CB 1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal

Saravia, Rocío; Flores, África; Plaza-Zabala, Ainhoa; Busquets-García, Arnau; Pastor, Antoni; Torre, Rafael de la; Marzo, Vincenzo Di; Marsicano, Giovanni; Ozaita, Andrés; Maldonado, Rafaël; Berrendero, Fernando

doi:10.1016/j.biopsych.2016.07.007

Cited by 27 publications

(37 citation statements)

References 58 publications

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“…All drugs were administered in a volume of 10ml per kg of body weight. Doses of nicotine, mecamylamine, cannabidiol and indomethacin were based on previous studies (Ren et al, 2009;Ho et al, 2015;Saravia et al, 2017;Stern et al, 2017).…”

Section: Drugsmentioning

confidence: 99%

“…Fourteen days after minipump implantation, nicotine withdrawal syndrome was precipitated by the administration of the nicotinic receptor antagonist mecamylamine (2mg/kg). Systemic administration of mecamylamine in nicotine-treated rodents is a wellestablished model to study the neurobiological mechanisms involved in the different aspects that characterize the nicotine withdrawal syndrome (Muldoon et al, 2015;Qi et al, 2015;Parikh et al, 2016;Saravia et al, 2017), typically observed in abstinent smokers.…”

Section: Nicotine Treatment and Withdrawalmentioning

confidence: 99%

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Anti-inflammatory agents for smoking cessation? Focus on cognitive deficits associated with nicotine withdrawal in male mice

Saravia

Ten-Blanco

Grande

et al. 2019

Brain, Behavior, and Immunity

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Nicotine withdrawal is associated with cognitive deficits including attention, working memory, and episodic memory impairments. These cognitive deficits are a hallmark of nicotine abstinence which could be targeted in order to prevent smoking relapse. The underlying mechanisms, however, are poorly understood. In this study, memory impairment was observed in mice 4 days after the precipitation of nicotine withdrawal by the nicotinic antagonist mecamylamine. The presence of cognitive deficits correlated with microglial activation in the hippocampus and the prefrontal cortex. Moreover, an increased expression of neuroinflammatory markers including IL1β, TNFα and IFNγ was found in both memory-related brain regions. Notably, flow cytometric analysis also revealed an enhancement of TNFα and IFNγ plasmatic levels at the same time point during nicotine withdrawal. Impaired neurogenesis, as shown by reduction in the expression of the endogenous cell proliferation marker Ki67 and the early neuron marker doublecortin, was also associated with nicotine abstinence. Treatment with the nonpsychoactive cannabinoid cannabidiol abolished memory impairment of nicotine withdrawal and microglia reactivity, reduced the expression of IL1β and IFNγ in the hippocampus and the prefrontal cortex, respectively, and normalized Ki67 levels. The nonsteroidal anti-inflammatory drug indomethacin also prevented cognitive deficits and microglial reactivity during withdrawal. These data underline the usefulness of antiinflammatory agents to improve cognitive performance during early nicotine abstinence.

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Section: Drugsmentioning

confidence: 99%

Section: Nicotine Treatment and Withdrawalmentioning

confidence: 99%

Anti-inflammatory agents for smoking cessation? Focus on cognitive deficits associated with nicotine withdrawal in male mice

Saravia

Ten-Blanco

Grande

et al. 2019

Brain, Behavior, and Immunity

Self Cite

View full text Add to dashboard Cite

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“…One of the endogenous ligands for the cannabinoid receptor (i.e., CB1R) (Saravia et al ., ) has been associated with cognitive deficits in memory and attention that emerge during early abstinence from smoking. In humans, these early cognitive impairments predict early relapse to smoking (Patterson et al ., ).…”

Section: Smoking Cessation and Relapsementioning

confidence: 99%

“…Two different models of stress-induced relapse to nicotine demonstrate the requisite involvement of neuropeptides: corticotropin-releasing factor in the central nucleus of amygdala in reinstatement of operant nicotine seeking (Bruijnzeel et al, 2009); dynorphin and kappa opioid receptors in basolateral nucleus of amygdala in conditioned place preference for nicotine (Nygard et al, 2016). One of the endogenous ligands for the cannabinoid receptor (i.e., CB1R) (Saravia et al, 2017) has been associated with cognitive deficits in memory and attention that emerge during early abstinence from smoking. In humans, these early cognitive impairments predict early relapse to smoking (Patterson et al, 2010).…”

Section: Animal Genetic Studiesmentioning

confidence: 99%

“…In humans, these early cognitive impairments predict early relapse to smoking (Patterson et al, 2010). In mice, mecamylamine-precipitated withdrawal from nicotine impaired memory and reduced dendritic spines in hippocampal pyramidal neurons (Saravia et al, 2017). These memory and morphological deficits, which correlated with increased synthesis of the CB1R ligand 2-AG (2-arachidonoylglycerol) in forebrain, were abolished by pretreatment with rimonabant, a CB1 antagonist, or molecular deletion of CB1R from forebrain GABA neurons.…”

Section: Animal Genetic Studiesmentioning

confidence: 99%

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Neurogenetic determinants and mechanisms of addiction to nicotine and smoked tobacco

Sharp

Chen

2018

Eur J of Neuroscience

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The single most preventable cause of disease, disability, and death in the United States is tobacco use. Decades of study show that the risk of becoming addicted to smoked cigarettes varies greatly amongst individuals and is heritable, yet environmental factors are also important contributors. In this review, we consider a wide range of methodologies and key published reports that have defined the inheritance of different stages of nicotine‐dependent smoking behavior, including preference, initiation, regular use, withdrawal and dependence as well as cessation and relapse. Major findings from both animal and human studies are discussed. Current findings converge primarily on the role of nicotinic cholinergic receptor subunits, although other neurotransmitter systems as well as nicotine metabolism enzymes are implicated. Various stages of nicotine addiction may share common genetic mechanisms, yet several lines of evidence indicate that each stage also has its own unique genetic determinants. Studies on the heritability of smoking initiation demonstrate substantial evidence for gene–environment interaction, although the precise molecular genetic mechanism(s) remains unknown. Considering the relatively few genes identified so far and the small to modest fraction of the variance in risk for a particular smoking phenotype (e.g., smoking initiation in late adolescence) attributable to these genes, a large gap remains to be filled in order to account for the heritability of key phenotypes involved in each stage of addiction to smoked tobacco. Looking forward, new research strategies involving both human and animal studies will produce the fundamental genetic insights that are the foundation for the precision medical treatment of individuals addicted to smoked tobacco.

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Endocannabinoid Signaling in Reward and Addiction: From Homeostasis to Pathology

Laredo

Marrs

Parsons

2017

Endocannabinoids and Lipid Mediators in Brain Functions

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CB 1 Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal

Abstract: These findings underline the interest of CBR as a target to improve cognitive performance during early nicotine withdrawal. Cognitive deficits in early abstinence are associated with increased relapse risk.

Cited by 27 publications

References 58 publications

Anti-inflammatory agents for smoking cessation? Focus on cognitive deficits associated with nicotine withdrawal in male mice

Anti-inflammatory agents for smoking cessation? Focus on cognitive deficits associated with nicotine withdrawal in male mice

Neurogenetic determinants and mechanisms of addiction to nicotine and smoked tobacco

Endocannabinoid Signaling in Reward and Addiction: From Homeostasis to Pathology

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