Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: Reduced dopaminergic modulation and immediate gene expression in limbic circuits.
The prefrontal cortex (PFC), amygdala and hippocampus display a coordinated activity during acquisition of associative fear memories. Evidence indicates that PFC engagement in aversive memory formation does not progress linearly as previously thought. Instead, it seems to be recruited at specific time windows after memory acquisition, which has implications for the treatment of post-traumatic stress disorders. Cannabidiol (CBD), the major non-psychotomimetic phytocannabinoid of the Cannabis sativa plant, is known to modulate contextual fear memory acquisition in rodents. However, it is still not clear how CBD interferes with PFC-dependent processes during post-training memory consolidation. Here, we tested whether intra-PFC infusions of CBD immediately after or 5h following contextual fear conditioning was able to interfere with memory consolidation. Neurochemical and cellular correlates of the CBD treatment were evaluated by the quantification of extracellular levels of dopamine (DA), serotonin, and their metabolites in the PFC and by measuring the cellular expression of activity-dependent transcription factors in cortical and limbic regions. Our results indicate that bilateral intra-PFC CBD infusion impaired contextual fear memory consolidation when applied 5h after conditioning, but had no effect when applied immediately after it. This effect was associated with a reduction in DA turnover in the PFC following retrieval 5days after training. We also observed that post-conditioning infusion of CBD reduced c-fos and zif-268 protein expression in the hippocampus, PFC, and thalamus. Our findings support that CBD interferes with contextual fear memory consolidation by reducing PFC influence on cortico-limbic circuits.
Department of Neuroscience and Behavior Science, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto - SP, Brazil. Electronic address: rossignoli.mt@gmail.com.
Matheus Teixeira
MT
Rossignoli
Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte - MG, Brazil. Electronic address: cleitonbiousp@gmail.com.
Cleiton
C
Lopes-Aguiar
Department of Neuroscience and Behavior Science, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto - SP, Brazil. Electronic address: rafaruggiero@gmail.com.
Rafael Naime
RN
Ruggiero
Department of Neuroscience and Behavior Science, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto - SP, Brazil. Electronic address: raqueldoval@ig.com.br.
Raquel Araujo
RA
Do Val da Silva
Department of Neuroscience and Behavior Science, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto - SP, Brazil. Electronic address: lezioneuro@gmail.com.
Lezio Soares
LS
Bueno-Junior
Department of Neuroscience and Behavior Science, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto - SP, Brazil. Electronic address: ludykandra@gmail.com.
Ludmyla
L
Kandratavicius
Department of Neuroscience and Behavior Science, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto - SP, Brazil. Electronic address: peixotosantos@yahoo.com.br.
José Eduardo
JE
Peixoto-Santos
Department of Neuroscience and Behavior Science, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto - SP, Brazil. Electronic address: jcrippa@fmrp.usp.br.
José Alexandre
JA
Crippa
Department of Neuroscience and Behavior Science, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto - SP, Brazil. Electronic address: jhallak@fmrp.usp.br.
Jaime Eduardo
JE
Cecilio Hallak
Department of Neuroscience and Behavior Science, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto - SP, Brazil. Electronic address: awzuardi@fmrp.usp.br.
Antonio Waldo
AW
Zuardi
Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte - MG, Brazil. Electronic address: reszawka@icb.ufmg.br.
Raphael Escorsim
RE
Szawka
Department of Morphology, Physiology and Basic Pathology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto - SP, Brazil. Electronic address: jaafranc@usp.br.
Janete
J
Anselmo-Franci
Department of Neuroscience and Behavior Science, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto - SP, Brazil. Electronic address: jpleite@fmrp.usp.br.
João Pereira
JP
Leite
Brain Institute, Federal University of Rio Grande do Norte, Natal - RN, Brazil. Electronic address: rnrpereira@neuro.ufrn.br.
Rodrigo Neves
RN
Romcy-Pereira
D000818:Animals; D002185:Cannabidiol / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000069077:Memory Consolidation / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D017208:Rats, Wistar; D013313:Stress Disorders, Post-Traumatic / Q000378:metabolism; D013997:Time Factors
D002185:Cannabidiol
C-fos; cannabidiol; contextual fear memory; dopamine; medial prefrontal cortex