlos III, Madrid, Spain.
(3)Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National
Research Council, Naples, Italy.
(4)Institut National de la Santé et de la Recherche Médicale, U862 NeuroCentre
Magendie, Group Endocannabinoids and Neuroadaptation, Bordeaux, France;
University of Bordeaux, Bordeaux, France.
(5)Laboratory of Neuropharmacology, Department of Experimental and Health
Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address:
.
BACKGROUND: Tobacco withdrawal is associated with deficits in cognitive function,
including attention, working memory, and episodic memory. Understanding the
neurobiological mechanisms involved in these effects is crucial because cognitive
deficits during nicotine withdrawal may predict relapse in humans.
METHODS: We investigated in mice the role of CB1 cannabinoid receptors (CB1Rs) in
memory impairment and spine density changes induced by nicotine withdrawal
precipitated by the nicotinic antagonist mecamylamine. Drugs acting on the
endocannabinoid system and genetically modified mice were used.
RESULTS: Memory impairment during nicotine withdrawal was blocked by the CB1R
antagonist rimonabant or the genetic deletion of CB1R in forebrain
gamma-aminobutyric acidergic (GABAergic) neurons (GABA-CB1R). An increase of
2-arachidonoylglycerol (2-AG), but not anandamide, was observed during nicotine
withdrawal. The selective inhibitor of 2-AG biosynthesis O7460 abolished
cognitive deficits of nicotine abstinence, whereas the inhibitor of 2-AG
enzymatic degradation JZL184 did not produce any effect in cognitive impairment.
Moreover, memory impairment was prevented by the selective mammalian target of
rapamycin inhibitor temsirolimus and the protein synthesis inhibitor anisomycin.
Mature dendritic spines on CA1 pyramidal hippocampal neurons decreased 4 days
after the precipitation of nicotine withdrawal, when the cognitive deficits were
still present. Indeed, a correlation between memory performance and mature spine
density was found. Interestingly, these structural plasticity alterations were
normalized in GABA-CB1R conditional knockout mice and after subchronic treatment
with rimonabant.
CONCLUSIONS: These findings underline the interest of CB1R as a target to improve
cognitive performance during early nicotine withdrawal. Cognitive deficits in
early abstinence are associated with increased relapse risk.
Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All
rights reserved.
DOI: 10.1016/j.biopsych.2016.07.007
PMID: 27737762 [Indexed for MEDLINE]