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\def\RunningAuthor{Hamdan S. Al-Malky}
\firstPage{847}
\articleType{Original Article}
\receivedDate{05.08.2019}
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\title{Neuropharmacology of nicotine dependence}
\author{Hamdan~S.~Al-malky\textsuperscript{*}~\\[5pt]{Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia}}

\begin{abstract}
The occurrence of withdrawal symptoms is regarded as the key to mediating smoking relapse amongst smokers. The present study acknowledged the high relapse rates emerging from the inability to address the causes of powerful addiction effects besides identifying chronic disorders caused by nicotine. The present study explored nicotine addiction and its effects on different smoking patterns to provide an informative platform to design interventions that would deliver effective ways of quitting smoking. The study utilized systemic reviews on publications of previous studies obtained from scholarly journal databases, including PubMed, Medline, EBSCO Host, Google Scholar, and Cochrane. Moreover, the study used secondary information obtained from health organizations using filters and keywords to retrieve relevant information. The use of search keywords and filters limited the study to relevant peer-reviewed journals. The study utilized information retrieved from 35 studies obtained from peer-reviewed journals on ``nicotine dependence,'' ``smoking cessation,'' and ``pharmacology of nicotine dependence and addiction.'' The drug tolerance arising in nicotine dependence involved minimized tolerance often occurring during recurrent administration of drugs translated to neuroadaptation. The brain tends to develop challenges in the absence of nicotine, particularly when individuals quit smoking, thus compelling them to backslide from their abstinence. Higher nicotine dependence demotivates individuals from quitting smoking, making the cessation interventions unfruitful, worsened by the inability to understand the causative factors. The solution to overcome nicotine dependence alongside tobacco usage involves a complex treatment technique that would aim to reduce the probability of relapse. Nicotine dependence, Nicotine addiction, Tobacco addiction cycle, Neural survival, Pharmacology of nicotine
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Nicotine dependence,\newline Nicotine addiction,\newline Tobacco addiction cycle,\newline Neural survival,\newline Pharmacology of nicotine
\end{keywords}
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\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Hamdan~S.~Al-malky~\\ Phone:\ +966 12 640 0000~\\  Email:\ hamdan27@hotmail.com
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\section{Introduction}
Nicotine is a naturally occurring drug found in tobacco making that acts as the leading dynamic element causing addiction. Similar to the use of cocaine and heroin, nicotine causes detrimental effects on human health that are worsened by its very addictive nature\unskip~\citep{640252:15023371}. The three primary findings in the 1998 Surgeon General of the United States report on tobacco and nicotine have been endorsed by several authorities, including the Royal College of Physicians, American Psychiatric Association (APA), and the World Health Organization (WHO). First, cigarettes and tobacco elements have high addictive effects\unskip~\citep{640252:15023424}. Second, the report identified that nicotine contained in tobacco exerted high addictive effects on human beings\unskip~\citep{640252:15023414}. Besides, the identification of tobacco addiction applies similar physiological and behavioral procedures to ascertain whether individuals are addicted to cocaine and heroin\unskip~\citep{640252:15023410}. 

Addiction to tobacco arises from repeated use of nicotine that translates into destructive health effects amongst addicts\unskip~\citep{640252:15023414,640252:15023416}. These effects, in turn, result in medical complications, such as cancer, lung diseases, heart complications, and increased vulnerability to secondary ailments\unskip~\citep{640252:15023414}. Most body organs of smokers are exposed to the highly damaging nature of nicotine. Addicts can quit smoking irrespective of their age, thereby decreasing the levels of dangers of nicotine. This awareness explains why a sizable number of smokers in the United States have developed a high interest in quitting smoking\unskip~\citep{640252:15023416}. By contrast, an estimated 80\% of individuals refraining from smoking are likely to backslide during their first month of moderation\unskip~\citep{640252:15023371}. Only a mere 3\% attain a 6-month abstinence period. Such occurrences demonstrate tobacco having powerful addiction effects besides the identified chronic disorders caused by nicotine\unskip~\citep{640252:15023411}. This creates the need to explore the nicotine addiction process and its effects varying with the smoking patterns, thereby providing an informative platform to devise the optimal smoking cessation intervention\unskip~\citep{640252:15023372,640252:15023387}.

\textbf{Nicotine-related statistics }

Tobacco usage and developing addiction are among the global leading health dangers identified to cause preventable premature deaths in developed and developing countries\unskip~\citep{640252:15023396}. Over 4,000 chemicals are estimated to be contained in tobacco smoke, with a sizable portion of them having detrimental properties, including carcinogenic effects and the ability to enhance addictive nicotine effects\unskip~\citep{640252:15023387}. 

Tobacco usage causes an approximated 5 million fatality every year, a number projected to hit double digits by 2025 with the sustenance of present smoking trends\unskip~\citep{640252:15023414}. Although the majority of individuals express the desire to quit smoking, only a few succeed. Factually, individuals backsliding to their past smoking habits is increasing each year to the current high of 80\% from their abstinence time, irrespective of acquitting medications and non-pharmacological therapies\unskip~\citep{640252:15023371,640252:15023396}.
    
\section{Materials and Methods}
The present study utilized systematic reviews of relevant studies published in peer-reviewed journals and medical reports. Relevant articles were obtained from scholarly databases using search words and search filters. Articles with relevant information were obtained from Medline, PubMed, Cochrane, and Ebsco Host databases. Further information was obtained from reports released by the Royal College of Physicians, APA, and WHO. The review embraced an exploratory approach using search keywords such as "nicotine dependence," "nicotine addiction," "pharmacology of nicotine," "mechanism of nicotine addiction," "tobacco addiction cycle," "nicotine-mediated desensitization," and "nicotine neuroadaptation." Further examination of the bibliography list was performed to identify sources with relevant information. Online articles featuring prospective and retrospective studies on nicotine dependence and addiction were selected. However, periodical articles were eliminated from the list for featuring subjective information. The study design was disregarded during the review of the extracted data with key attention on thematic analysis to explore the mechanism of nicotine dependence and tobacco addiction cycle relative to various smoking patters.

\textbf{Included/excluded articles}

Perspective articles were explored via the employment of scholar databases, through the utilization of keywords and search filters related to the topic of interest. Initial research yielded more than 500 retrospective and prospective studies related to the impact of nicotine use in humans and its neuropharmacology. To ensure the validity of the sources used in this study, articles resulting from the initial research were further filtered to maintain only those having undergone peer-reviewing; from these articles, the most appropriate ones for the study were selected. Finally, any letters and commentaries associated with this topic were excluded.

As a result of the initial scholar database research, 40 journals were selected; 5 related to the health impact of nicotine use and 35 on the neuropharmacology of nicotine. The most pertinent 35 neuropharmacology articles were further searched to identify any other potential articles of interest (Figure~\ref{f-cbb9f4b33c7e}).


\bgroup
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\caption{\boldmath {Flowchart of inclusion/exclusion of studies}}
\label{f-cbb9f4b33c7e}
\end{figure}
\egroup

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\caption{\boldmath {The action mechanism of nicotine within the central nervous system: Nicotine binds to the nicotinic acetylcholine receptors present in the mesolimbic{\textendash}dopamine system of the brain. The presence of nicotine forces the nicotinic receptors located within the tegmental area to release dopamine instantly}}
\label{f-f659fc1710bf}
\end{figure}
\egroup

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\caption{\boldmath {Molecular and behavioral aspects of nicotine addiction}}
\label{f-ab0126fd6ff6}
\end{figure}
\egroup

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\caption{\boldmath {The tobacco addiction cycle}}
\label{f-df759e704b68}
\end{figure}
\egroup

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\caption{\boldmath {De-nicotinized cigarettes with simple traces of 0.05 mg nicotine levels. De-nicotinized cigarettes entail simply trace nicotine levels (0.05 mg) with low nicotine cigarettes marked by 0.6 mg nicotine. These are obtained by smoking them through 2-FA PET scanning to identify if other smoking elements beyond nicotine deliver \ensuremath{\alpha }4\ensuremath{\beta }2 nAChRs occupancy. This trial revealed \ensuremath{\alpha }4\ensuremath{\beta }2 nAChRs occupancies of79\% for low-nicotine cigarettes and 26\% for de-nicotinized cigarettes. The assessment of both de-nicotinized and low-nicotine cigarettes shows smoking to cause \ensuremath{\alpha }4\ensuremath{\beta }2 nAChRs occupancy exclusively}}
\label{f-f00334ebb1f6}
\end{figure}
\egroup

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\makeatother 
\caption{\boldmath {Evidence of changeable smoking levels in PET images obtained from standard cigarettes. The images showed \ensuremath{\alpha }4\ensuremath{\beta }2 nAChRs occupancy of 0 for no puffs, 33\% for 1 puff, 75\%for 3 puffs, 88\% in full cigarette and 95\% in satiety}}
\label{f-8c9cd1a7d4a7}
\end{figure}
\egroup

    
\section{Results and Discussion}
\textbf{Overview of nicotine }

\textbf{Pharmacology of nicotine}

\textbf{Nicotine\textit{\space }} \textbf{properties\textit{}}

Nicotine is a major alkaloid that consists of two tertiary amines, namely ringed pyrrolidine and pyridine. This structural arrangement enables it to bind easily with the acetylcholine receptors [AChRs] located within the neuromuscular joints, ganglia joints, and the brain\unskip~\citep{640252:15023374}. The arousal decrement experienced by nicotine users qualifies it as a stimulant\unskip~\citep{640252:15023405}. The use of nicotine has yielded paradoxical outcomes, i.e., it can act both as a depressant and stimulant. Its stimulation effect is perceived to enhance  learning abilities, processing of observed and received information, and boost memory and alertness of users. On the contrary, the use of nicotine has been reported to be associated with increased anxiety and depression levels; moreover, individuals abusing nicotine have reported more pain\unskip~\citep{640252:15023389}. Inhaled nicotine merely takes 7 seconds to reach the brain, making it the quickest and the most preferred way of abuse by most users\unskip~\citep{640252:15023401,640252:15023370}.

\textbf{Nicotine } \textbf{pharmacokinetics\textit{\space }}

The uptake of nicotine into the body via inhalation through the lungs occurs in a manner identical to that of intravenous administration\unskip~\citep{640252:15023407}, increasing the dependency of users on it\unskip~\citep{640252:15023397}. The non-ionized nicotine passes through the membranes across the buccal mucosa before reaching the blood-brain barrier. The absorption occurring through the feeble base enables nicotine to convert into a less ionized form, thereby facilitating easier passage across membranes even in alkaline solutions. The transport of absorbed nicotine to other organs and tissues involves several metabolic processes, which take 10 to 20 minutes to transport nicotine to the brain tissues. The extensive volume of distributed nicotine increases its solubility and uptake in the individual, thereby reaching other body tissues\unskip~\citep{640252:15023397}. The presence of nicotine indicates apparent inter-individual changeability effects relative to the metabolic clearance from hepatic blood flow\unskip~\citep{640252:15023397}. While the liver facilitates the metabolization of nicotine, the kidneys function to excrete it from the body. 

\textbf{Nicotine receptor and neurotransmitter release}

\textbf{General mechanism of nicotine}


  
  \begin{enumerate}
  \item \relax The uptake of nicotine into the body tissues involves the distillation of smoke contents from the inhaled cigarette smoke before it is transmitted to the lungs for subsequent absorption across the membranes of pulmonary venous circulation.  
  \item \relax The nicotine subsequently enters the arterial circulation system, thereby swiftly getting transported into the brain tissues \unskip~\citep{640252:15023399}. 
  \item \relax Free distribution of absorbed nicotine is reported to occur within the brain tissues via its attachment to nicotinic acetylcholine receptors [nAChRs], regarded as ligand-gated ion channels. 
  \item \relax The presence of cholinergic agonists on the external sections of the channels facilitates the entry of cations that take calcium and sodium forms. The cations facilitate the activation of voltage-dependent calcium pathways, thereby aiding calcium entry into the tissues.
  \end{enumerate}
  \textbf{Nicotinic receptors}

Nicotine accomplishes pharmacological outcomes by activating nAChRs through the central nervous system (CNS). Receptors are considered ligand-gated ion channels owing to the following facts,


  
  \begin{enumerate}
  \item \relax The intricate nicotinic acetylcholine receptors have five subunits present on the peripheral and central regions of the nervous system. 
  \item \relax The existence of threefold \ensuremath{\beta } subunits [\ensuremath{\beta }2 to \ensuremath{\beta }4] and nine \ensuremath{\alpha } subunits within the range of \ensuremath{\alpha }2 to \ensuremath{\alpha }10\unskip~\citep{640252:15023404}. 
  \item \relax Human beings are identified to have \ensuremath{\alpha }4\ensuremath{\beta }2, \ensuremath{\alpha }3\ensuremath{\beta }4, and \ensuremath{\alpha }7-homomeric for their copious abilities. The \ensuremath{\alpha }4\ensuremath{\beta }2 is the dominant subtype, thus acting as the primary mediator of nicotine dependence in the human brain. 
  \item \relax The binding of nicotine to receptors occurs through mesolimbic dopaminergic and nigrostriatal neurons. These neurons possess the ability to stimulate nicotine receptors to facilitate the release of ACTH, nor-epinephrine, serotonin, acetylcholine, dopamine, growth hormone, and vasopressin. Furthermore, nicotine possesses equally delineated abilities that facilitate the dopamine reward pathway in the brain, as shown inFigure~\ref{f-f659fc1710bf},\unskip~\citep{640252:15023413}. 
  \item \relax The \ensuremath{\beta }2 subunit gene appears to eliminate behavioral effects exerted by nicotine in mice, as hindering the release of dopamine in the brain tissues would sustain self-discharge. Consequently, the \ensuremath{\alpha }4 subunit is regarded to play an active role in determining nicotine sensitivity levels\unskip~\citep{640252:15023365,640252:15023427}.
  \end{enumerate}
  \textbf{The nAChRs and other neurotransmitters}


  
  \begin{enumerate}
  \item \relax The involvement of the modulation section by nAChRs is noted to enhance the performance of neurotransmitters within the presynaptic terminals, dendrites, and neural cells.  
  \item \relax Nicotine-activated nAChRs facilitate the production of neurotransmitters, including noradrenaline, glutamate, acetylcholine, dopamine, and GABA, amongst others\unskip~\citep{640252:15023406,640252:15023417,640252:15023402,640252:15023422}. 
  \item \relax Further release of neurotransmitters, including acetylcholine, GABA, serotonin, norepinephrine, endorphins, and glutamate, helps to regulate different behaviors exhibited by nicotine.
  \item \relax The presynaptic nAChRs are involved in modulating nicotine-mediated discharge simultaneously with the neurotransmitter discharges.
  \end{enumerate}
  \textbf{Neuropharmacology of nicotine dependence}

\textbf{Nicotine-mediated desensitization of receptors}


  
  \begin{enumerate}
  \item \relax Neuroadaptation has been reported to occur, leading to increased tolerance with the exposure of receptors to nicotine, though this phenomenon is not observed in all nicotine effects\unskip~\citep{640252:15023418}. 
  \item \relax The affiliation with the neuroadaptation sites facilitating connections in the brain tissues to experience increased number. The emergence of such an increase supports the up-regulation occurring within the nicotine-mediated desensitization in the receptors. This is essential in strengthening the reliance and tolerance levels of nicotine in the brain tissues\unskip~\citep{640252:15023375}. 
  \item \relax Typically, it is feasible to pair both reasoning to allow smokers to retain their daytime smoking to achieve stabilized nicotine levels in the plasma, thereby preventing withdrawal symptoms. Similarly, fruitful outcomes could be obtained by overcoming habituated reinforcers identified with smoking, including feeling and tasting smoke\unskip~\citep{640252:15023378}. 
  \end{enumerate}
  \textbf{Nicotine addiction and dependence }

The APA and the WHO have, in the past, reported nicotine addiction and dependence phrases. The drug tolerance arising in nicotine dependence involves minimized tolerance often occurring during recurrent administration of drugs. This leaves the individual requiring more nicotine to derive effects experienced when they used lesser doses\unskip~\citep{640252:15023409}. This leads to neuroadaptation as the brain becomes used to the existence of nicotine, thus treating the administration of nicotine as necessary to sustain its normal functions. The brain tends to develop challenges in the absence of nicotine, particularly when an individual quits smoking, thus compelling him/her to backslide from their abstinence\unskip~\citep{640252:15023403}. Higher nicotine dependence demotivates the individuals from quitting smoking, making the interventions unfruitful, which are worsened by early morning smoking with initial cigarettes and leading to a subsequent increase in the daytime smoking Figure~\ref{f-ab0126fd6ff6}.

\textbf{The tobacco addiction cycle}

Smoking the first cigarette causes substantial pharmacologic impact, which is experienced as arousal effects responsible for subsequent tolerance to nicotine. The individual smokes the second piece upon realization of a declining tolerance rate in the brain tissues \unskip~\citep{640252:15023384}. The recurrence of this feeling orients the smoker to increasing nicotine levels in their bodies as they develop increased tolerance intensities. Such occurrences reveal themselves as withdrawal symptoms visible during subsequent smoking Figure~\ref{f-df759e704b68},\unskip~\citep{640252:15023388}. 

The shade displayed in Figure~\ref{f-df759e704b68} shows the effective region of neutrality involving nicotine threshold level, necessary to derive arousal and pleasure against threshold levels where withdrawal symptoms would arise. The smoker may experience transitory effects as nicotine levels increase in the brain over tolerance levels; however, basic euphoric influences decrease throughout the day\unskip~\citep{640252:15023373}. Benowitz found evidence of self-denial responsible for resensitization toward nicotine effects\unskip~\citep{640252:15023369}.

\textbf{Brain imaging of nicotinic acetylcholine receptors}

Conducting an in-depth study of the effects of tobacco smoking and nicotine on the brain is essential for eliminating backsliding and enhancing smoking alleviation treatments. A number of scanning techniques have been applied to examine the occurrence of chronic and acute effects caused by smoking cigarettes. The following tools are among the widely used.


  
  \begin{enumerate}
  \item \relax Positron emission tomography (PET)
  \item \relax Single-photon emission computed tomography (SPECT)
  \item \relax Functional magnetic resonance imaging 
  \end{enumerate}
  Application of the above imaging techniques tests the radiotracers affinities and specificity connections involving \ensuremath{\alpha }4\ensuremath{\beta }2\ensuremath{^{*}} to nAChRs. The 5-IA SPECT and 2-FA PET experiments in assessing acute effects associated with nicotine intake have found functional connectivity on \ensuremath{\alpha }4\ensuremath{\beta }2\ensuremath{^{*}} nAChR occupancy from cigarette smoking\unskip~\citep{640252:15023394,640252:15023393}.

\textbf{Up-regulation of nicotine receptors }

Literature reports the chronic effects of nicotine intake from continued smoking as up-regulation of nAChRs in the human brain as typical \ensuremath{\alpha }4\ensuremath{\beta }2\ensuremath{^{*}} nAChR. Studies examining the postmortem of human beings report chronic smokers to have higher \ensuremath{\alpha }4\ensuremath{\beta }2\ensuremath{^{*}} nAChRs when compared to non-smokers who successfully quit smoking, and had nAChR intensities similar to that of non-smokers. The literature on SPECT and PET assessments revealed up-regulation amongst smokers with higher \ensuremath{\alpha }4\ensuremath{\beta }2\ensuremath{^{*}}nAChRs, unlike the levels in non-smokers\unskip~\citep{640252:15023420}. 

\textbf{Occupancy of nicotine receptors}

The ability of receptors to assume varying stoichiometries and existence of potential connection areas in ligands during high and low sensitivities leaves \ensuremath{\alpha }4\ensuremath{\beta }2 nAChRs pharmacology experiencing intricate conditions. The emergence of such combination increases the occupancy levels of such receptors occurring in different allosteric conformations while revealing subsequent sensitivity from ligand binding. This demonstrates the nicotine effect amongst smokers alongside addiction phases, as demonstrated in Figure~\ref{f-f00334ebb1f6} and Figure~\ref{f-8c9cd1a7d4a7}\unskip~\citep{640252:15023374,640252:15023376}. 

\textbf{Pharmacological intervention of nicotine dependence}

The knowledge derived from pharmacotherapy helps in addressing nicotine dependence. Besides, pharmacotherapy is useful in enabling smokers to avoid smoking, although it has no effect on special addictive situations\unskip~\citep{640252:15023392}. Nicotine replacement therapy (NRT) is among the highly engaged pharmacotherapy solution used in overcoming nicotine reliance. However, pharmacologic therapies in use today to reduce nicotine addiction have yielded not much success. The failures emerging in pharmacotherapy arise from frequent quitting attempts, where individuals fail to stop smoking, and hence, fail to engage the majority of requisite termination aids. 

\textbf{Nicotine replacement therapy}

The need to reduce the harm surfacing as withdrawal symptoms from nicotine usage reflects the reason behind the use of NRT to treat nicotine dependence. This involves taking advantage of enhancing and optimizing the quitting process, specifically by replacing nicotine previously obtained from tobacco and, hence, delivering nicotine-mediated neuropharmacological effects\unskip~\citep{640252:15023376}. The NRT process reduces withdrawal symptoms while reducing the reinforcing effects obtained from tobacco-delivery nicotine. In this regard, nicotine medications seek similar outcomes for patients dependent on cigarettes to deliver a pleasing mood and continued alert state, a highly demanding and tedious exercise\unskip~\citep{640252:15023394,640252:15023392}.

\textbf{Nicotine in drug therapy}

Dysfunctions arising in neuronal nicotinic receptors have been reported to cause diverse neurodegenerative ailments, such as Parkinson's disease (PD), schizophrenia, autism, and Alzheimer's disease (AD)\unskip~\citep{640252:15023380}. 

\textbf{Alzheimer's disease}

The initial stages of AD are characterized by cholinergic deficits manifested as cognitive symptoms, confusion, lost memory, impaired reasoning, and thinking\unskip~\citep{640252:15023377}. Its occurrence results in severe primary cholinergic losses in the brain regions responsible for attention, and episodic and spatial memory during initial AD phases. Consequently, the ability of nicotine and nicotine analogs in delivering augmented cholinergic performances using nicotinic receptors support the therapeutic approaches in addressing AD\unskip~\citep{640252:15023377}. Thus, it is applicable during the initial stages of the ailment and seen as a general therapeutic approach in treating AD\unskip~\citep{640252:15023408}. 

A number of \textit{in vitro} and \textit{in vivo} studies illustrate nicotine possessing the potential to facilitate survival through reactionary processes when exposed to several neurotoxic insults. Recent literature shows enhanced learning and memory induced by nicotine transmitted through the neuropeptide receptors found in the AD rat model. The study of human beings has shown the effect of administering nicotine through intravenous and subcutaneous means on individuals identified with AD\unskip~\citep{640252:15023377}. There emerges a similar possibility of nicotine exhibiting preventive actions against AD that hinders clinical dementia from setting in through minimizing frequent neuronal losses or enhancing its corresponding functional outcomes\unskip~\citep{640252:15023428}. Examination of aged individuals has shown abilities to reduce brain A\ensuremath{\beta } from chronic nicotine levels from dependent usage of tobacco, although the action mechanisms involved have remained unclear. The aforementioned findings reveal that the occurrence of nicotinic cholinergic stimulations necessitates performing additional examinations as potential solutions for AD\unskip~\citep{640252:15023381}. Considering that nicotine is identified to cause negative impacts, such as enhancing cardiovascular risks, disrupted behavior, and sleep disorders, it is prudent to conduct further examination of safety and competence levels amongst patients suffering from AD. 

\textbf{Parkinson's disease }

There is a likelihood of cholinergic dysfunction, translating to neurotransmitter imbalances identified as PD. A review of existing literature affirms that dopaminergic and cholinergic systems execute their functions simultaneously, leaving the cognitive functions and control of motor alignment from likely impairment in PD cases\unskip~\citep{640252:15023391}. The beginning of particular subunits of nicotinic receptors can induce anti-inflammatory pathways while facilitating the survival of neurons\unskip~\citep{640252:15023367}. Such receptors have the potential to highly overcome neuroinflammation while facilitating neural survival in the brain regions impaired by PD. The capability of the subtypes of nicotinic receptors is a reason for being considered as therapeutic objectives against PD. A number of epidemiological assessments performed on tobacco users demonstrated reduced prevalence and severity of PD, with a 40\% reduced rate of suffering from PD when compared to non-smokers\unskip~\citep{640252:15023390}. Further examinations have shown smoking to overcome motor complications striking PD patients. This finding emerges from nicotine intake rather than cigarette smoking\unskip~\citep{640252:15023366}. While several studies have demonstrated nicotine to cause asymptomatic effects in PD, these are found to have negligible effects with signs of variations\unskip~\citep{640252:15023366,640252:15023379}.

The use of modern data obtained from examining non-human primates indicates dyskinesias occurring through levodopa-induced attenuation caused by nicotine, though regarded as emerging from negative side effects associated with patients undergoing levodopa therapy\unskip~\citep{640252:15023398}. Simultaneously, the assessments and perceptions above show the tendency of either CNS-selective nicotinic receptor ligands or nicotine having the capability to improve disease progression and facilitate symptoms while suppressing levodopa-induced dyskinesias, thus enhancing PD therapy\unskip~\citep{640252:15023412}. 

\textbf{Autism}

Irregularities occurring in the cholinergic system are considered to cause autism. This is affirmed by an in-depth examination of the brain performed during the post-mortem of adults who suffered autism. It showed declined delineation within the cerebral cortex, affecting several subunits of nicotinic receptors, responsible for their reduced expressions as noted in the neurochemical pathology of autism cases\unskip~\citep{640252:15023383,640252:15023415}. The loss of cholinergic activity, associated with the autistic brain, leads to likely restoration and improved cholinergic transmission induced by nicotinic receptor ligands to counter the imbalance arising from the loss with highly declined cognitive variations noted in autism\unskip~\citep{640252:15023400}. 

\textbf{Schizophrenia}

The occurrence of dysfunction cases occurring in the hippocampal cholinergic system is heritably linked with schizophrenia. More smokers are reported to dominate the list of schizophrenia patients compared with the normal population. This occurrence is considered to deliver self-medication, resulting from normalization and alleviation of sensory and cognitive deficits from nicotine intake. The emergence of undesired smoking health effects creates a need for a secondary response for nicotine receptors. Previous research conducted to examine schizophrenia patients identified nicotine by causing alleviated negative symptoms and cognitive deficits alongside neuroleptic side effects\unskip~\citep{640252:15023368}. Smoking causes momentarily reduction of negative schizophrenia symptoms by facilitating processes of dopaminergic and glutamatergic transmission\unskip~\citep{640252:15023423}. Uptake of nicotine enhances several cognitive scarcities in schizophrenia patients including shortages occurring in sensory gating alongside irregularities in the smooth eye motion controlled by nicotine administration\unskip~\citep{640252:15023395,640252:15023385}. Conversely, smoking is associated with enhancing the non-inhibition observed in schizophrenic patients\unskip~\citep{640252:15023419}. 

\textbf{Recommendations for future research}
  
  \begin{enumerate}
  \item \relax A number of constraints exist that hinder the specificity of nAChR antagonists and agonists, leading to the generation of mice expressing genetic nAChR subtypes adjustments to mark a supportive practical approach in assessing their appropriate participation to alter the pharmacologic effects from nicotine intake.
  \item \relax The current administration of vaccines in nicotine immunotherapy trails leads to probable errors in addressing nicotine reliance\unskip~\citep{640252:15023421}. 
  \item \relax Administration of nicotine immunotherapies induces the generation of antibodies in the immune system, thereby reducing the speed and degree of nicotine entry into the brain and modifying nicotine pharmacokinetics while decreasing the reinforced effect of nicotine\unskip~\citep{640252:15023386}.
  \item \relax Further assessment of smoking cessation should be conducted to study the impact of using derived treatments on the genotype and prototype relative to effectually addressing nicotine dependence\unskip~\citep{640252:15023382}. 
  \item \relax There is a need to avail relevant biomarkers and addiction signals to have less toxic and less addictive elements in tobacco products as a solution to overcome the likely expense of complicated, addictive techniques\unskip~\citep{640252:15023382,640252:15023426}.
  \item \relax It is indefinite to use phrases, indicating the emergence of relative comparison when examining the abuse potential across products or assessing threshold to gauge abuse capacity levels. 
  \item \relax It is important to accomplish expanded acceptance on the use of varying design features in tobacco products rather than focusing only on nicotine components inducing addiction to adequately address withdrawal, commencement, and relapse after quitting smoking\unskip~\citep{640252:15023425}. This mandates the use of current neuro systems statistics identified with conditioning effects and enhancing and ceasing nicotine dependence to generate a feasible approach to anticipate discoveries in the smoking field. 
  \end{enumerate}
  
    
\section{Conclusions}
Tobacco products present efficient conveyance systems in administering nicotine into the body. Nicotine causes extreme addictive effects with a potential of severe pharmacologic effects. It orients the body to the dopamine pathway in the brain, leading to stronger recurrent tobacco use. Individuals who develop nicotine dependence embrace self-standardizing tobacco intake to ensure sustenance of satisfying impacts besides overcoming withdrawal. The occurrence of nicotine dependence is considered a chronic ailment for the brain. Tobacco usage involves intricate disorders involving interchanges between pharmacodynamics and pharmacokinetics, categorized as pharmacology. Overcoming nicotine dependence alongside tobacco use involves a complex treatment technique that would reduce the probability of backsliding. 
    

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