The aim of this study was to determine the effectiveness of nicotine in increasing working memory and positive emotion in patients with MCI. The results of present study showed that there was a statistically significant difference between the scores of working memory and positive emotion between the experimental and control groups after intervention. This means that nicotine increases working memory and positive emotion in patients with MCI. This finding is consistent by the results of researches done by Sutherland et al., Kutlu et al., Jensen et al., Bombardi et al., Grus et al., and Grundey et al. [20–25]. In this regard, the result of Hahn et al. have shown that nicotine has cognitive enhancers including improved fine motor functions, attention, working memory, and episodic memory [26]. Also, the results of Myers et al. showed that people who used nicotine nasal spray, had better cognitive performance and more computational power comparing to the control group [27]. Newhouse et al. concluded in their study that chronic nicotine therapy for cognitive function and memory in the elderly are beneficial, and nicotine therapy improves attention in the elderly who suffer mild cognitive function [28]. Finally, Nop et al. examined the benefits of nicotine use and its important role in maintaining cognitive cues as a way to improve nerve damage in old age [29] that is consistent with our results.
In order to explain the findings, it can be said that acetylcholine which is hydrolyzed by the enzyme cholinesterase enters the synaptic cleft in a few milliseconds after its release. Nicotine then crosses the synapse in cleft and binds to nicotine Acetylcholine receptors and activates it, which is longer than the nicotine receptor by the agonist. This active prolonged exposure of the receptor to nicotine intake causes receptors to become insensitive and consequently its temporary ability is reduced by Nicotine agonist activity [30]. Most nicotinic acetylcholine receptors in the brain direct several neurotransmitters including Serotonin, Glutamate, Gamma-Aminobutyric acid (GABA) and Norepinephrine [31, 32].
Primary targets of nicotine effect on nicotinic Acetylcholine receptors (nAChRs) are including Ligand ion channels consisting of different pentameric compounds of 9 subunits a (a2a10) and 3 subunits β (β2β4) which are around central different pores and are permeable to sodium, potassium, and calcium ions. Most nAChR nerves act fast in CNS stimulants and balance the release of other neurotransmitters including Acetylcholine, Dopamine, Serotonin, Glutamate, GABA and Norepinephrine [33, 34]. Although the effects of nicotine on desensitization and positive regulation of nAChRs is clear, the role of these processes in the cognitive effects of nicotine is complex and incomplete [35]. Evidence suggests that both areas of the anterior cortex of the brain and brain hippocampus are involved in the cognitive effects of nicotine, and cognitive enhancement may be due to improved signal noise or facilitation of synaptic ductility in specific neural circuits [21]. At the clinical level, evidence shows that α7 nAChRs play a role in cognitive deficits in many neuropsychiatric disorders including Alzheimer's disease, Parkinson's disease, autism spectrum disorders and schizophrenia [36].
Heishman et al. in their study to investigate the direct cognitive effects of nicotine, found that nicotine had significant positive effects on fine motor skills, short-term episodic memory, and working memory performance [37] that is consistent with the our results. In addition, the results of the study by Posner et al. showed that nicotine consumption has a positive effect on maintaining alertness and paying attention to sensory events. However, the effect of nicotine on cognitive function is not dose-dependent throughout, indicating the heterogeneous pharmacodynamics nature of nicotine [38].
In addition to these findings in long-term smokers, studies also show differences in the effect of nicotine on cognitive function among smokers and non-smokers. While nicotine consumption improves working memory performance in non-smoker individuals, but no improvement was observed in smokers' working memory function [25]. On the other hand, the results of Valentine et al. showed that the cognitive enhancing effects of nicotine may contribute to mood enhancing or mood stabilizing effects [12]. Altogether, the results of studies show that nicotine has different effects on human cognition based on smoking history and status. Nicotine withdrawal depends on the time of the test, and that the cognitive increase due to smoking may be altered by the change in bias Smokers' attention and have fewer effects on mood [39].
In Stein et al. study, the nicotine used intravenously in non-deprived smokers. Nicotine Increased signals that depends on the level of oxygenation in the blood in a number of subcortical and cortical regions related to reward and cognitive function [40]. In another study that used nicotine gum, a marked increase in the signal in the frontal and parietal areas of the brain was reported [41]. The results of Falcon et al. showed that people with psychological disorders such as depression and schizophrenia often try smoking to improve concentration and short-term memory [42], which is consistent with the results of the present study.
Also, the results of studies on the effect of nicotine on cognitive function show that nicotine definitely improves motor skills, attention and accuracy and short-term memory response time and long-term memory [1, 12, 43]. For example the use of nicotine patch and nicotine administered intravenously have had positive results in Alzheimer's patients, including improved memory, increased attention, accuracy and memory time [1]. The results of McClernon et al. showed that low-dose nicotine temporarily reduces depression when used in non-smokers [44]. Also the results of Trojak et al. showed that nicotine gum therapy reduced negative mood associated with withdrawal more compared with placebo [45] that is consistent with the results of our study. In this regard, the results of other studies also show that the negative mood caused by withdrawal symptoms in smokers are eliminated by using nicotine substitutes in the form of drugs or chewing gum or nasal spray, as a result the positive mood increases [27, 31, 46] which is consistent with the our results.
Lack of control of intervening variables such as environmental conditions, emotional state and personal issues of the subjects, small numbers of samples were some of the limitations of this study that could affect the generalization of the findings to other populations.