International Research Journal of Engineering and Technology (IRJET) e-ISSN:2395-0056
Volume:12Issue:08|Aug2025 www.irjet.net p-ISSN:2395-0072
Nicotine Addiction Pathways: Neurotransmitter Involvement and Receptor Sensitivity
Kumbha Ravindra1 , Arumalla Mahitha1 , Tekimudi Lova kumari2
1Department of Pharmaceutical Engineering, Kakinada Institute of Technological Sciences, Ramachandrapuram 2Head of the Department, Department of Pharmaceutical Engineering, Kakinada Institute of Technological Sciences, Ramachandrapuram.
Abstract
Nicotineaddictionisaglobalhealthconcerncharacterizedbyitsinteractionwithmultipleneurotransmittersystemsand receptor subtypes in the central nervous system. This study reviews the biochemical pathways involved in nicotine dependence, with a focus on the roles of dopamine, serotonin, acetylcholine, glutamate, GABA, and their respective receptors, particularly the nicotinic acetylcholine receptors (nAChRs). The paper also explores genetic polymorphisms, desensitizationofreceptors,neuroplasticity,andbehaviouralsensitizationcontributingtoaddiction.The findingssuggest thatunderstandingthesepathwayscaninformthedevelopmentofnoveltherapeuticstrategies.
Keywords
Nicotine, Addiction, Neurotransmitters, Receptors, Dopaminergic Pathway, nAChRs, Neuroplasticity
1. Introduction
Nicotineexertsitsaddictiveeffectsprimarilythroughits interaction with nicotinic acetylcholine receptors (nAChRs), which are widely distributed across the central and peripheral nervous systems. When inhaledthroughcigarette smoke, nicotine rapidlyenters the bloodstream and crosses the blood-brain barrier withinseconds, bindingto these receptorsinareassuch asthe ventraltegmentalarea(VTA)[1].Thisinteraction leads to the release of dopamine in the nucleus accumbens, a core component of the brain's mesolimbic reward pathway. Dopamine release generates pleasurable sensations, reinforcing the behaviorandpromotingrepeateduse.Overtime,chronic exposure causes receptor desensitization and compensatory upregulation, making the brain dependentonnicotinefornormalfunctioning.[7]
In addition to dopamine, nicotine affects other neurotransmitter systems, including glutamate, GABA (gamma-aminobutyric acid), serotonin, and norepinephrine. Nicotine-induced stimulation of glutamatergic neurons enhances excitatory signals, whichfurtherpromotesdopaminerelease.Conversely,it inhibits GABAergic inhibitory neurons, reducing the brain’s natural checks on excitatory neurotransmission. This imbalance between excitation and inhibition is crucial in the development of tolerance, craving, and withdrawal symptoms. The serotonergic system’s involvementexplainswhynicotinealsoinfluences mood regulation and stress response, making it appealing
for individuals experiencing anxiety or depression. These multidimensional effects help explain the complex behavioral patterns of addiction, which combine physiological dependence with psychological reinforcement.[2]
Repeatednicotineusecauseslong-termchangesinbrain function, leading to structural adaptations such as altered synaptic plasticity and gene expression. This neuroadaptation is supported by findings from epigeneticstudies,whichdemonstratethatnicotinecan alterDNAmethylation patterns,histone acetylation,and microRNA regulation, ultimately influencing the expression of genes related to reward, stress, and learning.Suchepigeneticmodificationsmayhelpexplain why some individuals develop stronger dependencies than others, even with similar levels of nicotine exposure. Furthermore, genetic predispositions, such as variations in dopamine transporter genes or CYP2A6 (a key enzyme in nicotine metabolism), can influence boththe intensityofaddiction andthe effectivenessof cessationtherapies
Nicotine withdrawal is characterized by a range of symptoms, including irritability, anxiety, depression, impaired concentration, and intense cravings. These symptoms often appear within a few hours of the last cigaretteandpeakwithinthefirstfewdaysofcessation. The neurochemical imbalance created by sudden nicotine removal leads to dysphoria and reduced cognitive function, which drives the high relapse rate seeninsmokersattemptingtoquit.Understandingthese
International Research Journal of Engineering and Technology (IRJET) e-ISSN:2395-0056
Volume:12Issue:08|Aug2025 www.irjet.net p-ISSN:2395-0072
mechanisms has allowed the development of several pharmacological treatments, such as nicotine replacement therapy (NRT), bupropion, and varenicline. These drugs aim to reduce withdrawal symptoms by either mimicking nicotine’s effects, modulating neurotransmitter levels, or partially activating nAChRs without producing the full addictive response.
While pharmacotherapy offers clinical benefits, behavioralsupportandpublichealthpolicies remain critical in combating nicotine addiction. Psychological approaches like cognitive-behavioral therapy (CBT) help individuals reframe their relationship with smoking, identify triggers, and develop coping mechanisms. On a societal level, tobacco control policies, including taxation, graphic health warnings, advertising bans, and smoking cessation campaigns, have significantly reduced smoking rates in many countries. However, emerging nicotine delivery systems like e-cigarettesandvapingdevices posenew challenges. Though marketed as safer alternatives, they still deliver addictive doses of nicotine and have been shown to initiate dependence in non-smokers, particularlyamongadolescents.
Advancements in neuroimaging and bioinformatics have opened new avenues for understanding nicotine addictionata systemsbiologylevel.Functional MRIand PET scans have revealed how nicotine modifies brain connectivity, particularly in regions responsible for decision-making, impulse control, and emotional regulation.Meanwhile, multi-omicstechnologies such as transcriptomics, proteomics, and metabolomics provide a detailed view of how nicotine alters cellular processes and metabolic pathways. These insights are critical for identifying biomarkers for addiction and developing personalized therapies tailored to an individual's biological makeup. In the future, precision medicinemayallowclinicianstopredictwhoisathigher risk of developing addiction and what type of therapy willworkbestforthem.
Nicotine’sinfluenceextendsbeyondindividualhealthto affect public health systems and global economies The burden of tobacco-related diseases, including cardiovascular diseases, chronic obstructive pulmonary disease (COPD), and various cancers, strains the healthcare infrastructure and increases mortality rates. Additionally, secondhand smoke exposes non-smokers, especially children and pregnant women, to harmful chemicals, contributing to developmental disordersandrespiratoryissues.Despite widespread knowledge of these dangers, tobacco companies continue to market aggressively, often targeting vulnerable populations in low- and middle-
income countries. Combating nicotine addiction, therefore, requires a multifaceted approach that integrates scientific research, healthcare innovation, policyenforcement,andpubliceducation.
2. Pharmacokinetics of Nicotine
Nicotine, the primary addictive component in tobacco, has distinct pharmacokinetic properties that explain its rapid action and high potential for dependence. It is absorbed through various routes, including the lungs (from smoking), oral and nasal mucosa (from chewing tobacco or snuff), and skin (via transdermal patches). Inhalation through smoking results in rapid absorption through the pulmonary alveoli, allowing nicotine to reach the brain within 10 to 20 seconds. Approximately 90% of inhaled nicotine is absorbed, while oral routes havelowerbioavailability(around20–45%)duetofirstpass hepatic metabolism. Once absorbed, nicotine is quicklydistributedthroughoutthebody,readilycrossing the blood–brain barrier and the placenta, and is also excretedinbreastmilk.Ithasavolumeofdistributionof about 2–3 liters per kilogram, and peak plasma concentrations are reached within minutes when smoked, but more slowly when delivered via patches or gum.Metabolismoccursmainlyintheliver,whereabout 70–80% of nicotine is converted primarily by the enzyme CYP2A6 into cotinine, the main metabolite with a longer half-life of 16 to 20 hours. Other metabolites include nicotine-N-oxide and nornicotine. Nicotine and its metabolites are mostly eliminated through the kidneys, with about 10% excreted unchanged; urinary pH can influence the rate of excretion, with acidic urine increasing elimination. Nicotine itself has a half-life of around 2 hours in adults. These pharmacokinetic properties especially the rapid brain delivery and relatively short half-life contribute to its strong reinforcing effects and addictive potential. Genetic variations in CYP2A6 can affect the rate of nicotine metabolism, influencing individual smoking behaviors and dependence levels. Nicotine replacement therapies are designed to deliver nicotine more slowly and at lower peaks than smoking, helping to reduce addiction riskwhileeasingwithdrawalsymptoms.[10][9]
3. Neurotransmitter Pathways Involved
3.1DopaminergicSystem
The mesolimbic dopamine pathway, involving the ventral tegmental area (VTA) and nucleus accumbens, is a critical player in nicotine-induced reinforcement. Nicotine stimulates nicotinic acetylcholine receptors (nAChRs) in the VTA, causing dopamine release in the nucleus accumbens, producing rewardingsensations.[7]
International Research Journal of Engineering and Technology (IRJET) e-ISSN:2395-0056
Volume:12Issue:08|Aug2025 www.irjet.net p-ISSN:2395-0072
3.2Serotonin(5-HT)
Serotonin modulates mood, aggression, and anxiety factors involved in the initiation and maintenance of tobaccouse.Nicotineinfluencesserotonergicneuronsin the dorsal raphe nucleus, affecting withdrawal symptomsandrelapsepotential.
3.3Acetylcholine
Nicotinemimicstheactionofacetylcholinebybindingto nicotinic receptors. Chronic nicotine exposure leads to desensitization and upregulation of these receptors, particularly the α4β2 and α7 subtypes, which are essentialfordevelopingdependence.
3.4GlutamateandGABA
Nicotine increases glutamate release and suppresses GABAergic inhibition in the VTA, leading to enhanced dopaminergic activity. This disinhibition facilitates stronger reinforcement and learning associated with nicotinecues. [3][7]
4. Receptor Sensitivity and Genetic Involvement
4.1NicotinicAcetylcholineReceptors(nAChRs)
These ligand-gated ion channels are widely distributed throughoutthebrain.Prolongednicotineexposureleads to receptor desensitization and upregulation, altering synapticplasticity.
4.2GeneticPolymorphisms
Polymorphisms in genes like CHRNA5, CHRNA3, and CHRNB4 have been associated with higher risk for nicotine dependence and lower cessation success. Genome-wide association studies (GWAS) have confirmed these variants' involvement in nicotine metabolismandreceptorbindingaffinity.[3]
5. Neuroplasticity and Behavioral Sensitization
Chronic nicotine exposure induces long-term potentiation (LTP) in reward pathways. This synaptic strengthening enhances responsiveness to nicotinerelatedstimuli.Behavioralsensitization,whererepeated exposure increases locomotor and psychological response, is a hallmark of nicotine-induced neuroadaptation.[4]
6. Therapeutic Targets and Interventions
6.1NicotineReplacementTherapy(NRT)
Nicotine Replacement Therapy (NRT) is a treatment approach designed to help people stop smoking by delivering controlled, lower doses of nicotine without the harmful chemicals found in tobacco smoke. NRT works by partially satisfying the body’s physical dependenceonnicotine,reducingwithdrawalsymptoms and cravings, and allowing people to focus on breaking the behavioral and psychological aspects of smoking addiction. Common forms of NRT include nicotine patches (transdermal), gum, lozenges, nasal sprays, and inhalers. The transdermal patch provides a steady, slow release of nicotine over 16–24 hours, while gum, lozenges, nasal sprays, and inhalers deliver nicotine more rapidly to manage sudden cravings. Compared to cigarettes, these products result in lower peak nicotine levelsandslowerabsorption,whichsignificantlyreduces their addictive potential. NRT is generally considered safe and effective, and it approximately doubles the chances of quitting successfully when combined with behavioral support. Treatment plans often start with higher doses that gradually taper down over weeks to months, helping to wean the individual off nicotine altogether. By addressing the physical dependence separately from the habitual act of smoking, NRT is a valuable tool in comprehensive smoking cessation programs.[4][5]
6.2Varenicline
Varenicline is a partial agonist at α4β2 nAChRs. It reduces cravings by stimulating these receptors moderatelywhilesimultaneouslyblockingnicotinefrom binding.[6]
6.3Bupropion
Bupropion is an atypical antidepressant that inhibits dopamine and norepinephrine reuptake, thereby reducingwithdrawalsymptomsandtheurgetosmoke.[6]
6.4NovelTargets
Emergingtherapiesinclude:
â—Ź CB1 receptor antagonists (endocannabinoid system)
â—Ź mGluR5 antagonists (glutamatergic modulation)
â—Ź GABA-B receptor agonists Theseaimtomodulatetherewardcircuitryand reducerelapsepotential.
International Research Journal of Engineering and Technology (IRJET) e-ISSN:2395-0056
Volume:12Issue:08|Aug2025 www.irjet.net p-ISSN:2395-0072
7. Future Research Directions
1. Multi-omics Analysis: Integrating genomics, proteomics, and metabolomics to identify novel addictionbiomarkers.
2. AI and Computational Modeling: Using machinelearningtopredict individualaddiction profilesandresponsetotherapy.
3. Phytochemical Screening: In silico and in vivo screening of plant-based compounds as nontoxictherapeuticalternatives.
4. Epigenetic Studies: Understanding how nicotine modifies gene expression through methylationandhistoneacetylation.
8. Conclusion
Nicotine addiction is a neurobiological disorder influenced by multiple neurotransmitters and receptor systems, primarily the dopaminergic pathway. The desensitization and upregulation of nAChRs, coupled with genetic and environmental factors, drive the cycle of dependence. A multi-targeted therapeutic approach addressing the neurochemical and behavioral aspects of addiction is essential. Future research integrating systems biology, pharmacogenomics, and bioinformatics could pave the way for personalized anti-addiction strategies.
References
1. Liu, J., Rensch, J., Wang, J. et al. Nicotine pharmacokinetics and subjective responses after using nicotine pouches with different nicotine levels compared to combustible cigarettes and moist smokeless tobacco in adult tobacco users. Psychopharmacology 239, 2863–2873 (2022). https://doi.org/10.1007/s00213022-06172-y
2. Markou, Athina. “Neurobiology of Nicotine Dependence.” Philosophical Transactions of the Royal Society B: Biological Sciences, vol. 363, no. 1507, 18 July 2008, pp. 3159–3168, https://doi.org/10.1098/rstb.2008.0095.
3. Benowitz,N.L.(2010). Nicotineaddiction. The New England Journal of Medicine, 362(24), 2295–2303.
4. Molyneux, Andrew. “Nicotine Replacement Therapy.” BMJ,vol. 328, no. 7437,19 Feb.2004, pp. 454–456, https://doi.org/10.1136/bmj.328.7437.454
5. Silagy, C, et al. “Nicotine Replacement Therapy for Smoking Cessation.” Cochrane Database of Systematic Reviews, 21 Oct. 2002, https://doi.org/10.1002/14651858.cd000146
6. Kirenga, B J, et al. “Rapid Assessment of the Demand and Supply of Tobacco Dependence Pharmacotherapy in Uganda.” Public Health Action, vol. 6, no. 1, 17 Feb. 2016, pp. 35–37, https://doi.org/10.5588/pha.15.0070. Accessed 26July2025.
7. Dani, J. A., & De Biasi, M. (2013). Mesolimbic dopamine and nicotinic acetylcholine receptors:emergingroleinaddiction. Trends inPharmacologicalSciences,34(9),506–513.
8. Govind, A. P., Vezina, P., & Green, W. N. (2009). Nicotine-induced upregulation of nicotinic receptors: underlying mechanisms and relevance to nicotine addiction. Biochemical Pharmacology,78(7),756–765.
9. Liu,J.Z.,Tozzi,F.,Waterworth,D.M.,Pillai,S.G., Muglia,P.,Middleton,L.,...&Lathrop,M.(2010). Meta-analysis and imputation refines the association of 15q25 with smoking quantity. NatureGenetics,42(5),436–440.
10. Picciotto,M.R.,&Kenny,P.J.(2013). Molecular mechanismsunderlyingbehaviorsrelatedto nicotine addiction. Cold Spring Harbor PerspectivesinMedicine,3(1),a012112.