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

Abstract

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.

Microglia morphology and proinflammatory signaling in the nucleus accumbens during nicotine withdrawal

“…In addition, withdrawal from nicotine leads to a diverse array of clinical symptoms, spanning cognitive, affective, and motivational domains. A recent study using a model of precipitated nicotine withdrawal showed that elements of cognitive disruption in this model correlate with microglial activation in the hippocampus and prefrontal cortex ( 59 ). However, it is important to note that mecamylamine, which is used in the precipitated withdrawal model, has cognitive-depressive effects on its own in rodents ( 60 ), monkeys ( 61 ), and even humans ( 62 ).…”

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“…Object recognition memory was assessed with the V-maze (Panlab, Barcelona, Spain) to measure cognitive performance, as previously described (Puighermanal et al, 2009; Saravia et al, 2019). V-maze consisted on an apparatus made of black plexiglass with two corridors (30 cm long × 4.5 cm wide) set in V with a 90° angle and 15 cm-high walls.…”

Cannabidiol Treatment Might Promote Resilience to Cocaine and Methamphetamine Use Disorders: A Review of Possible Mechanisms

“…Other studies have also demonstrated that CBD exerted a neuroprotective effect against the adverse consequences of alcohol in the hippocampus [46] and reduced the microglia reactivity induced by nicotine withdrawal. This attenuated the increase in the levels of neuroinflammatory markers IL1β in the hippocampus and IFNγ in the PFC [100]. According to these data, it could be hypothesized that CBD may prevent the microglial reactivity and neuroinflammation induced by cocaine.…”

“…In mice, the pre-treatment with an intermediate dose of CBD (20 mg/kg) for 10 days facilitated the novel object recognition task and increased learning markers, such as BDNF expression and neural progenitor proliferation in the hippocampus [54]. CBD blunted the cognitive impairment induced by THC in an adenosine A2A receptor-dependent manner [113] and abolished the memory impairment in the object recognition task induced by nicotine withdrawal (precipitated by the administration of the nicotinic antagonist mecamylamine) as well as the neuroinflammatory response and the impairment in neurogenesis associated with these cognitive deficits (as previously commented) [100].…”