The health risks of nicotine are well known, but there is some evidence of its beneficial effects on cognitive function. The present review focused on the reported benefits of nicotine in the brain and summarizes the associated underlying mechanisms. Nicotine administration can improve cognitive impairment in Alzheimer's disease (AD), and dyskinesia and memory impairment in Parkinson's disease (PD). In terms of its mechanism of action, nicotine slows the progression of PD by inhibiting Sirtuin 6, a stress-responsive protein deacetylase, thereby decreasing neuronal apoptosis and improving neuronal survival. In AD, nicotine improves cognitive impairment by enhancing protein kinase B (also referred to as Akt) activity and stimulating phosphoinositide 3-kinase/Akt signaling, which regulates learning and memory processes. Nicotine may also activate thyroid receptor signaling pathways to improve memory impairment caused by hypothyroidism. In healthy individuals, nicotine improves memory impairment caused by sleep deprivation by enhancing the phosphorylation of calmodulin-dependent protein kinase II, an essential regulator of cell proliferation and synaptic plasticity. Furthermore, nicotine may improve memory function through its effect on chromatin modification via the inhibition of histone deacetylases, which causes transcriptional changes in memory-related genes. Finally, nicotine administration has been demonstrated to rescue long-term potentiation in individuals with sleep deprivation, AD, chronic stress and hypothyroidism, primarily by desensitizing α7 nicotinic acetylcholine receptors. To conclude, nicotine has several cognitive benefits in healthy individuals, as well as in those with cognitive dysfunction associated with various diseases. However, further research is required to shed light on the effect of acute and chronic nicotine treatment on memory function.
Nicotine, or 3-(1-Methylpyrrolidin-2-yl) pyridine, is an alkaloid that is found in the tobacco plant (1,2). Nicotine use can lead to a number of health complications, including heart and lung diseases, and increases the risk of cancer occurrence (3) and the susceptibility to several infectious diseases, including tuberculosis, pneumonia and sexually transmitted diseases such as chlamydia (4). However, increasing evidence suggests that nicotine also has beneficial health effects, particularly in terms cognitive function.
Nicotine acts as an agonist of nicotinic cholinergic receptors (nAChRs), which are found in both the central nervous system (CNS) and the peripheral nervous system (2,5,6). Each nAChR comprises five α or β subunits (7). There are nine potential α subunits and three β subunits, and different nAChR receptor subtypes possess varying compositions of these subunits (8,9). The most abundant receptor subtypes present in the human brain are α4β2, α3β4 (heterogenic) and α7 (homomeric) (10). The α3β4 nAChR is known to mediate the cardiovascular effects of nicotine (11), while the homomeric α7 nAChR is speculated to be involved in synaptic transmission, as well as in learning and sensory gating (12,13). Stimulation of nAChRs in the CNS by nicotine or acetylcholine regulates the release of a variety of neurotransmitters, such as dopamine, glutamate, serotonin, norepinephrine and γ-aminobutyric acid (14,15). Therefore, alterations in the expression or function of nAChRs, as a result of a disease, may alter the release of other neurotransmitters and, thus, affect brain function.
It is commonly known that long-term exposure to nicotine causes nAChR desensitization (16), leading to memory impairment in otherwise healthy individuals (17). Such nicotine-induced cognitive dysfunction is associated with several mechanisms, including activation of the phosphodiesterase-5 (PDE-5) signaling pathway and inhibition of estrogen biosynthesis (18,19). In particular, nicotine stimulates the expression of PDE-5 (19,20), which plays a role in cleaving cyclic guanosine monophosphate and cyclic adenosine monophosphate that activate downstream signaling pathways contributing to memory impairment (21–23). Nicotine also blocks estrogen synthase (aromatase) in the brain, which is important for estrogen biosynthesis (18,24). Estrogen activates estrogen receptors in the brain, which function as transcriptional factors and enhance the expression of several neurotransmitters (including glutamate, acetylcholine, serotonin and noradrenaline), and thus stimulate the neuronal circuits required for memory encoding (25). Therefore, alterations in estrogen biosynthesis due to nicotine (20,26), as well as the nicotine-induced elevation of PDE-5 levels, can lead to cognitive impairment in healthy individuals.
In contrast to these detrimental effects of nicotine on cognitive function, some studies report that nicotine also has beneficial effects on memory and learning processes. Thus, the present review summarizes the potential benefits of nicotine on cognition (Fig. 1).
Benefits of nicotine in Alzheimer's disease (AD)
AD is a neurodegenerative disease that primarily affects older adults and causes dementia (27). AD is characterized by the deposition of toxic amyloid-β (Aβ) and tau proteins in the brain (28,29). In particular, the accumulation of Aβ has been demonstrated to inhibit mitochondrial function, leading to increased reactive oxygen species formation and the stimulation of inflammatory processes (30). Indeed, several studies have revealed that Aβ deposition alters the physiological function of the brain and causes neuronal dysfunction (31,32). Unfortunately, there is still no cure for AD, and the disease is currently managed by slowing its progression with the administration of antioxidants and drugs such as cholinesterase inhibitors (33).
According to the cholinergic hypothesis, the cognitive decline in AD arises from deficiencies in central cholinergic neurotransmission due to the loss of acetylcholine (34). Therefore, cholinesterase inhibitors (such as donepezil and galantamine), which block the degradation of acetylcholine, remain the first-line approach to restore central cholinergic function in AD. Moreover, changes in the expression and density of α7 nAChRs in the hippocampus have been observed in AD and appear to have the most impact on cognitive function (35). Such α7 nAChRs have also been found to be co-localized with plaques in AD (36). Therefore, agonists of α7 nAChRs, including nicotine, may be useful for treating AD.
The stimulation of nAChRs by nicotine also likely affects downstream signaling molecules, including protein kinases, which are important regulators of synaptic plasticity and memory (37). In particular, protein kinase B (also referred to as Akt) is a central molecule of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, which plays a vital role in the regulatory functions of neurons in the CNS, including neuronal survival (38–42), and learning and memory encoding (38,43,44). Therefore, it is hypothesized that the stimulation of nAChRs by nicotine or its analogs activates the PI3K/Akt signaling pathway, which, in turn, regulates learning and memory processes (42,45). Indeed, acute and chronic administration of nicotine was reported to improve cognitive impairment in patients with AD (46–48). Moreover, acute nicotine administration during electroencephalography (EEG) performed in patients with AD who received cholinesterase inhibitors was found to shift the EEG readings towards normal levels (49). Thus, nicotine administration may have a beneficial effect on the cognitive decline observed in AD.
Benefits of nicotine in Parkinson's disease (PD)
PD is the second most common neurodegenerative disorder after AD that affects older individuals (50). Although the exact cause of PD is still not fully understood, its pathogenesis involves the loss or degeneration of the dopaminergic neurons (dopamine-producing neurons) in the substantia nigra of the midbrain (51). This loss of dopaminergic neurons causes impairment of motor control, tremors, rigidity and bradykinesia, and cognitive impairment (52,53). Studies in animal models of PD have revealed that nicotine can protect the brain cells from damage (54,55). Smoking cigarettes is also reported to reduce the risk of PD occurrence (53), and nicotine may help improve some symptoms of PD, such as dyskinesia and memory impairments (55). Indeed, the neuroprotective effects of nicotine in PD have been examined in vitro and in vivo, and are hypothesized to be primarily due to its pro-survival effects on dopaminergic neurons (56).
In addition to activating pro-survival signaling pathways in the brain, such as the aforementioned PI3K/Akt pathway, nicotine may also slow the progression of PD by inhibiting Sirtuin 6 (SIRT6), an NAD+-dependent class III deacetylase (57). This suppression of SIRT6 was found to reduce apoptosis and increase neuron survival (57). Consistently, several studies reported that the overexpression of SIRT6 impairs contextual fear memory formation (58,59). Despite this, another study found that loss of SIRT6 in the brain also causes memory impairment (60). Therefore, the downstream effects of nicotine on SIRT6 in PD require further investigation.
Benefits of nicotine on memory processes in patients with thyroid disease
Studies have revealed that thyroid hormones (61), including thyroxine (T4) and triiodothyronine (T3), regulate brain development, neurogenesis, synaptogenesis and myelination (62,63). T3 and T4 are synthesized in the thymus (64,65), released into the bloodstream, and eventually exert their effects by binding to a nuclear receptor termed the thyroid hormone receptor (TR), which is present in two different isoforms, α and β (66). The expression levels of these isoforms differ among tissues: The α1 receptor is primarily expressed in the heart and the skeletal muscle (67), whereas β1 is mainly expressed in the liver, kidney and brain (68).
TRs are also abundantly expressed in the hippocampus, which is the part of the brain that is responsible for memory formation (63). Therefore, in diseases such as hyperthyroidism, hypothyroidism and cretinism, in which abnormal thyroid hormone levels are present (69,70), hippocampal function may be affected, thus resulting in cognitive impairment (71). Indeed, neuroimaging studies have demonstrated that the structure and function of the hippocampus are altered in patients with hypothyroidism (72–74).
Of note, acute nicotine administration has been reported to activate TRs (particularly TRβ in the brain) and, thus, may enhance learning and memory processes in certain individuals (66). Furthermore, TRβ knockout in mice did not affect memory function following nicotine administration, confirming the role of TRβ in memory processes (75). In addition, memory impairment caused by hypothyroidism was revealed to be improved by nicotine via the modulation of calcineurin, which regulates the function of calmodulin-dependent protein kinase II (CaMKII) to improve synaptic plasticity (76). However, the precise underlying mechanisms of nicotine administration in improving cognitive impairments in patients with thyroid diseases require further investigation.
Effects of nicotine on cognitive function in healthy individuals
There is mounting evidence that nicotine administration may improve memory in otherwise healthy individuals. For example, research revealed that sleep deprivation causes memory impairment by downregulating the phosphorylation of CaMKII, which is an essential regulator of cell proliferation and synaptic plasticity (77–79). CaMKII was previously found to regulate the expression of glutamate receptor subunit-1 and its trafficking to the synaptic surface, which is necessary for normal brain function and memory formation (80). Consistently, acute nicotine administration was found to improve memory impairments caused by sleep deprivation by enhancing the phosphorylation of CaMKII (81). Therefore, nicotine may improve memory impairments caused by a lack of sleep in otherwise healthy individuals.
Nicotine-induced chromatin modifications may improve memory and learning
Some studies have indicated that nicotine affects chromatin in the cell nucleus (82–84). Chromatin is composed of four subunits, called histones, which can be modified via acetylation, methylation or phosphorylation (85), thereby regulating gene transcription (86,87). In particular, histone acetyltransferases and histone deacetylases (HDACs) play essential roles in the chromatin modifications involved in various cellular functions, including memory and synaptic plasticity (88,89). For example, inhibition of HDACs can increase the expression of key genes involved in memory processes, which are regulated by the cAMP response element-binding protein (CREB)-CREB-binding protein transcriptional complex (89). In particular, HDAC4 has been demonstrated to be crucial for learning and memory processes (89,90). As cigarette smoking has been reported to modulate the regulation of chromatin by altering the functionality of HDACs, such as HDAC6, in the lungs (83), it may also have a similar effect in the CNS. Indeed, it has been revealed that nicotine can inhibit HDACs in the brain, and, thus, improve memory function (84). However, further study is required to investigate the effect of nicotine on cognitive function through chromatin modulation.
Electrophysiological effects of nicotine: Strengthening synapses
The neurons in the brain interconnect to form networks, which are organized according to function (91). Therefore, understanding these connections allows certain areas to be stimulated and recorded, to monitor neurotransmitter release and receptor response in particular regions of the brain. Long-term potentiation (LTP) is used to measure synaptic plasticity, and can provide a cellular model of learning and memory encoding. For example, an increase in the level of glutamate released from the presynaptic to the postsynaptic neurons was found to enhance excitatory postsynaptic potential in the hippocampus during spatial learning tasks (92). Previously, studies have reported that acute nicotine exposure rescues LTP in individuals with sleep deprivation (81). In addition, chronic administration of nicotine has been revealed to improve LTP in AD, chronic stress models and hypothyroidism models (74,93,94). There is also mounting evidence that the restoration of LTP due to nicotine exposure is related to the normalization of the phosphorylation of essential kinases, such as CREB and CaMKIV (48,78,95). Therefore, nicotine administration may strengthen synapses between two neurons, leading to improved memory in both healthy individuals and those with diseases such as AD or hypothyroidism.
Conclusions
The findings reported in the studies included in the present review article indicate that nicotine can stimulate memory function. Therefore, although nicotine is similar to other psychoactive substances, in that it can induce dependence or abuse, it also has certain beneficial effects, including enhancing cognitive function in healthy individuals and restoring memory function in patients with diseases, such as AD, PD and hypothyroidism.
Acknowledgements
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Author's contributions
AA designed the review paper, performed the literature search and wrote the manuscript.
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Competing interests
The authors declare that they have no competing interests.
ReferencesBenowitzNLHukkanenJJacobPIIINicotine chemistry, metabolism, kinetics and biomarkers19229602009doi: 10.1007/978-3-540-69248-5_210.1007/978-3-540-69248-5_2BroideRSWinzer-SerhanUHChenYLeslieFMDistribution of alpha7 nicotinic acetylcholine receptor subunit mRNA in the developing mouse1376201910.3389/fnana.2019.0007631447654MishraAChaturvediPDattaSSinukumarSJoshiPGargAHarmful effects of nicotine362431201510.4103/0971-5851.15177125810571BagaitkarJDemuthDRScottDATobacco use increases susceptibility to bacterial infection412200810.1186/1617-9625-4-1219094204UnwinNNicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: Insights from Torpedo postsynaptic membranes46283322201310.1017/S003358351300006124050525SkokVINicotinic acetylcholine receptors in autonomic ganglia97111200210.1016/S1566-0702(01)00386-112036180GottiCZoliMClementiFBrain nicotinic acetylcholine receptors: Native subtypes and their relevance27482491200610.1016/j.tips.2006.07.00416876883DaniJANeuronal nicotinic acetylcholine receptor structure and function and response to nicotine124319201510.1016/bs.irn.2015.07.00126472524HoneAJMcIntoshJMNicotinic acetylcholine receptors in neuropathic and inflammatory pain59210451062201810.1002/1873-3468.1288429030971ZaveriNJiangFOlsenCPolgarWTollLNovel α3β4 nicotinic acetylcholine receptor-selective ligands. Discovery, structure-activity studies, and pharmacological evaluation5381878191201010.1021/jm100614820979364AbergerKChitravanshiVCSapruHNCardiovascular responses to microinjections of nicotine into the caudal ventrolateral medulla of the rat892138146200110.1016/S0006-8993(00)03250-911172759LevinEDBettegowdaCBlosserJGordonJAR-R17779, and alpha7 nicotinic agonist, improves learning and memory in rats10675680199910.1097/00008877-199911000-0001410780509HajosMHurstRSHoffmannWEKrauseMWallTMHigdonNRGroppiVEThe selective alpha7 nicotinic acetylcholine receptor agonist PNU-282987 [N-[(3R)- 1-Azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride] enhances GABAergic synaptic activity in brain slices and restores auditory gating deficits in anesthetized rats31212131222200510.1124/jpet.104.07696815523001BenowitzNLPharmacology of nicotine: Addiction, smoking-induced disease, and therapeutics495771200910.1146/annurev.pharmtox.48.113006.09474218834313D'SouzaMSMarkouANeuronal mechanisms underlying development of nicotine dependence: Implications for novel smoking-cessation treatments6416201122003417PicciottoMRAddyNAMineurYSBrunzellDHIt is not ‘either/or’: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood84329342200810.1016/j.pneurobio.2007.12.00518242816SunZSmythKGarciaKMattsonELiLXiaoZNicotine inhibits memory CTL programming8e68183201310.1371/journal.pone.006818323844169Echeverria MoranVBrain effects of nicotine and derived compounds460201310.3389/fphar.2013.0006023717281HotstonMRJeremyJYBloorJKoupparisAPersadRShuklaNSildenafil inhibits the up-regulation of phosphodiesterase type 5 elicited with nicotine and tumour necrosis factor-alpha in cavernosal vascular smooth muscle cells: Mediation by superoxide99612618200710.1111/j.1464-410X.2006.06618.x17176295HendersonVWCognitive changes after menopause: Influence of estrogen51618626200810.1097/GRF.0b013e318180ba1018677155Domek-ŁopacińskaKStrosznajderJBCyclic GMP metabolism and its role in brain physiology56(Suppl 2)S15S342005CuiQSoKFInvolvement of cAMP in neuronal survival and axonal regeneration79209212200410.1111/j.1447-073x.2004.00089.x15633459PeixotoCANunesAKGarcia-OstaAPhosphodiesterase-5 inhibitors: Action on the signaling pathways of neuroinflammation, neurodegeneration, and cognition2015940207201510.1155/2015/94020726770022BiegonAKimSWLoganJHookerJMMuenchLFowlerJSNicotine blocks brain estrogen synthase (aromatase): In vivo positron emission tomography studies in female baboons67774777201010.1016/j.biopsych.2010.01.00420188349BeanLAIanovLFosterTCEstrogen receptors, the hippocampus, and memory20534545201410.1177/107385841351986524510074LuineVNEstradiol and cognitive function: Past, present and future66602618201410.1016/j.yhbeh.2014.08.01125205317NeugroschlJWangSAlzheimer's disease: Diagnosis and treatment across the spectrum of disease severity78596612201110.1002/msj.2027921748748MurphyMPLeVineHIIIAlzheimer's disease and the amyloid-beta peptide19311323201010.3233/JAD-2010-122120061647DeshpandeAMinaEGlabeCBusciglioJDifferent conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons2660116018200610.1523/JNEUROSCI.1189-06.200616738244SchillingTEderCAmyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia22632953302201110.1002/jcp.2267521321937PalopJJMuckeLAmyloid-beta-induced neuronal dysfunction in Alzheimer's disease: From synapses toward neural networks13812818201010.1038/nn.258320581818JagustWIs amyloid-β harmful to the brain? Insights from human imaging studies1392330201610.1093/brain/awv32626614753Mendiola-PrecomaJBerumenLCPadillaKGarcia-AlcocerGTherapies for prevention and treatment of Alzheimer's disease20162589276201610.1155/2016/258927627547756GrossbergGTCholinesterase inhibitors for the treatment of Alzheimer's disease: Getting on and staying on64216235200310.1016/S0011-393X(03)00059-624944370ChengQYakelJLThe effect of α7 nicotinic receptor activation on glutamatergic transmission in the hippocampus97439444201510.1016/j.bcp.2015.07.01526212541BuckinghamSDJonesAKBrownLASattelleDBNicotinic acetylcholine receptor signalling: Roles in Alzheimer's disease and amyloid neuroprotection613961200910.1124/pr.108.00056219293145GieseKPMizunoKThe roles of protein kinases in learning and memory20540552201310.1101/lm.028449.11224042850DiezHGarridoJJWandosellFSpecific roles of Akt iso forms in apoptosis and axon growth regulation in neurons7e32715201210.1371/journal.pone.003271522509246HuangEJReichardtLFNeurotrophins: Roles in neuronal development and function24677736200110.1146/annurev.neuro.24.1.67711520916Del PuertoAWandosellFGarridoJJNeuronal and glial purinergic receptors functions in neuron development and brain disease7197201324191147BrunetADattaSRGreenbergMETranscription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway11297305200110.1016/S0959-4388(00)00211-711399427ShuYZhangHKangTZhangJJYangYLiuHZhangLPI3K/Akt signal pathway involved in the cognitive impairment caused by chronic cerebral hypoperfusion in rats8e81901201310.1371/journal.pone.008190124339978HorwoodJMDufourFLarocheSDavisSSignalling mechanisms mediated by the phosphoinositide 3-kinase/Akt cascade in synaptic plasticity and memory in the rat2333753384200610.1111/j.1460-9568.2006.04859.x16820027ChiangHCWangLXieZLYauAZhongYPI3 kinase signaling is involved in A beta-induced memory loss in Drosophila10770607065201010.1073/pnas.090931410720351282YiJHBaekSJHeoSParkHJKwonHLeeSJungJParkSJKimBCLeeYCDirect pharmacological Akt activation rescues Alzheimer's disease like memory impairments and aberrant synaptic plasticity128282292201810.1016/j.neuropharm.2017.10.02829079294NewhousePKellarKAisenPWhiteHWesnesKCoderreEPfaffAWilkinsHHowardDLevinEDNicotine treatment of mild cognitive impairment: A 6-month double-blind pilot clinical trial7891101201210.1212/WNL.0b013e31823efcbb22232050MajdiAKamariFSadigh-EteghadSGjeddeAMolecular insights into memory-enhancing metabolites of nicotine in brain: A systematic review121002201810.3389/fnins.2018.0100230697142SrivareeratMTranTTSalimSAleisaAMAlkadhiKAChronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer's disease32834844201110.1016/j.neurobiolaging.2009.04.01519464074KnottVEngelandCMohrEMahoneyCIlivitskyVAcute nicotine administration in Alzheimer's disease: An exploratory EEG study41210220200010.1159/00002666210828731ShererTBChowdhurySPeabodyKBrooksDWOvercoming obstacles in Parkinson's disease2716061611201210.1002/mds.2526023115047BarberMStewartDGrossetDMacPheeGPatient and carer perception of the management of Parkinson's disease after surgery30171172200110.1093/ageing/30.2.171-a11395349KinoshitaKITadaYMuroiYUnnoTIshiiTSelective loss of dopaminergic neurons in the substantia nigra pars compacta after systemic administration of MPTP facilitates extinction learning1372836201510.1016/j.lfs.2015.07.01726209139MaCLiuYNeumannSGaoXNicotine from cigarette smoking and diet and Parkinson disease: A review618201710.1186/s40035-017-0090-828680589LuJYDSuPBarberJEMNashJELeADLiuFWongAHCThe neuroprotective effect of nicotine in Parkinson's disease models is associated with inhibiting PARP-1 and caspase-3 cleavage5e3933201710.7717/peerj.393329062606QuikMO'LearyKTannerCMNicotine and Parkinson's disease: Implications for therapy2316411652200810.1002/mds.2190018683238BarretoGEIarkovAMoranVEBeneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson's disease6340340201510.3389/fnagi.2014.0034025620929NicholatosJWFranciscoABBenderCAYehTLugayFJSalazarJEGloriosoCLibertSNicotine promotes neuron survival and partially protects from Parkinson's disease by suppressing SIRT66120201810.1186/s40478-018-0625-y30409187KimHKimHSKaangBKElevated contextual fear memory by SIRT6 depletion in excitatory neurons of mouse forebrain1149201810.1186/s13041-018-0391-630189861YinXGaoYShiHSSongLWangJCShaoJGengXHXueGLiJLHouYNOverexpression of SIRT6 in the hippocampal CA1 impairs the formation of long-term contextual fear memory618982201610.1038/srep1898226732053KaluskiSPortilloMBesnardASteinDEinavMZhongLUeberhamUArendtTMostoslavskyRSahayAToiberDNeuroprotective functions for the histone deacetylase SIRT61830523062201710.1016/j.celrep.2017.03.00828355558RoussetBDupuyCMiotFDumontJChapter 2 Thyroid Hormone Synthesis and SecretionFeingoldKRAnawaltBBoyceAMDText.com, Inc.South Dartmouth, MA2000https://www.ncbi.nlm.nih.gov/books/NBK285550/September22015DiezDGrijota-MartinezCAgrettiPDe MarcoGTonaccheraMPincheraAde EscobarGMBernalJMorteBThyroid hormone action in the adult brain: Gene expression profiling of the effects of single and multiple doses of triiodo-L-thyronine in the rat striatum14939894000200810.1210/en.2008-035018467437DesouzaLALadiwalaUDanielSMAgasheSVaidyaRAVaidyaVAThyroid hormone regulates hippocampal neurogenesis in the adult rat brain29414426200510.1016/j.mcn.2005.03.01015950154FeketeCLechanRMCentral regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions35159194201410.1210/er.2013-108724423980MariottiSBeck-PeccozPPhysiology of the Hypothalamic-Pituitary Thyroidal SystemDe GrootLJBeck-PeccozPChrousosGMDText.com, Inc.South Dartmouth, MA2000https://www.ncbi.nlm.nih.gov/books/NBK278958August142016ChengSYMultiple mechanisms for regulation of the transcriptional activity of thyroid hormone receptors1918200010.1023/A:101005210121411704997BradleyDJTowleHCYoungWSIIISpatial and temporal expression of alpha- and beta-thyroid hormone receptor mRNAs, including the beta 2-subtype, in the developing mammalian nervous system1222882302199210.1523/JNEUROSCI.12-06-02288.19921607941WilliamsGRCloning and characterization of two novel thyroid hormone receptor beta isoforms2083298342200010.1128/MCB.20.22.8329-8342.200011046130BrentGAMechanisms of thyroid hormone action12230353043201210.1172/JCI6004722945636YenPMPhysiological and molecular basis of thyroid hormone action8110971142200110.1152/physrev.2001.81.3.109711427693GeJFPengLHuCMWuTNImpaired learning and memory performance in a subclinical hypothyroidism rat model induced by hemi-thyroid electrocauterisation24953961201210.1111/j.1365-2826.2012.02297.x22324892CookeGEMullallySCorreiaNO'MaraSMGibneyJHippocampal volume is decreased in adults with hypothyroidism24433440201410.1089/thy.2013.005824205791SinghSRanaPKumarPShankarLRKhushuSHippocampal neurometabolite changes in hypothyroidism: An in vivo (1) H magnetic resonance spectroscopy study before and after thyroxine treatment282016doi: 10.1111/jne.12399AlzoubiKHAleisaAMGergesNZAlkadhiKANicotine reverses adult-onset hypothyroidism-induced impairment of learning and memory: Behavioral and electrophysiological studies84944953200610.1002/jnr.2101416902999LeachPTKenneyJWConnorDAGouldTJThyroid receptor β involvement in the effects of acute nicotine on hippocampus-dependent memory93155163201510.1016/j.neuropharm.2015.01.02625666034AlzoubiKHAleisaAMAlkadhiKAMolecular studies on the protective effect of nicotine in adult-onset hypothyroidism-induced impairment of long-term potentiation16861874200610.1002/hipo.2021716897721PiHJOtmakhovNEl GaamouchFLemelinDDe KoninckPLismanJCaMKII control of spine size and synaptic strength: Role of phosphorylation states and nonenzymatic action1071443714442201010.1073/pnas.100926810720660727AleisaAMAlzoubiKHGergesNZAlkadhiKAChronic psychosocial stress-induced impairment of hippocampal LTP: Possible role of BDNF22453462200610.1016/j.nbd.2005.12.00516530419MisraniATabassumSWangMChenJYangLLongCCitalopram prevents sleep-deprivation-induced reduction in CaMKII-CREB-BDNF signaling in mouse prefrontal cortex1551118202010.1016/j.brainresbull.2019.11.00731743748MaoLMJinDZXueBChuXPWangJQPhosphorylation and regulation of glutamate receptors by CaMKII66365372201424964855AleisaAMHelalGAlhaiderIAAlzoubiKHSrivareeratMTranTTAl-RejaieSSAlkadhiKAAcute nicotine treatment prevents REM sleep deprivation-induced learning and memory impairment in rat21899909201120865738ShilatifardAChromatin modifications by methylation and ubiquitination: Implications in the regulation of gene expression75243269200610.1146/annurev.biochem.75.103004.142422MarwickJAKirkhamPAStevensonCSDanahayHGiddingsJButlerKDonaldsonKMacneeWRahmanICigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs31633642200410.1165/rcmb.2004-0006OC15333327VolkowNDEpigenetics of nicotine: Another nail in the coughing3107ps143201110.1126/scitranslmed.3003278KouzaridesTChromatin modifications and their function128693705200710.1016/j.cell.2007.02.00517320507BrehoveMWangTNorthJLuoYDreherSJShimkoJCOttesenJJLugerKPoirierMGHistone core phosphorylation regulates DNA accessibility2902261222621201510.1074/jbc.M115.66136326175159ZhangYGriffinKMondalNParvinJDPhosphorylation of histone H2A inhibits transcription on chromatin templates2792186621872200410.1074/jbc.M40009920015010469LegubeGTroucheDRegulating histone acetyltransferases and deacetylases4944947200310.1038/sj.embor.embor94114528264VecseyCGHawkJDLattalKMSteinJMFabianSAAttnerMACabreraSMMcDonoughCBBrindlePKAbelTWoodMAHistone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP-dependent transcriptional activation2761286140200710.1523/JNEUROSCI.0296-07.200717553985KimMSAkhtarMWAdachiMMahgoubMBassel-DubyRKavalaliETOlsonENMonteggiaLMAn essential role for histone deacetylase 4 in synaptic plasticity and memory formation321087910886201210.1523/JNEUROSCI.2089-12.201222875922PulvermullerFGaragnaniMWennekersTThinking in circuits: Toward neurobiological explanation in cognitive neuroscience108573593201410.1007/s00422-014-0603-924939580Richter-LevinGCanevariLBlissTVLong-term potentiation and glutamate release in the dentate gyrus: Links to spatial learning663740199510.1016/0166-4328(94)00121-U7755896AleisaAMAlzoubiKHAlkadhiKANicotine prevents stress-induced enhancement of long-term depression in hippocampal area CA1: Electrophysiological and molecular studies83309317200610.1002/jnr.2071616307449AlkadhiKAChronic stress and Alzheimer's disease-like pathogenesis in a rat model: Prevention by nicotine9587597201110.2174/15701591179837630722654719AlzoubiKHAlkadhiKAChronic nicotine treatment reverses hypothyroidism-induced impairment of L-LTP induction phase: Critical role of CREB4912451255201410.1007/s12035-013-8594-424277525
Illustration of the proposed mechanisms of nicotine in improving memory dysfunction. Nicotine activates nAChR, which can activate or inhibit the expression and functions of various proteins. Nicotine can activate PDE-5, TRβ and CaMKII, and activation of these proteins can lead to increased neuronal communication that ultimately improves memory function. In addition, nicotine activates the pro-survival PI3K/AKT pathway that increases LTP and improves memory dysfunction caused by AD. Also, nicotine can inhibit HDACs and SIRT6, which are increased in PD, thus reducing the activity of these proteins reduces neural apoptosis and improves memory dysfunction. PDE-5, phosphodiesterase-5; HDAC, histone deacetylases; PD, Parkinson's disease; SIRT6, Sirtuin 6; LTP, long-term potentiation; p-, phosphorylated; CAMKII, calmodulin-dependent protein kinase II; TRβ, thyroid receptor subunit β; PI3K, phosphoinositide 3-kinase; AD, Alzheimer's disease; nAChR, nicotinic cholinergic receptors.