Nicotine addiction is a severe public health problem. The aim of this study was to investigate the alterations in key neurotransmissions after 60 days of withdrawal from seven weeks of intermittent cigarette smoke, e-cigarette vapours, or an e-cigarette vehicle. In the nicotine withdrawal groups, increased depressive and anxiety/obsessive-compulsive-like behaviours were demonstrated in the tail suspension, sucrose preference and marble burying tests. Cognitive impairments were detected in the spatial object recognition test. A significant increase in Corticotropin-releasing factor (Crf) and Crf1 mRNA levels was observed, specifically after cigarette withdrawal in the caudate-putamen nucleus (CPu). The nociceptin precursor levels were reduced by cigarette (80%) and e-cigarette (50%) withdrawal in the CPu. The delta opioid receptor showed a significant reduction in the hippocampus driven by the exposure to an e-cigarette solubilisation vehicle, while the mRNA levels doubled in the CPu of mice that had been exposed to e-cigarettes. Withdrawal after exposure to e-cigarette vapour induced a 35% Bdnf mRNA decrease in the hippocampus, whereas Bdnf was augmented by 118% by cigarette withdrawal in the CPu. This study shows that long-term withdrawal-induced affective and cognitive symptoms associated to lasting molecular alterations in peptidergic signalling may determine the impaired neuroplasticity in the hippocampal and striatal circuitry.
Keywords: Bdnf; Crf; Crf receptors; addiction models; e-cigarette; nicotine addiction; nociceptin; opioid peptides; opioid receptors; orexin receptors.