3.1.1 Small cell lung cancer

Small cell lung cancer (SCLC) is a typical neuroendocrine lung cancer. The influence of smoking on SCLC is particularly crucial. Notably, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a nitrosation product of nicotine, has been identified as a potent carcinogen in tobacco smoke, and its affinity for α7nAChR is much higher than that of nicotine (Schuller and Orloff, 1998). Studies have shown that nicotine or NNK stimulates the release of autocrine growth factors serotonin and mammalian bombesin in a dose-dependent manner by binding to α7nAChRs (Cattaneo et al., 1993), which subsequently activates downstream protein kinase C (PKC)/Raf-1/mitogen-activated protein kinase (MAPK)/c-Myc mitogenic signaling pathway and promotes the growth of SCLC cell subpopulations in vitro (Jull et al., 2001). In addition, nicotine stimulates the release of serotonin and the proliferation of SCLC in vitro, which can be blocked by α-bungarotoxin (α-Bgt), indicating that α7nAChR is critical in the process of nicotine absorption, promoting the secretion of related endogenous neurotransmitters and mitosis (Codignola et al., 1994).

In addition, smoking promotes tumor production and induces cancer cell metastasis. The main members of the calpain family, μ-calpain and m-calpain, are widely expressed in SCLC cells. NNK activates ERK1 and ERK2 through α7nAChR/Ca²⁺ Influx/PKC/Raf/MAPK/ERK kinase (MEK) to phosphorylate μ-calpain and m-calpain, leading to calpain activation and secretion and promoting the migration and spread of cancer cells in vivo. As shown in Figure 3B, NNK significantly enhanced cell migration, which was blocked by PD98059 (inhibiting ERK1/2 activation) and α-Bgt, indicating that calpain is vital in this process (Xu and Deng, 2004). In addition, nicotine also promotes angiogenesis in various environments, such as inflammation, ischemia, and tumors, and this process is mainly mediated by α7nAChR. The stimulation of angiogenesis by α7nAChR is completely dependent on the phosphatidylinositol-3-kinase (PI3K)/MAPK/nuclear factor kappa-B (NF-κB) pathway and partially on vascular endothelial growth factor (VEGF). Therefore, pharmacological inhibition or genetic interference with α7nAChR expression can significantly reduce ischemia- and inflammation-induced angiogenesis. Similarly, inhibiting nAChR activity by mecamylamine can reduce angiogenesis and inhibit tumor growth (Figure 3C) (Heeschen et al., 2002).

3.1.2 Non-small cell lung cancer

Non-small cell lung cancers include squamous cell carcinoma, lung adenocarcinoma, and large-cell carcinoma. Here, smoking is also a critical environmental factor. Squamous cell carcinoma mainly develops from bronchial epithelial cell lesions. In contrast, most lung adenocarcinomas arise from bronchiolar epithelial and alveolar type II cell lesions, in which both homomeric α7nAChRs and heteromeric α4β2nAChRs are present. However, exposure to nicotine concentrations comparable to those in smokers results in long-term inactivation of α4β2nAChRs, whereas α7nAChRs are largely unaffected (Kawai and Berg, 2001).

Studies on the above cells have shown that nicotine or NNK can rapidly activate PI3K/PKB (protein kinase B) to phosphorylate various downstream substrates, such as glycogen synthase kinase-3 alpha (GSK-3α), glycogen synthase kinase-3 beta (GSK-3β), p70 ribosomal protein S6 kinase (p70S6K), a binding protein for eukaryotic translation initiation factor 4E (4EBP-1), and a member of the forkhead transcription factor family (FKHR), ultimately inhibiting epithelial cell apoptosis. The above signal is mediated by nAChRs containing α3/α4 subunits (Brognard et al., 2001; West et al., 2003). As shown in Figure 3D, nicotine (10 µM) could prevent apoptosis induced by UV irradiation and serum-free culture. However, pretreatment with PI3K inhibitor LY294002 or α3/α4nAChR antagonist dihydro-β-erythroidine (DHβE) could reduce the anti-apoptotic effect of nicotine. Therefore, developing drugs that target the α3nAChR/PI3K/PKB signaling pathway may be promising for cancer treatment.

In addition, nicotine inhibits apoptosis induced by chemotherapeutic drugs. In three groups of human non-small cell lung cancers cells (A549, H23, and H1299), nicotine upregulated the X-linked inhibitor of apoptosis protein and survivin to inhibit apoptosis induced by gemcitabine, cisplatin, and taxol, which also depends on PKB regulation. When X-linked inhibitor of apoptosis protein and survivin are depleted, the inhibitory effect on apoptosis is lost (Dasgupta et al., 2006a). In another experiment, nicotine reduced serum deprivation or chemotherapy-induced apoptosis, which depends on NF-κB activation (Tsurutani et al., 2005).

In addition to inhibiting apoptosis, nicotine can promote cell proliferation through α7nAChR/β-arrestin/Src/Rb-Raf-1 pathway. Blocking either β-arrestin or Rb-Raf-1 interaction inhibits nicotine-induced proliferation (Dasgupta et al., 2006b). Consequently, nicotine can promote tumor development by inducing epithelial cell transformation. A study on normal bronchial epithelial cells showed that repeated stimulation with nicotine induces cells to differentiate into a neuron-like phenotype and secrete various neural cell adhesion molecules, thus enhancing intercellular adhesion after differentiation. Figure 3E shows the number of filamentous filopodia produced in normal human bronchial epithelial cells treated with different doses of nicotine. This process is associated with nicotine-mediated shedding of heparin binding epidermal growth factor (HB-EGF) and phosphorylation of the epidermal growth factor receptor (EGFR); while adding AG1478 (an inhibitor of EGFR tyrosine phosphorylation) can inhibit this effect (Martinez-Garcia et al., 2008).

3.2.1 Cardiovascular diseases

Atherosclerosis mainly occurs in the coronary arteries, cerebral arteries, and aorta and is the pathological basis of many cardiovascular diseases. After the endothelial cells are damaged, they capture adhesion molecules, attract lymphocytes and monocytes to infiltrate the arterial wall and induce inflammation. White blood cells, fat, and cholesterol floating in the blood vessels are then deposited, resulting in plaque formation, stiffness, and thickening of the arterial inner wall (Tabas et al., 2015). Once the plaque ruptures, platelets accumulate at the top, plugging the already narrowed lumen and restricting oxygen and nutrient uptake by the associated cells. If this process occurs in the blood vessels of the heart, it causes myocardial infarction and death of heart muscle cells that do not receive nutrients. Stroke occurs when an embolism blocks the blood flow to the brain. During this process, there is increased proliferation and migration of vascular smooth muscle cells (VSMCs). Nicotine is involved in almost all stages of atherosclerosis occurrence and development.

Nicotine promotes the secretion of various cytokines, such as basic fibroblast growth factor, transforming growth factor beta, VEGF, and platelet-derived growth factor (PDGF), stimulating the vascular growth process (Grozio et al., 2007). A study on VSMCs found that nicotine modulates aortic production of basic fibroblast growth factor and transforming growth factor beta, which is critical in developing neointimal fibroplasia (Cucina et al., 2000). In addition, Carty et al. found that in human smooth muscle cells (SMCs), nicotine and its metabolite cotinine promoted the production and secretion of basic fibroblast growth factor and upregulated the expression of several matrix metalloproteinases (MMPs), such as collagenase-1, stromelysin-1 and gelatinase A, which are crucial in cell migration (Carty et al., 1996). When exposed to nicotine, the expression of tissue factor, a small molecular glycoprotein involved in the regulation of blood coagulation, hemostasis, and thrombus formation, is significantly increased in endothelial cells (ECs) and SMCs (Figure 4B). This process is regulated by the transcription factor NF-κB (Cirillo et al., 2006). Tissue factor forms a tissue factor-Vlla complex with coagulation factor Vlla to activate factors IX and X to generate thrombin (Toschi et al., 1997). To sum up, nicotine regulates the secretion of various growth factors and promotes the development of atherosclerosis.

Therefore, the role of inflammation in disease development should not be underestimated. Nicotine binds to nAChR to promote the opening of ion channels and regulate intracellular Na⁺, K⁺, Ca²⁺, and other ion concentrations, thereby activating different signaling cascade pathways and promoting atherosclerotic inflammation. Among them, the signal transducer and activator of transcription 3 (STAT3) is an important transcription factor involved in regulating various extracellular signals associated with cell growth and inflammation. After STAT3 activation, it enters the nucleus to promote the transcription of target genes. Studies have shown that there is a direct interaction between STAT3 and α1nAChR. After knocking out α1nAChR, the upregulation of p-STAT3, p-PKB, and p-mechanistic target of rapamycin (mTOR) induced by nicotine in vitro was significantly reduced, whereas the effect was opposite when α1nAChR was overexpressed (Xu et al., 2019). Staining for activated STAT3 in sections of human atherosclerotic lesions showed that the nuclei of cells in areas of inflammation stained strongly, in contrast to those of cells in areas with little or no inflammation. Endothelial STAT3 knock-out mice have smaller atherosclerotic lesions, and this inhibition may involve the PKB/mTOR/MMP2 signaling pathway. As shown in Figure 4C, nicotine upregulated levels of the pro-inflammatory factor interferon-γ (IFN-γ), which was inhibited by AG490 (STAT3 inhibitor) and rapamycin (mTOR inhibitor) (Gharavi et al., 2007; Xu et al., 2019). In another study on VSMCs, nicotine upregulated the production of reactive oxygen species (ROS). It activated the pattern recognition NOD-like receptor thermal protein domain associated protein 3 (NLRP3). NLRP3 activation leads to elevated C-reactive protein levels, an inflammatory cytokine that induces vascular inflammation. In addition, pro-caspase-1 formed inflammasomes by combining with NLRP3, simultaneously releasing inflammatory factors interleukin (IL)-18 and IL-1β, thus aggravating the inflammatory response (Hecker et al., 2015; Yao et al., 2019). By treating human aortic endothelial cells with nicotine, the above signaling pathway was found to mediate pyroptosis, and the nicotine-NLRP3-apoptosis-associated speck-like protein containing CARD (ASC)-pyroptosis pathway was activated by ROS (Wu et al., 2018).

Endothelial dysfunction and altered vascular smooth muscle function are involved in the progression of atherosclerosis. Reduced NO production is a typical feature of endothelial dysfunction. Nicotine causes significant structural and functional changes in the aorta. The combination of nicotine and nAChR promoted the activation of ERK1/2 and activated NF-κB, which stimulated the synthesis of intercellular adhesion molecule one and vascular cell adhesion molecule 1 (Egleton et al., 2009). In addition, nicotine can also stimulate macrophages to secrete tumor necrosis factor alpha (TNF-α) and IL-1β, increase the expression of human EC adhesion molecules, and lead to increased ahesion of monocytes to human umbilical vein ECs (Wang Y. et al., 2004), which may be one of the causes of EC disorders. In addition, Wang et al. found that nicotine-induced autophagy promoted VSMC phenotypic transformation and is partially mediated through the nAChRs/ROS/NF-κB signaling pathway (Wang Y. et al., 2004). NF-κB was also involved in the upregulation of nicotine-induced cytoskeletal proteins through α7nAChR. As shown in Figure 4D, the α7nAChR inhibitor α-Bgt and the NF-κB inhibitor PDTC significantly inhibited the expression of nicotine-induced cytoskeletal proteins, including actin, α-actin, and myosin (Wang et al., 2013). Another study showed that nicotine activated the death-associated protein kinase 3/AMP-activated protein kinase (AMPK) signaling cascade through receptors in VSMCs, thereby inducing endoplasmic reticulum stress-related protein expression and VSMC differentiation (Li K. X. et al., 2019).

3.3.1 Chronic obstructive pulmonary disease

COPD is a classic lung disease characterized by persistent airflow limitation. It is often associated with an increased chronic inflammatory response of the airways and lungs to noxious particles or gases, ultimately leading to accelerated aging of the lungs. It includes chronic obstructive bronchitis (narrowing of the small airways) and emphysema (damage to the alveoli). In the lungs of healthy individuals, alveoli attach to the small airways to keep them open, whereas in patients with COPD, the peripheral wall of the bronchioles is thickened, small airways are narrowed, alveoli are damaged, and mucus production increases (Christenson et al., 2022). Smoking is the main risk factor for developing COPD. Therefore, understanding its physiological mechanism is essential for the treatment and prevention of the disease.

Smoking causes small airway remodeling. In a guinea pig model, exposure to cigarette smoke produced symptoms similar to small airway remodeling, such as increased airway resistance, decreased airflow, and air trapping (Wright et al., 2007). A study showed that nicotine promoted the proliferation of human airway smooth muscle cells, and this process was associated with the α5nAChR-mediated Ca²⁺ influx dependent on transient receptor potential canonicals (TRPCs) channels. Knocking out the TRPC3 gene attenuated nicotine-induced Ca2⁺ influx and cell proliferation effects (Jiang et al., 2019). Another study explored the impact of nicotine addiction on the expression of 1800 genes using microarray bioinformatics analysis. Through integration, several overexpressed genes were found to be involved in the MAPK pathway, among which ERK1/2 and c-Jun N-terminal kinase (JNK) were more likely to function (Tsai et al., 2006). In addition, the MAPK pathway mediates IL-8 production. As an important pro-inflammatory factor, IL-8 may be associated with lung inflammation and tumorigenesis. As shown in Figure 5B, nicotine increased the synthesis of IL-8, which was inhibited by PD98059 (ERK 1/2 inhibitor) or SP600125 (JNK inhibitor); however, the inhibitor of ribonuclease P protein subunit p38 (p38) SB203580 had little effect on this process. Another characteristic of COPD is increased airway smooth muscle mass, in which PKB plays an important role. PKB, also known as protein kinase B, as an essential signaling hub, participates in various signaling pathways related to cell proliferation, apoptosis, and migration (Liang and Slingerland, 2003). In a vitro rat airway smooth muscle cell model, nicotine bound to nAChRs and subsequently activated the PI3K/PKB/GSK-3β/cyclin D1/retinoblastoma protein (RB)/early two factor (E2F) signaling cascade, ultimately leading to a significant increase in DNA synthesis and cell number. As shown in Figure 5C, nicotine treatment at concentrations of 0.1, 1, 10, and 100 μM significantly increased the number of cells (He et al., 2014). In addition, studies have shown that patients with COPD have a significantly increased risk of developing SCLC (Purdue et al., 2007). In this experiment, mice with COPD were more prone to develop neuroendocrine tumors after exposure to nicotine, whereas healthy mice in the control group had no tumors (Schuller et al., 1995).

3.4.1 Preterm birth

Several studies have suggested that nicotine is contributed to the increased risk of preterm birth associated with smoking. Schuller et al. found that smoking increased the risk of preterm birth due to premature rupture of membranes and bleeding in late pregnancy (Kyrklund-Blomberg et al., 2005). Günther et al. found that all smoking groups had the higher preterm birth rate compared to nonsmokers and the majority of preterm infants were male except for very heavy smokers (≥22 cigarettes/day) (Figure 6B). Women who used snus and continued smoking had an increased risk of preterm birth compared with women who had quit smoking, as tested using a multiple logistic regression model. The nicotine content in snus is similar to that absorbed from cigarettes but contains no other ingredients, clarifying the role of nicotine in inducing preterm birth (Baba et al., 2012). A subsequent study recommended a reduction in nicotine use during pregnancy and showed that snus was associated with preterm birth. The study also demonstrated that smoking cessation before antenatal appointments was not associated with an increased risk of preterm birth (Dahlin et al., 2016).

4.1.1 Alzheimer’s disease

AD is a typical neurodegenerative disorder. In the early stages of the disease, it often manifests as learning and memory decline and mild language and movement impairments. As the disease progresses, patients eventually lose the ability to live independently and remain in bed for a long time until death. (Alan et al., 2023).

AD is marked by the deposition of extracellular amyloid beta (Aβ) and the aggregation of tubulin tau in neurons (Knopman et al., 2021). Among them, Aβ is produced in the cracking process of amyloid precursor protein (APP) and further accumulates to form amyloid fibers, causing neurotoxicity. In addition, α7nAChR has a strong affinity for Aβ, which can promote Aβ to enter cells through endocytosis. Lysis occurs when neurons are overburdened, and Aβ is released extracellularly, where further accumulation creates plaques (Ma and Qian, 2019).

Epidemiological studies have shown a significant negative correlation between smoking and AD incidence (Fratiglioni and Wang, 2000). In a 4-week transdermal nicotine treatment for patients with AD, nicotine significantly improved the patient’s attention performance (White and Levin, 1999). In another study of APP (V717I) transgenic mice, nicotine treatment reduced the accumulation of insoluble Aβ in the cortex and hippocampus, as shown in Figure 9B, which is associated with the MAPK/NF-κB/c-myc pathway mediated by α7nAChR. In addition, there appears to be a connection between cell cycle-related proteins and neuronal loss. Nicotine regulates the cell cycle and apoptotic processes to reduce neuronal loss by decreasing the mRNA and protein levels of cyclin D1 and CDK4 and the pro-apoptotic factors Bax and caspase-3 (Liu et al., 2007).

Another study published by Inestrosa et al. pointed out that nicotine prevents Aβ-induced neuronal synapse damage through the α7nAChR/PI3K pathway. In addition, Wnt/β-catenin signaling may be crucial in neuroprotection. The Wnt signaling pathway can regulate synaptic transmission and plasticity, and increased β-catenin expression can improve the structure of dendrites. Activating Wnt can promote α7nAChR expression, and nicotine prevents Aβ-induced β-catenin reduction through α7nAChR. In addition, nicotine has been shown to improve memory in APP/PS1 transgenic mice (Inestrosa et al., 2013; Inestrosa and Varela-Nallar, 2014).

4.1.2 Parkinson’s disease

PD is the second most prevalent neurodegenerative disorder, affecting 2%–3% of people >65 years of age. Patients often present with motor symptoms such as bradykinesia, rigidity, resting tremor, and persistent cognitive, autonomic, and mood disturbances. Neuropathological features include striatal dopamine deficiency due to loss of substantia nigra dopaminergic neurons and extensive intracellular α-synuclein aggregates (Dickson et al., 2009). Neuronal damage is associated with multiple factors such as α-synuclein aggregates, mitochondrial dysfunction, and neuroinflammation (Poewe et al., 2017b).

Studies have shown a significant negative correlation between PD incidence and smoking, coffee consumption, and drinking alcohol (Nicoletti et al., 2010). Further research showed that nicotine can protect animal models of PD from nigrostriatal damage. In rats, administering nicotine before injury effectively reduced striatal dopamine loss (Costa et al., 2001), and in MPTP-treated monkeys, chronic oral nicotine decreased dopamine turnover, enhanced synaptic plasticity, and improved substantia nigra function after striatal injury (Quik et al., 2006), but this protective effect only occurred before striatal injury. This indicated that nicotine can only exert a protective effect on striatal injury rather than a repairing effect (Huang et al., 2009).

Nicotine-mediated neuroprotection also involves nAChRs and is subsequently divided into calcium-dependent and calcium-independent pathways (Quik et al., 2012). The calcium-dependent pathway involves an increase in intracellular Ca²⁺ concentration, which may be mediated by nAChR or other membrane channels, thereby activating different downstream signaling channels to exert neuroprotective effects. In a study by Toulorge et al., nicotine promoted cell survival by activating downstream calmodulin (CaM)/PI3K/PKB-dependent signaling. As shown in Figure 9C, in the presence of K⁺-channel blocker tetraethyl ammonium (TEA), nicotine treatment exerted more significant neuronal protective effects (Toulorge et al., 2011). The calcium-independent pathways involve the JAK2-STAT3 signaling cascade. Blocking downstream inhibitor of nuclear factor kappa B alpha (IκBα) phosphorylation and NF-κB translocation can reduce neuronal inflammation, which depends on α4β2nAChR (Hosur and Loring, 2011).

As reported by Holmes et al., nicotine selectively affected the non-smokers’ controlled semantic processing that is impaired in PD patients in a cognitive test, which may be attributed to nicotine’s enhancement of expectation or inhibition mechanism (Holmes et al., 2011). Villafane et al. found that chronic high-dose transdermal nicotine treatment in five PD patients resulted in improved motor scores and reduced dopaminergic responses, but with side effects such as nausea and vomiting (Villafane et al., 2007). Itti et al. studied six PD patients who received nicotine therapy for 1 year and found that motor function improved at 3 months, but the improvement was less sustained after 1 year. Dopamine transporter imaging showed that the density of striatal neurons in the treated patients was relatively stable, indicating that nicotine has pharmacological and neuroprotective effects (Itti et al., 2009). PD patients often have symptoms of low blood pressure. DiFrancisco et al. found that patients’ systolic blood pressure would increase within 10 min after taking 4 mg nicotine gum and remain elevated within 90 min by studying 10 subjects (DiFrancisco-Donoghue et al., 2019). Another study on two PD patients found that nicotine gum and patch treatment improved the patients’ motor delay and confusion (Fagerström et al., 1994). Nicotine gum is rapidly absorbed and is expected to become a new type of treatment. Although nicotine has shown some value in the treatment of PD, it seems that larger-scale population trials are needed to confirm its application if to be widely promoted.

4.1.3 Schizophrenia

Schizophrenia is a serious mental illness classified into three categories: positive, negative, and cognitive. Positive symptoms are often accompanied by delusions, hallucinations, and behavioral disturbances; negative symptoms are often accompanied by depression, anhedonia, and social withdrawal; and cognitive symptoms mainly manifest as cognitive dysfunction (Kahn et al., 2015). Presently, the etiology of the disease remains unclear, and patients mainly rely on drug therapy. Drug therapy can improve positive symptoms but cannot effectively relieve negative and cognitive symptoms (Stępnicki et al., 2018).

Smoking is a high-risk factor for patients with schizophrenia; however, the biological mechanisms underlying this association remain unclear. Liu et al. investigated the relationship between alterations in intrinsic brain activity associated with schizophrenia pathology and nicotine addiction. The authors found that smoking reversed intrinsic brain activity in the right striatum and prefrontal cortex, consistent with the pharmacological theory of schizophrenia. Furthermore, addictive effects are independent of the disease (Liu et al., 2018). Interestingly, Whitton et al. found that dopamine D2 receptor antagonists reduced the reward-enhancing effects of nicotine and were associated with increased smoking rates in patients, which explains why patients taking potent dopamine D2 receptor antagonists often exhibit more symptoms of nicotine dependence (Whitton et al., 2019).

Smucny et al. examined the effect of nicotine on the connectivity within a ventral attention network. When patients performed a selective attention task, the connectivity between the ventral parietal cortex seeds and the inferior frontal gyrus decreased, and nicotine increased this connectivity (Smucny et al., 2016). Another study found that in a mouse model, nicotine treatment increased gamma oscillations in the prefrontal cortex, which was associated with enhanced visual attention. As shown in Figure 9D, nicotine exposure increased visual attention accuracy in rats (Bueno-Junior et al., 2017).

The prefrontal cortex is fundamental to higher cognitive processes and regulated by nAChRs. A genome-wide association study found that single-nucleotide polymorphisms (SNPs) in the CHRNA5 gene encoding the α5nAChR subunit were associated with an increased risk of smoking and schizophrenia. In mice expressing α5-SNP and α5-knockout mice, interneuron inhibition of layer II/III pyramidal neurons increases, activity reduces, and frontal function declines. However, chronic nicotine administration modulates layer II/III inhibition circuitry through nAChR, reversing the above effects (Koukouli et al., 2017). A subsequent study showed that these prefrontal cortex circuit dynamics involved changes in the structure of active-state stability and that changes in amplitude were associated with reduced cone firing rates in α5 SNP mice. In addition, this experiment demonstrated that nicotine induced the desensitization and upregulation of β2nAChR on somatostatin interneurons but not the activation of α5nAChR on vasoactive intestinal polypeptide interneurons, which explains why the activity of α5 SNP mice normalized after nicotine treatment. In addition, the study showed that nicotine withdrawal may exacerbate SNP-induced frontal hypocreasia (Rooy et al., 2021).

4.1.4 Attention-deficit/hyperactivity disorder

ADHD is a common neurodevelopmental disorder caused by multiple genetic and environmental factors. Typical features include inattention and hyperactive impulsiveness, which affect approximately 5% of children and adolescents worldwide, with huge financial costs and family stress. For now, medication remains an effective way to reduce ADHD symptoms (Faraone et al., 2015).

Molecular genetic studies have shown that susceptibility to ADHD is associated with three genes: D4 dopamine receptor, D2 dopamine receptor, and dopamine transporter genes. Neurological deficits in children include executive function and working memory deficits, which may be associated with dysfunction in the frontal lobar cortex (Faraone and Biederman, 1998).

Nicotine has been shown to improve attentional performance in this disorder. In a rat model, nicotine administration improved working memory in the radial-brachial maze, an effect associated with α4β2nAChR and α7nAChR in the ventral hippocampus and basolateral amygdala. Local infusion of α4β2nAChR and α7nAChR antagonists induced working memory deficits, whereas ventral hippocampal α4β2nAChR blockade-induced working memory deficits were reversed by systemic nicotine treatment (Levin, 2002). In addition, patients with ADHD appear to have a higher risk of smoking and failure to quit, perhaps because of the “self-medication hypothesis.” Accordingly, patients’ active or continued exposure to cigarettes is attributed to nicotine in tobacco products that can supplement the lack of dopamine in the cortico-striatal pathway, thereby relieving symptoms. In addition, the nicotine analogs varenicline and bupropion improved ADHD-related symptoms and also supported the above hypothesis (Taylor et al., 2022). Nicotine patches and stimulant medications, alone or in combination, have been found to reduce concentration difficulties and core symptoms in patients with ADHD (Figure 9E) (Gehricke et al., 2006). Another acute nicotine treatment in patients with ADHD revealed that these patients had improved recognition memory, increased delay tolerance, and a corresponding reduction in reaction time in a stop-signal task (Potter and Newhouse, 2008). A recent study pointed out that nicotine improved two pathways involving the VTA; one normalized abnormal activity in animal models of ADHD, and the other induced atypical brain responses in animals with ADHD (Poirier et al., 2017a).