INTRODUCTION:

Welcome to the captivating world of acetylcholine and its intricate interaction with receptors within the human body. At the forefront of this fascinating interplay are the ligand-channelled ion conduits known as nicotinic receptor, which have undergone comprehensive structural and functional investigations, establishing them as extensively studied allosteric membrane proteins^[1].Cholinergic receptors, encompassing nicotinic and muscarinic receptors, are activated by the ligands nicotine and muscarine, respectively¹. Nicotinic receptors can be further classified into two primary subtypes: N1 and N2. The N1 receptor, also known as the muscle or peripheral receptor type, predominantly resides at the neuromuscular junction in skeletal muscle, facilitating intricate neural-muscular communication².

On the other hand, the N2 receptor, referred to as the central or neuronal receptor subtype, is found in both the PNS & CNS, including the cell bodies of postganglionic nerves in the sympathetic and parasympathetic dissections, as well as the adrenallic medulla of the sympathetic system³.

In contrast to the diverse distribution of nicotinic receptors, muscarinic receptors primarily function within the autonomic nervous system, specifically mediating parasympathetic activity. These specialized receptors perform a fundamental protagonist in conducting brain impulses within the intricate framework of the somatic and autonomic nervous systems, orchestrating synchronized responses throughout the body⁴. Understanding the intricate mechanisms and nuances underlying acetylcholine receptors and their diverse subtypes provides invaluable insights into the complex functioning of the nervous system and its profound significance in various physiological processes. By delving deeper into the scientific exploration of these receptor systems, we unveil the captivating secrets that govern neural communication, ultimately shedding light on their profound impact on human health and well-being.

Nicotine, a highly addictive substance found in tobacco products and electronic cigarettes⁵, exerts a range of profound physiological effects on the human body. It has been reported that consumption of nicotine results in increase blood flow to heart and B.P, thereby posing a significant risk for cardiovascular complications, including heart attacks and arterial wall damage⁶. It also damages the cells that are lined across coronary arteries and other blood vessels.⁷The kidney, lung, reproductive system, and heart are particularly vulnerable to the detrimental consequences of nicotine exposure. It served as a leading cause of cancers of oral and throat, vocal cords, lungs and many more.⁸ Importantly, the availability and absorption of nicotine within the body are influenced by the pH of the surrounding environment. As a dibasic molecule, uncharged lipophilic nicotine concentrations increase with rising pH, facilitating its active transmembrane transport across biological membranes ⁶. Notably, the oral cavity, lungs, skin, and gastrointestinal tract serve as potential entry points for nicotine absorption, with oral absorption being enhanced when tobacco is combined with slaked lime and catechu⁹.

The absorption of nicotine is influenced by various factors, including pH and the form of consumption. Nicotine, derived from burning tobacco and inhaled with tar droplets, crosses cellular membranes based on its pKa value of 8.0 as a weak base. In acidic conditions, such as with flue-cured tobacco (pH 5.5-6.0), limited buccal absorption occurs due to nicotine ionization¹⁰. Conversely, air-cured tobacco, found in pipes and cigars, produces more alkaline smoke, enhancing nicotine absorption through the oral mucosa¹¹. Recent hypotheses propose higher pH levels in cigarette smoke, promoting rapid lung absorption¹². In the respiratory system, nicotine rapidly enters the bloodstream via the lung's small airways and alveoli. With a large surface area and nicotine's ability to dissolve in lung fluid (pH 7.4), efficient absorption occurs, leading to peak nicotine levels shortly after smoking^13,14. The swift transfer of nicotine across membranes allows for quick reinforcement and makes smoking the most addictive route of administration¹⁵. Post absorption, nicotine moves in the circulation, with approximately 69% ionized and 31% unionized at pH 7.4. Only a small fraction, less than 5%, binds to plasma proteins. Nicotine is widely scattered in human tissues, where liver, kidney, spleen, and lung showing the maximum affinity. Nicotine amasses in gastric and salivary secretions, with higher concentration ratios compared to plasma levels. It also accumulates in breast milk and crosses the placental barrier, potentially accumulating in greater amount in foetal serum and amniotic fluid in comparison to maternal serum¹⁶.

METABOLISM OF NICOTINE: UNVEILING THE TRANSFORMATION:

Nicotine undergoes extensive metabolism in the liver, leading to the formation of various metabolites. Among these metabolites, cotinine, a lactam derivative, emerges as the primary metabolite in most mammalian species. In humans, approximately 70-80% of nicotine is transformed to cotinine through a two-step method. The initial stage involves the formation of the nicotine-1' (5')-iminium ion, primarily mediated by the enzyme CYP2A6, which exists in equipoise with 5'-hydroxynicotine. The subsequent stage is facilitated by a cytoplasmic aldehyde oxidase. The alkylating properties of the nicotine iminium ion have attracted significant attention, potentially influencing the pharmacological effects of nicotine¹⁷. Different biochemical strategies have been projected to clarify this association between smoking and body mass together with nicotine’s impact on metabolism and its character as an appetite suppressor.¹⁸

EXCRETION PATHWAYS: BID FAREWELL TO NICOTINE AND ITS METABOLITES:

It is supposed that high rate of smoking is sustained owing to nicotine dependency. Nicotine craving also serves a key contributor to tobacco consumption amongst circadian smokers.¹⁹After being broken down in the body, nicotine and its byproducts are flushed out by several excretory systems. Approximately 3-5% of it is excreted as nicotine glucuronide, and 4-7% as nicotine N'-oxide, according to studies by Benowitz et al.¹⁷ and Byrd et al.²⁰. Only a limited percentage of cotinine (10-15 percent of the nicotine and its metabolic residue in urine) is really metabolised. Despite making up just 4-7% of the nicotine consumed by smokers, nicotine N'-oxide is an important metabolite. Studies in animals have shown that the diastereomers 1'-(R)-2'-(S)-cis and 1'-(S)-2'-(S)-trans are produced during the conversion of nicotine to nicotine N'-oxide by the flavin-containing monooxygenase 3 (FMO3)^21,22. On the other hand, trans-isomer nicotine N'-oxide is produced preferentially in humans. The excretion pathways of nicotine and its metabolite is briefed out in Fig. 1. Urine examination reliably reveals merely the trans-isomer of nicotine N'-oxide regardless of the mode of delivery, whether it i.v. infusion, transdermal blotch, or smoking^23,24.

Fig. 1: The excretion pathway of eliminating nicotine and its metabolites from the body.

Nicotine is widely recognized as the primary reinforcing component of tobacco, with its euphoric effects stemming from the activation of the mesolimbic dopamine reward pathways, a crucial aspect of tobacco addiction^25-27. When administered independently, nicotine generally exhibits limited reinforcing properties. Smokers overwhelmingly prefer cigarette smoking to alternative nicotine delivery methods like patches, gum, nasal spray, or inhalers, unless actively attempting to quit²⁸. Notably, the reinforcing effects of smoking are not solely attributable to nicotine. Growing evidence from human studies suggests that non-nicotine components present in cigarette smoke, such as acetaldehyde and monoamine oxidase inhibitors, alone or in combination with nicotine, contribute to reinforcement²⁹. The promptness of the mesolimbic dopamine pathway, associated with primary reinforcement of psychomotor stimulants, seems to arbitrate the reinforcing responses of nicotine in specific cranial regions, like the posterior ventral tegmental area (VTA) or central linear nucleus^30,31. Understanding the complex interplay between nicotine, non-nicotine components, and sensory cues is crucial for developing effective strategies to combat tobacco addiction and guide targeted interventions.

INVOLVEMENT OF DIVERSE nAChR SUBMIT IN NICOTINE REWARD:

The involvement of different subunits of the nicotinic acetylcholine receptor (nAChR) system in nicotine reward has focus brightness on complex nature of nicotine addiction. Among these subunits, nAChR subunit 6 has emerged as a key player in mediating the release of dopamine in response to nicotine within the striatum, a region closely associated with reward and reinforcement³². Coexpressed with nAChR subtypes linked to behaviors related to nicotine dependence, the α6 subunit indicates its potential role in nicotine addiction³³. Its expression is primarily observed in dopamine-rich brain areas like nucleus accumbens (NAc) and the ventral tegmental area (VTA)³³. Nicotine induces an increase in dopaminergic neuron firing in the NAc and VTA, contributing to its rewarding properties³⁴. Conversely, in the course of nicotine withdrawal, a decreament in dopamine neuronal activity in the VTA and a reduction in dopamine output in the NAc visualised³⁵. The α6-containing nAChRs, particularly the 462* subtype, are responsible for nicotine-triggered dopamine flow in the striatum, and their expression is predominantly found in catecholaminergic nuclei like the VTA³⁶. Experimental studies have demonstrated the involvement of the α6 subunit in nicotine's locomotor effects and mesolimbic dopamine transmission³⁷. α6-selective nAChR antagonists, such as α-conotoxin H9A;L15A (MII[H9A;L15A]), have been used to investigate the function of α6 subunit-comprising nAChRs in nicotine's acute effects, reward-related behavior, and withdrawal-related measures³⁸. Nicotine withdrawal causes dejected mood, insomnia, tetchiness, thwarting or annoyance, anxiety, trouble with attentiveness, impatience, dwindled heart rate, faintness etc³⁹.

NEUROTRANSMITTERS IN NICOTINE REWARD: UNRAVELING THE COMPLEX INTERPLAY:

1. Nicotine's Impact on Brain Activity: Insights from Brain Imaging:

Nicotine first stimulates and then depresses Vagal and Vasomotor Ganglia. It also stimulates and then paralyses the cerebral and spinal centres.⁴⁰Research utilizing brain-imaging techniques has revealed that nicotine intensely upsurges bustle in key brain regions, including the prefrontal cortex, thalamus, and sight system. This instigation pattern aligns with an involvement of corticobasal ganglia-thalamic brain circuits, providing valuable insights into the neural effects of nicotine⁴¹.

2. The Dominance of Dopamine: Nicotine's Key Neurotransmitter:

Dopamine plays a pivotal role as the primary neurotransmitter released in response to nicotine's stimulation of central nicotinic acetylcholine receptors (nAChRs). Nicotine triggers the dopamine flow in various brain zones, like the frontal cortex, corpus striatum, and mesolimbic system. Notably, the discharge of dopamine in the NAc shell and the dopaminergic nerves of theVTA is particularly significant, as it is closely linked to the gratifying assets of drug-induced paraphernalia^42,43.

3. Beyond Dopamine: The Multifaceted Role of Other Neurotransmitters:

Dopamine, nicotine exerts its effects through the modulation of various additional neurotransmitters. Norepinephrine, acetylcholine, serotonin, γ-aminobutyric acid (GABA), glutamate, and endorphins all contribute for diverse actions of nicotine. The interplay between these neurotransmitter systems further contributes to the complexity of nicotine reward and addiction^44,45. Nicotine increases the acetylcholine and nor epinephrine to increase the sensation of arousal or wakefulness. An increases level of beta-endorphin due to nicotine even reduced anxiety.⁴⁶

CHOLINERGIC RECEPTOR DYSFUNCTION: IMPLICATIONS AND CLINICAL CONSIDERATIONS:

Dysfunction of cholinergic receptors has broad implications due to their widespread distribution. Muscarinic receptors in CNS regulate autonomic role in key organ systems, and aberrant muscarinic receptor function has been associated with disorders examples, Alzheimer's, Parkinson's, schizophrenia, and epilepsy. The dopamine reward system involves both nicotinic and muscarinic receptors⁴⁷.

COMPLEXITY OF NICOTINIC SIGNALING IN SCHIZOPHRENIA SPECTRUM DISORDERS:

Nicotinic receptors at the neuromuscular junction play a role in facilitating voluntary movement. In conditions like myasthenia gravis, autoimmune dysfunction can result in competitive receptor inhibition, leading to severe loss of neuromuscular function. Clinical interventions that induce paralysis at the neuromuscular junction must be used with caution in patients with motor neuron denervation, trauma, infection, or burn injuries, as these conditions may upregulate nicotinic receptors. Furthermore, the use of succinylcholine, a neuromuscular blocker for paralysis, carries the risk of potentially fatal electrolyte imbalances⁴⁸.

COMPLEXITY OF NICOTINIC SIGNALING IN SCHIZOPHRENIA SPECTRUM DISORDERS:

The diverse subunit combinations of acetylcholine receptors and their dispersal within the CNS influence the intricate relationship between nicotinic signaling and schizophrenia⁴⁸. While it is evident that nicotinic signaling contributes to the general cognitive decline observed in schizophrenia spectrum disorders and may have a modest impact on cognition improvement, its involvement in delusions remains inconclusive^49,50. Controversy surrounds the connection between the development and maintenance of delusional thinking and cognitive deficits in schizophrenia. Furthermore, studies indicate that non-schizophrenic smokers experience a careful rise in number of A42 receptors in the striatum, a phenomenon not observed to the same extent in schizophrenic smokers^51-53.

Smoking stimulates and desensitizes nicotinic acetylcholine receptors (nAChRs) due to the presence of nicotine in tobacco. Nicotine permeates the entire brain at concentrations ranging from 20 to 100 nM. While various aparts of the brain are involved, the nicotinic receptors in the midbrain dopamine area execute an important part in the early stages of the addiction process⁵⁴. Within the midbrain, specific nAChRs consisting of 42 subunits are present on both dopamine (DA) and gamma-aminobutyric acid (GABA) neurons. These receptors, located postsynaptically, exhibit a high affinity for nicotine. There are also other nAChR subtypes, including the high-affinity 42* nAChRs and the lower-affinity 7* nAChRs. When nicotine enters the midbrain DA area, it stimulates these receptors⁵⁴. Nicotine's activation of presynaptic nAChRs causes an escalation in glutamate liberation. This activation, which often involves the nAChRs nevertheless solely, augments the release of glutamate neurotransmitter⁵⁵. Postsynaptic (and somatic) activation of nAChRs increases action potential firing in DA neurons. By depolarizing and triggering the firing of these neurons, the NMDA receptors' divalent cation block is removed. This allows the NMDA receptors to contribute in the chronic synaptic potentiation of glutamatergic afferents onto midbrain dopamine nerves, contributing to the effects of nicotine^56-59.

PHARMACOKINETICS OF NICOTINE: METABOLISM AND ABSORPTION IN THE BODY:

1. Action of Nicotine receptors:

Nicotine's association with nAChRs in the brain plays a crucial role in its effects and addiction potential^63,64. The chemical structure of nicotine closely resembles that of acetylcholine, the primary neurotransmitter involved in cognitive functions, reward, mood regulation, and motor control ⁶⁵. As a result, nicotine readily crosses cellular membranes and acts as an agonist for nAChRs, mimicking the effects of acetylcholine⁶³. Nicotine's stimulation of nAChRs brings the release of various neurotransmitters, including dopamine, norepinephrine, and serotonin⁵⁷. Dopamine release, in particular, is associated with the gratifying results of nicotine and adds to its reinforcing properties. The increased firing of neurons in specific brain regions due to nAChR activation enhances neuronal excitability⁶⁶.The interaction between nicotine and nAChRs is a critical factor in the development of nicotine addiction. With repeated exposure, the brain adapts by desensitizing and downregulating nAChRs, reducing their sensitivity⁶⁷. This desensitization and downregulation impact the progress of tolerance and dependence, making it challenging to quit nicotine use⁶⁷. Nicotine's reinforcing properties mediated by nAChR activation and dopamine release can lead to the compulsive seeking and use of nicotine, even in the face of adverse consequences^63,66. Apart from its role in addiction, nicotine's interaction with nAChRs also influences cognitive processes, including attention, memory, and learning. Acetylcholine, the neurotransmitter primarily involved in these cognitive functions, is modulated by nicotine⁶³. Studies have shown that nicotine can improve attention, working memory, and cognitive performance in certain tasks such as I treatment of Alzheimer and consideration discrepancy hyperactivity disorder^64-68.

Fig. 2: The desensitization of the receptor occurs when it undergoes an opening state upon binding with acetylcholine, after which it returns to a resting state or is replaced.

2. Genetic of Nicotine Addiction:

Genetic studies have made significant strides in unraveling the complex nature of nicotine addiction and smoking behavior⁶⁹. These investigations have reported that both genetic and environmental aspects serving towards the improvement and progression of nicotine addiction^70,71. Among the genes implicated in nicotine addiction based on GWAS findings, the nicotinic receptor genes -5, -3, and -4 have shown notable associations. These genes encode nicotinic acetylcholine receptors (nAChRs), which are the chief targets of nicotine in the nerves. Variations in these receptor genes can influence an individual's response to nicotine and affect their susceptibility to addiction⁷². The nicotinic receptor genes, other genetic loci have been identified in association with nicotine addiction. These include neurexin 1, VPS13A (a vacuolar sorting protein), KCNJ6 (a potassium channel), and the GABA A4 receptor gene. These genes play roles in different cell phenomenonas, like cell communication and ion channel regulation, which may helping towards the expansion and preservation of nicotine addiction⁷³. GWAS studies have revealed common genetic factors among different addictions, including nicotine addiction. It is significant to remember that the field of nicotine addiction genetics is continuously advancing, and further research is needed to fully comprehend the intricate genetic architecture underlying nicotine addiction. Future studies with larger sample sizes, functional characterization of identified genetic variants, and investigation of gene-environment interactions will provide deeper insights into the genetic mechanisms contributing to nicotine addiction⁷⁴.

CLINICAL IMPLICATIONS AND THERAPEUTIC OPPORTUNITIES:

1. Nicotine replacement therapies and their effects on neurotransmitters:

Nicotine replacement therapies (NRTs) are effective interventions designed to aid smoking cessation and manage nicotine dependence. NRTs provide controlled doses of nicotine without the harmful toxins found in tobacco smoke, making them a safer alternative to smoking. These therapies come in various forms, such as patches, gums, lozenges, nasal sprays, and inhalers, all aimed at reducing withdrawal symptoms and cravings associated with quitting smoking⁷⁵. When using NRTs, nicotine binds to nAChRs in the brain, similar to smoking, leading to a liberation of dopamine in the reward pathway, which induces feelings of pleasure and reinforcement. By providing a regulated and gradual nicotine delivery, NRTs help prevent the intense dopamine surges linked to smoking, reducing the risk of addiction. Moreover, NRTs moderately modulate other neurotransmitter systems, like serotonin, GABA, and glutamate, which contribute to the management of mood and withdrawal symptoms. This multifaceted effect helps alleviate negative feelings associated with quitting, making the process more manageable and less daunting⁷⁶. One of the significant advantages of NRTs is the flexibility they offer in tailoring the quit plan to individual needs. The gradual reduction in nicotine strength available in NRTs also allows individuals to wean off nicotine slowly, minimizing the chances of severe withdrawal symptoms and cravings that could lead to relapse. Although NRTs are generally safe and effective, they may cause mild side effects, such as nausea and headaches, in some individuals. These adverse responses are generally transient and diminish over time as the body adapts to the therapy. As with any medical intervention, it is essential to consult healthcare professionals before starting NRTs to ensure their safety and appropriateness for individual needs⁷⁷.

TARGETING NEUROTRANSMITTER SYSTEMS IN SMOKING CESSATION INTERVENTIONS:

Targeting neurotransmitter systems in smoking cessation interventions is a promising approach to help individuals quit smoking and manage nicotine dependence. Understanding the role of neurotransmitters in nicotine addiction can guide the development of tailored interventions that address both the physical and psychological aspects of smoking cessation (Fig. 3).

Fig. 3: Role of different neurotransmitters during nicotine cessation and their respective treatment and management to overcome symptoms of nicotine withdrawal.

1. Dopaminergic System: It plays a major role in showing after effect of nicotine. Smoking leads to a surge in dopamine release, creating feelings of pleasure and reinforcing the smoking behavior. Targeting this system in smoking cessation interventions involves medications that interact with dopamine receptors or affect dopamine reuptake. By modulating dopamine activity, these medications can help reduce the rewarding properties of nicotine and alleviate withdrawal symptoms⁷⁸.

2. Serotonergic System: Serotonin is involved in mood regulation, and imbalances in this system have been linked to depression and anxiety, which can be exacerbated during smoking cessation. Targeting the serotonergic system in smoking cessation may involve medications that influence serotonin levels or receptor activity, helping to stabilize mood and reduce negative feelings associated with quitting⁷⁹.

3. GABAergic System: The GABAergic system plays a role in anxiety and stress regulation⁸⁰. During smoking cessation, GABA activity may be disrupted, leading to increased anxiety. Targeting this system with appropriate medications can help reduce anxiety and promote a calmer state, facilitating the quitting process⁸¹.

4. Glutamatergic System: It mainly works for learning and memory centre of brain. Modulating glutamate activity in smoking cessation interventions may aid in reducing cravings and reinforcing the learning of new behaviors to replace smoking habits⁸².

5. Cholinergic System: Nicotine interacts with the cholinergic system, particularly with nicotinic acetylcholine receptors (nAChRs). Medications that selectively target nAChRs can help reduce cravings and withdrawal symptoms without the harmful effects of tobacco smoke^83,84.

Potential Therapeutic uses of Nicotine and Neurotransmitter modulators in Neurological and Psychiatric disorders:

Nicotine and neurotransmitter modulators have shown promising potential as therapeutic agents in various neurological and psychiatric disorders, sparking interest in their therapeutic applications beyond their well-known addictive properties. In neurodegenerative disorders like Alzheimer's and Parkinson's disease, nicotine's ability to modulate cholinergic transmission and influence other neurotransmitter systems has led to investigations into its neuroprotective effects and its potential to improve cognitive function⁸⁵. Additionally, studies exploring nicotine's impact on dopamine and norepinephrine systems have raised the possibility of using nicotine to manage symptoms of conditions like ADHD and schizophrenia, though alternative approaches with reduced addictive potential are actively being explored. Furthermore, selective modulation of neurotransmitter systems, such as serotonin and norepinephrine, is at the forefront of treatment for mood disorders. Medications targeting these neurotransmitters have been effective in regulating mood and alleviating symptoms of depression and anxiety. The addictive nature of nicotine necessitates careful consideration when using these therapies in this context⁸⁶. While the potential therapeutic uses of nicotine and neurotransmitter modulators show promise, auxiliary investigation is imperative to elucidate their safety, lasting efficacy, and optimal dosages for specific medical conditions⁸⁶. As the field advances, a deeper understanding of these therapeutic approaches may open up new avenues for treating neurological and psychiatric disorders, offering hope for improved outcomes and enhanced quality of life for affected individuals⁸⁶.

CONCLUSION:

Nicotine addiction, driven by the exceedingly addictive property of nicotine in tobacco smoke, is a complex and multifaceted phenomenon prejudiced by both genetic and environmental aspects. Genetic studies, particularly through genome-wide association studies (GWAS), have made great progress in our comprehension of the genetic basis of nicotine addiction. Notably, genes encoding nicotinic acetylcholine receptors (nAChRs), such as five, three, and four, have shown significant associations, highlighting the role of these receptors as primary targets of nicotine in the brain. Other genetic loci, including neurexin 1, VPS13A, KCNJ6, and GABA A4 receptor gene, have also been implicated, contributing to various cellular processes that potentially the emergence and maintenance of nicotine addiction. While our understanding of nicotine addiction genetics has made significant progress, further research is essential to fully comprehend the intricate genetic architecture underlying this addiction. Future studies should involve larger sample sizes, functional characterization of genetic variants, and exploration of gene-environment interactions to gain deeper insights into the underlying mechanisms. By enhancing our knowledge of the genetic mechanisms contributing to nicotine addiction, we can inform the development of more targeted interventions and personalized approaches to prevent and treat nicotine addiction, ultimately improving public health outcomes.

CONFLICTS OF INTEREST:

No competing interests to declare.

ACKNOWLEDGEMENT

We extend our sincere appreciation to Zodprobe Scientific for their invaluable assistance in data collection and structuring of this review article, contributing significantly to its scientific rigor and coherence.

REFERENCES:

1. Gupta S, Kulhara P. Cellular and molecular mechanisms of drug dependence: An overview and update. Indian Journal of Psychiatry. 2007; 49(2): 85.

2. Parri HR, Hernandez CM, Dineley KT. Research update: Alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer's disease. Biochem. Pharmacol. 2011; 82(8): 931-42.

3. Tutka P. Vinnikov D, Courtney RJ, Benowitz NL. Cytisine for nicotine addiction treatment: a review of pharmacology, therapeutics and an update of clinical trial evidence for smoking cessation. Addiction. 2019; 114(11): 1951-69.

4. Elrashidi MY, Ebbert JO. Emerging drugs for the treatment of tobacco dependence: 2014 update. Expert Opinion on Emerging Drugs. 2014; 19(2): 243-60.

5. Rosy JS. E cigarette. IJANM. 2019; 7(1): 74-76.

6. Haustein K, Krause J, Haustein H, et al. Effects of cigarette smoking or nicotine replacement on cardiovascular risk factors and parameters of haemorheology. J. Intern. Med. 2002; 252:130–9. doi: 10.1046/j.1365-2796.2002.01014.x

7. Khandakar AM. Smoking and chewing tobacco: obstacle towards sustainable development. Res. J. Humanit Soc Sci. 2013; 4(4): 603-607.

8. Jadhav RP, Kengar MD, Nikam NR, Bhutkar MA. Tobacco Cancer: A Review. Asian J Res Phar+ Sci. 2019; 9(4): 276-281.

9. Chiu J, Chien S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol Rev. 2011; 91: 327–87. doi: 10.1152/physrev.00047.2009

10. Aveleira C, Botelho M, Cavadas C. NPY/neuropeptide Y enhances autophagy in the hypothalamus: a mechanism to delay aging? Autophagy. 2015; 11: 1431–3. doi: 10.1080/15548627.2015.1062202

11. Peng S, Zhou Y, Song Z, Lin S. Effects of neuropeptide y on stem cells and their potential applications in disease therapy. Stem Cells Int. 2017; 2017: 6823917. doi: 10.1155/2017/6823917

12. Yang Z, Han S, Keller M, et al. Structural basis of ligand binding modes at the neuropeptide Y Y receptor. Nature. 2018; 556: 520–524. doi: 10.1038/s41586-018-0046-x.

13. Businaro R, Scaccia E, Bordin A, et al. Platelet lysate-derived neuropeptide y influences migration and angiogenesis of human adipose tissue-derived stromal cells. Sci Rep. 2018; 8: 14365. doi: 10.1038/s41598-018-32623-8

14. Mormède P, Castagné V, Rivet J, Gaillard R, et al. Involvement of neuropeptide Y in neuroendocrine stress responses. Central and peripheral studies. J Neural Transm. 1990; 29: 65–75. doi: 10.1007/978-3-7091-9050-0_8

15. Comeras L, Herzog H, Tasan R. Neuropeptides at the crossroad of fear and hunger: a special focus on neuropeptide Y. Ann NY Acad Sci. 2019; 1455: 59–80. doi: 10.1111/nyas.14179

16. Chen Y, Essner R, Kosar S, et al. Sustained NPY signaling enables AgRP neurons to drive feeding. eLife. 2019; 8: e46348. doi: 10.7554/eLife.46348

17. Cheng Y, Tang X, Li Y, et al. Depression-induced neuropeptide y secretion promotes prostate cancer growth by recruiting myeloid cells. Clin Cancer Res. 2019; 25: 2621–32. doi: 10.1158/1078-0432.Ccr-18-2912

18. Mahadeva Rao US, Yusoff HBM. Unraveling the association of tobacco smoking (nicotine) with gut and adipocyte appetite regulator hormones – a systematic review. Res. J. Pharm. Technol. 2019; 12(2): 913-919.

19. Park IS, Yun HK. Factors associated with smoking frequency among intermittent smokers focused on male adolescents. Res. J. Pharm. Technol. 2017; 10(7): 2345-2349.

20. Reichmann F, Holzer P. Neuropeptide Y: a stressful review. Neuropeptides. 2016; 55: 99–109. doi: 10.1016/j.npep.2015.09.008

21. Hassan A, Mancano G, Kashofer K, et al. High-fat diet induces depression-like behaviour in mice associated with changes in microbiome, neuropeptide Y, and brain metabolome. Nutri Neurosci. 2019; 22: 877–93. doi: 10.1080/1028415x.2018.1465713

22. Imai Y, Patel H, Hawkins E, et al. Insulin secretion is increased in pancreatic islets of neuropeptide Y-deficient mice. Endocrinology. 2007; 148: 5716–23. doi: 10.1210/en.2007-0404

23. Yu J, Loh K, Song Z, et al. Update on glycerol-3-phosphate acyltransferases: the roles in the development of insulin resistance. Nutrit Diab. 2018; 8: 34. doi: 10.1038/s41387-018-0045-x

24. Chen Z, Feng G, Nishiwaki K, et al. Possible roles of neuropeptide Y Y3-receptor subtype in rat aortic endothelial cell proliferation under hypoxia, and its specific signal transduction. Am J Physiol Heart Circul Physiol. 2007; 293: H959–67. doi: 10.1152/ajpheart.00886.2006

25. Qiu J, Bosch M, Zhang C, et al. Estradiol protects neuropeptide y/agouti-related peptide neurons against insulin resistance in females. Neuroendocrinology. 2020; 110: 105–18. doi: 10.1159/000501560

26. Donoso M, Miranda R, Irarrázaval M, Huidobro-Toro J. Neuropeptide Y is released from human mammary and radial vascular biopsies and is a functional modulator of sympathetic cotransmission. J. Vasc Res. 2004; 41: 387–99. doi: 10.1159/000080900

27. Lagraauw H, Westra M, Bot M, et al. Vascular neuropeptide Y contributes to atherosclerotic plaque progression and perivascular mast cell activation. Atherosclerosis. 2014; 235: 196–203. doi: 10.1016/j.atherosclerosis.2014.04.025

28. Wu W, Peng S, Shi Y, et al. NPY promotes macrophage migration by upregulating matrix metalloproteinase-8 expression. J Cell Physiol. 2020; 236: 1903–12. doi: 10.1002/jcp.29973

29. Robich M, Matyal R, Chu L, et al. Effects of neuropeptide Y on collateral development in a swine model of chronic myocardial ischemia. J. Mol Cell Cardiol. 2010; 49: 1022–30. doi: 10.1016/j.yjmcc.2010.08.022

30. Thorsell A, Slawecki C, El Khoury A, et al. The effects of social isolation on neuropeptide Y levels, exploratory and anxiety-related behaviors in rats. Pharmacol Biochem Behav. 2006; 83: 28–34. doi: 10.1016/j.pbb.2005.12.005

31. Hoirisch-Clapauch S. Anxiety-related bleeding and thrombosis. Sem Thromb Hemost. 2018; 44: 656–61. doi: 10.1055/s-0038-1639501

32. Rojas J, Stafford J, Saadat S, et al. Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats. Am J Physiol Endocrinol Metab. 2012; 303: E1479–88. doi: 10.1152/ajpendo.00351.2012

33. Cho Y, Kim C. Neuropeptide Y promotes beta-cell replication via extracellular signal-regulated kinase activation. Biochem Biophys Res Commun. 2004; 314: 773–80. doi: 10.1016/j.bbrc.2003.12.170

34. Kulkarni R, Wang Z, Wang R, et al. Glibenclamide but not other sulphonylureas stimulates release of neuropeptide Y from perifused rat islets and hamster insulinoma cells. J Endocrinol. 2000; 165: 509–18. doi: 10.1677/joe.0.1650509

35. Sun W, Li L, Huang X, et al. The central mechanism of risperidone-induced hyperprolactinemia. Progress Neuro-Psychopharm Biol Psychiatry. 2017; 76: 134–9. doi: 10.1016/j.pnpbp.2017.03.009

36. Choi B, Shin M, Kim E, et al. Elevated neuropeptide y in endothelial dysfunction promotes macrophage infiltration and smooth muscle foam cell formation. Front Immunol. 2019; 10: 1701. doi: 10.3389/fimmu.2019.01701

37. Aydin C, Oztan O, Isgor C. Vulnerability to nicotine abstinence-related social anxiety-like behavior: molecular correlates in neuropeptide Y, Y2 receptor and corticotropin releasing factor. Neurosci Lett. 2011; 490: 220–5. doi: 10.1016/j.neulet.2010.12.056

38. Dietrich P, Moleda L, Kees F, et al. Dysbalance in sympathetic neurotransmitter release and action in cirrhotic rats: impact of exogenous neuropeptide Y. J Hepatol. 2013; 58: 254–61. doi: 10.1016/j.jhep.2012.09.027

39. Kudari A. Smoking kills: Help an individual in quit smoking; nursing consideration. Asian J. Nur. Edu. Research. 2017; 7(3): 441-446.

40. Krishnamurthy K, Zin T, Priyamvatha K, Mahadeva Rao US, Suganya M. Detection of nicotine by a new system. Asian J. Pharm. Anal. 2022; 12(3): 179-0.

41. Lundberg J, Franco-Cereceda A, Hemsén A, et al.. Pharmacology of noradrenaline and neuropeptide tyrosine (NPY)-mediated sympathetic cotransmission. Fund. Clin. Pharm. 1990; 4: 373–91. doi: 10.1111/j.1472-8206.1990.tb00692.x

42. Tsurumaki T, Nagai S, Bo X, et al. Potentiation by neuropeptide Y of 5HT2A receptor-mediated contraction in porcine coronary artery. Europ J. Pharm. 2006; 544: 111–7. doi: 10.1016/j.ejphar.2006.06.036

43. Hubers S, Wilson J, Yu C, et al. DPP (Dipeptidyl Peptidase)-4 inhibition potentiates the vasoconstrictor response to NPY (Neuropeptide Y) in humans during renin-angiotensin-aldosterone system inhibition. Hypertension. 2018; 72: 712–9. doi: 10.1161/hypertensionaha.118.11498

44. Movafagh S, Hobson J, Spiegel S, et al. Neuropeptide Y induces migration, proliferation, and tube formation of endothelial cells bimodally via Y1, Y2, and Y5 receptors. FASEB J. 2006; 20: 1924–6. doi: 10.1096/fj.05-4770fje

45. Eshun D, Saraf R, Bae S, et al. Neuropeptide Y incorporated into PVAX nanoparticle improves functional blood flow in a murine model of hind limb ischemia. J Appl Physiol. 2017; 122: 1388–97. doi: 10.1152/japplphysiol.00467.2016

46. Koli MR, Girase CJ, Patil PA. Scientific approach to treat tobacco addiction – a review. Res. J. Pharmacogn Phytochem. 2020; 12(4): 231-234.

47. Zukowska-Grojec Z, Karwatowska-Prokopczuk E, Rose W, et al. Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium. Circul. Res. 1998; 83: 187–95. doi: 10.1161/01.res.83.2.187

48. Ribatti D, Conconi M, Nussdorfer G. Nonclassic endogenous novel [corrected] regulators of angiogenesis. Pharmacol. Rev. 2007; 59: 185–205. doi: 10.1124/pr.59.2.3

49. Klinjampa R, Sitticharoon C, Souvannavong-Vilivong X, Sripong C, Keadkraichaiwat I, Churintaraphan M, et al. Placental Neuropeptide Y (NPY) and NPY receptors expressions and serum NPY levels in preeclampsia. Exp Biol Med. 2019; 244: 380–8. doi: 10.1177/1535370219831437

50. Zhu P, Sun W, Zhang C, et al. The role of neuropeptide Y in the pathophysiology of atherosclerotic cardiovascular disease. Int. J. Cardiol. 2016; 220: 235–41. doi: 10.1016/j.ijcard.2016.06.138

51. Grundemar L, Håkanson R. Neuropeptide Y effector systems: perspectives for drug development. Trends Pharm. Sci. 1994; 15: 153–9. doi: 10.1016/0165-6147(94)90076-0

52. Zhou J, Zhang L, Wei H, et al. Neuropeptide Y induces secretion of high-mobility group box 1 protein in mouse macrophage via PKC/ERK dependent pathway. J Neuroimmunol. 2013; 260: 55–9. doi: 10.1016/j.jneuroim.2013.04.005

53. Zaldivia M, Hering D, Marusic P, et al. Successful renal denervation decreases the platelet activation status in hypertensive patients. Cardiovasc Res. 2020; 116: 202–10. doi: 10.1093/cvr/cvz033

54. Xue J, Scotti E, Stoffel M. CDK8 regulates insulin secretion and mediates postnatal and stress-induced expression of neuropeptides in pancreatic β cells. Cell Rep. 2019; 28: 2892–904.e7. doi: 10.1016/j.celrep.2019.08.025

55. Long M, Zhou J, Li D, et al. Long-term over-expression of neuropeptide y in hypothalamic paraventricular nucleus contributes to adipose tissue insulin resistance partly via the Y5 receptor. PLoS ONE. 2015; 10: e0126714. doi: 10.1371/journal.pone.0126714

56. Gomes R, Bueno F, Schamber C, et al. Maternal diet-induced obesity during suckling period programs offspring obese phenotype and hypothalamic leptin/insulin resistance. J. Nutr Biochem. 2018; 61: 24–32. doi: 10.1016/j.jnutbio.2018.07.006

57. Ritz T, Trueba A. Airway nitric oxide and psychological processes in asthma and health: a review. Ann Allergy Asthma Immunol. 2014; 112: 302–8. doi: 10.1016/j.anai.2013.11.022

58. Yue Y, Xu D, Wang Y, et al. Effect of inducible nitric oxide synthase and neuropeptide Y in plasma and placentas from intrahepatic cholestasis of pregnancy. J. Obstetr Gynaecol Res. 2018; 44: 1377–383. doi: 10.1111/jog.13681

59. Patle P, Tenpe C, Rathod S, Gautam D. Effect 1 of NMDA receptor agonist and antagonist on nicotine withdrawal induced hyperexcitability in mice. Asian J. Res. Pharm. Sci. 2021; 11(3): 205-2.

60. Zukowska Z, Pons J, Lee E, Li L. Neuropeptide Y: a new mediator linking sympathetic nerves, blood vessels and immune system? Can J. Physiol. Pharmacol. 2003; 81: 89–94. doi: 10.1139/y03-006

61. Tan C, Green P, Tapoulal N, et al. The role of neuropeptide Y in cardiovascular health and disease. Front Physiol. 2018; 9: 1281. doi: 10.3389/fphys.2018.01281

62. Huang L, Winzer-Serhan U. Nicotine regulates mRNA expression of feeding peptides in the arcuate nucleus in neonatal rat pups. Dev Neurob. 2007; 67: 363–77. doi: 10.1002/dneu.20348

63. Hiremagalur B, Sabban E. Nicotine elicits changes in expression of adrenal catecholamine biosynthetic enzymes, neuropeptide Y and immediate early genes by injection but not continuous administration. Brain Res Molecular Brain Res. 1995; 32: 109–5. doi: 10.1016/0169-328x(95)00068-4

64. Cavadas C, Silva A, Mosimann F, et al. NPY regulates catecholamine secretion from human adrenal chromaffin cells. J Clin Endocrinol Metab. 2001; 86: 5956–63. doi: 10.1210/jcem.86.12.8091

65. Jahng J, Houpt T, Joh T, Wessel T. Expression of catecholamine-synthesizing enzymes, peptidylglycine alpha-amidating monooxygenase, and neuropeptide Y mRNA in the rat adrenal medulla after acute systemic nicotine. J Mol Neurosci. 1997; 8: 45–52. doi: 10.1007/bf02736862

66. De Sousa P, Cherian G, Thomas J, Thulesius O. Coronary artery constriction is enhanced with nicotine and propranolol, particularly after endothelial damage. Clin Physiol. 1991; 11: 143–52. doi: 10.1111/j.1475-097x.1991.tb00107.x

67. Herring N, Tapoulal N, Kalla M, et al. Neuropeptide-Y causes coronary microvascular constriction and is associated with reduced ejection fraction following ST-elevation myocardial infarction. Europ Heart J. 2019; 40: 1920–29. doi: 10.1093/eurheartj/ehz115

68. Prieto D, Arcos L, Martínez P, et al. Heterogeneity of the neuropeptide Y (NPY) contractile and relaxing receptors in horse penile small arteries. Br J Pharmacol. 2004; 143: 976–86. doi: 10.1038/sj.bjp.0706005

69. Mirman B, Ikeda I, Zhang Z, et al. Effects of neuropeptide Y on the microvasculature of human skeletal muscle. Surgery. 2020; 168: 155–9. doi: 10.1016/j.surg.2020.04.020

70. Pedrazzini T, Pralong F, Grouzmann E. Neuropeptide Y: the universal soldier. CMLS. 2003; 60: 350–77. doi: 10.1007/s000180300029

71. Pablo Huidobro-Toro J, Verónica Donoso M. Sympathetic co-transmission: the coordinated action of ATP and noradrenaline and their modulation by neuropeptide Y in human vascular neuroeffector junctions. Europ J Pharm. 2004; 500: 27–35. doi: 10.1016/j.ejphar.2004.07.008

72. Komaru T, Ashikawa K, Kanatsuka H, et al.. Neuropeptide Y modulates vasoconstriction in coronary microvessels in the beating canine heart. Circul Res. 1990; 67: 1142–51. doi: 10.1161/01.res.67.5.1142

73. Woo N, Ganguly P. Altered neuropeptide Y effects on noradrenaline levels in the paraventricular nucleus of rats following aortic constriction. Can J. Cardiol. 1994; 10: 471–6.

74. Calvillo L, Gironacci M, Crotti L, et al. Neuroimmune crosstalk in the pathophysiology of hypertension. Nat Rev Cardiol. 2019; 16: 476–90.

75. Fabi F, Argiolas L, Ruvolo G, del Basso P. Neuropeptide Y-induced potentiation of noradrenergic vasoconstriction in the human saphenous vein: involvement of endothelium generated thromboxane. Br J. Pharm. 1998; 124: 101. doi: 10.1038/sj.bjp.0701808

76. Stephens D, Saad A, Bennett L, et al. Neuropeptide Y antagonism reduces reflex cutaneous vasoconstriction in humans. Am J Physiol Heart Circul Physiol. 2004; 287: H1404–9. doi: 10.1152/ajpheart.00061.2004

77. Kaipio K, Vahlberg T, Suominen M, Pesonen U. The role of non-synonymous NPY gene polymorphism in the nitric oxide production in HUVECs. Biochem Biophys Res Commun. 2009; 381: 587–91.

78. Olver T, Hiemstra J, Edwards J, et al. Loss of female sex hormones exacerbates cerebrovascular and cognitive dysfunction in aortic banded miniswine through a neuropeptide Y-Ca-activated potassium channel-nitric oxide mediated mechanism. J Am Heart Assoc. 2017; 6:e007409. doi: 10.1161/jaha.117.007409

79. Sajib S, Zahra F, Lionakis M, et al. Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions. Angiogenesis. 2018; 21: 1–4. doi: 10.1007/s10456-017-9583-4

80. Geetha P, Raksha VR, Ishak MJ, Shanmugasundaram P. A Review on Generalized Anxiety Disorder. Res. J. Pharm. Technol. 2017; 10(11): 4043-4046.

81. Saraf R, Mahmood F, Amir R, Matyal R. Neuropeptide Y is an angiogenic factor in cardiovascular regeneration. Europ J. Pharm. 2016; 776: 64–70. doi: 10.1016/j.ejphar.2016.02.033

82. Chen X, Zhou Y, Liang S, et al. Overexpression of UHRF1 promoted the proliferation of vascular smooth cells via the regulation of Geminin protein levels. Biosci Rep. 2019; 39: BSR20181341.

83. Heeschen C, Weis M, Cooke J. Nicotine promotes arteriogenesis. J Am Coll Cardiol. 2003; 41: 489–96. doi: 10.1016/s0735-1097(02)02818-8

84. Jiang Z, Zhou Y, Chen X, et al. Different effects of neuropeptide Y on proliferation of vascular smooth muscle cells via regulation of Geminin. Mol Cell Biochem. 2017; 433: 205–11.

85. Lee E, Michalkiewicz M, Kitlinska J, et al. Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles. J Clin Invest. 2003; 111: 1853–62. doi: 10.1172/jci16929

86. Li L, Najafi A, Kitlinska J, et al. Of mice and men: neuropeptide Y and its receptors are associated with atherosclerotic lesion burden and vulnerability. J Cardiovasc Transl Res. 2011; 4: 351–62. doi: 10.1007/s12265-011-9271-5.

Received on 02.09.2023 Modified on 16.12.2023

Research J. Pharm. and Tech 2024; 17(6):2605-2612.

DOI: 10.52711/0974-360X.2024.00407

Effects/Positive Reinforcement	Changes of Transmitters Involved	Effects/Negative Reinforcement	Changes of Transmitters Involved	References
Pleasure	Dopamine (↑), Norepinephrine (↑), Beta-Endorphin (↑), Cortisol (↑)	Reduction of anxiety and tension	Endorphin (↑), Cortisol (↑)	58,60
Improvements of mental performance	Acetylcholine (↑), Norepinephrine (↑)	Ant nociception	Acetylcholine (↑), Beta-Endorphin (↑)	60,61
Improvement of memory	Acetylcholine (↑), Norepinephrine (↑), Vasopressin (↑)	Avoidance of weight gain		60
Counteraction of withdrawal symptoms of nicotine		Reduction of emotional arousal	Dopamine (↑), Norepinephrine (↑), Acetylcholine (↑), Serotonin (↑), 5-HT (↑)	58, 61, 62