Contribution of CNS nicotine metabolites to the neuropharmacological effects of nicotine and tobacco smoking

doi:10.1016/S0006-2952(97)00117-2

Biochemical Pharmacology

Volume 54, Issue 7, 1 October 1997, Pages 743-753

https://doi.org/10.1016/S0006-2952(97)00117-2 Get rights and content

Abstract

Nicotine, the principal alkaloid in tobacco products, is generally accepted to be the active pharmacological agent responsible for CNS effects resulting from tobacco use. Arguments are presented in this commentary which take issue with this popular dogma, by providing evidence that nicotine metabolites may also be responsible for the CNS effects commonly attributed to nicotine. CNS effects attributed to nicotine include reinforcing effects, mood elevation, arousal, locomotor stimulant effects, and learning and memory enhancement. The reinforcing and locomotor stimulant effects of nicotine have been suggested to be the result of activation of CNS dopaminergic systems, and nicotine-induced modulation of dopaminergic neurotransmission has been studied in detail. Nicotine acts at a family of nicotinic receptor subtypes composed of multiple subunits; however, the exact composition of the subunits in native nicotinic receptors and the functional significance of the receptor subtype diversity are currently unknown. This nicotinic subtype diversity increases the complexity of the potential mechanisms of action of nicotine and its metabolites. Although peripheral metabolism of nicotine has been studied extensively, metabolism in the CNS has not been investigated to any great extent. Recently, studies from our laboratory have demonstrated that several nicotine metabolites are present in the CNS after acute nicotine administration. Moreover, nicotine metabolites are pharmacologically active in neurochemical and behavioral assays. Thus, CNS effects resulting from nicotine exposure may not be due solely to nicotine, but may result, at least in part, from the actions of nicotine metabolites.

References (183)

J.E. Henningfield et al.
Nicotine as a reinforcer in human subjects and laboratory animals
Pharmacol Biochem Behav
(1983)
S. Banerjee et al.
[³H]Mecamylamine binding to rat brain membranes
Biochem Pharmacol
(1990)
R. Loiacono et al.
Multiple binding sites for nicotine receptor antagonists in inhibiting [³H](−)-nicotine binding in rat cortex
Neuropharmacology
(1993)
T.J. O'Dell et al.
Mecamylamine is a selective non-competitive antagonist of $N- methyl - d - aspartate$ and aspartate-induced currents in horizontal cells dissociated from the catfish retina
Neurosci Lett
(1988)
J.A. Court et al.
Nicotine reduces the binding of [³H]MK-801 to brain membranes, but not via the stimulation of high-affinity nicotinic receptors
Brain Res
(1990)
C. Reavill et al.
High affinity binding of [³H](−)nicotine to rat brain membranes and its inhibition by analogues of nicotine
Neuropharmacology
(1988)
J.W. Gorrod et al.
The metabolism of tobacco alkaloids
Essays Toxicol
(1975)
E.S. Deneris et al.
Pharmacological and functional diversity of neuronal nicotinic acetylcholine receptors
Trends Pharmocol Sci
(1991)
A. Karlin
Structure of nicotinic acetylcholine receptors
Curr Opin Neurobiol
(1993)
L.W. Role
Diversity in primary structure and function of neuronal nicotinic acetylcholine receptor channels
Curr Opin Neurobiol
(1992)

B.J. Morris et al.

Distinct regional expression of nicotinic acetylcholine receptor genes in chick brain

Mol Brain Res

(1990)

R. Anand et al.

Neuronal nicotinic acetylcholine receptors expressed in Xenopus have a pentameric quaternary structure

J Biol Chem

(1991)

W.G. Conroy et al.

The α5 gene product assembles with multiple acetylcholine receptor subunits to form distinctive: receptor subtypes in brain

Neuron

(1992)

A.B. Vernallis et al.

Neurons assemble acetylcholine receptors with as many as three kinds of subunits while maintaining subunit segregation among receptor subtypes

Neuron

(1993)

M. Amar et al.

Agonist pharmacology of the neuronal α7 nicotinic receptor expressed in Xenopus oocytes

FEBS Lett

(1993)

M.W. Decker et al.

Diversity of neuronal nicotinic acetylcholine receptors: Lessons from behavior and implications for CNS therapeutics

Life Sci

(1995)

W.A. Corrigall et al.

Nicotine self-administration and locomotor activity are not modified by the 5-HT₃ antagonists ICS 205-930 and MDL 72222

Pharmocol Biochem Behav

(1994)

C.A. Sannerud et al.

The effects of sertraline on nicotine self-administration and food-maintained responding in squirrel monkeys

Eur J Pharmacol

(1994)

P.J. Fudala et al.

Pharmacologic characterization of nicotine-induced conditioned place preference

Pharmocol Biochem Behav

(1985)

F.O. Risinger et al.

Nicotine-induced conditioned place preference and conditioned place aversion in mice

Pharmacol Biochem Behav

(1995)

L.T. Meltzer et al.

Investigations on the CNS sites of action of the discriminative stimulus effects of arecoline and nicotine

Pharmocol Biochem Behav

(1981)

P.B.S. Clarke

Dopaminergic mechanisms in the locomotor stimulant effects of nicotine

Biochem Pharmocol

(1990)

AC Collins et al.

Dissociation of the apparent relationship between nicotine tolerance and upregulation of nicotinic receptors

Brain Res Bull

(1990)

C Ksir et al.

Exposure to nicotine enhances the behavioral stimulant effect of nicotine and increases binding of [³H]acetylcholine to nicotinic receptors

Neuropharmacology

(1985)

Y.K. Fung et al.

Receptor mechanisms of nicotineinduced locomotor hyperactivity in chronic nicotine-treated rats

Eur J Pharmacol

(1988)

E.P. Lapin et al.

Action of nicotine on accumbens dopamine and attenuation with repeated administration

Eur J Pharmacol

(1989)

A Imperato et al.

Nicotine preferentially stimulates dopamine release in the limbic system of freely moving rats

Eur J Pharmacol

(1986)

G Damsma et al.

Lack of tolerance to nicotine-induced dopamine release in the nucleus accumbens

Eur J Pharmacol

(1989)

M.P. Brazell et al.

Acute administration of nicotine increases the in vivo extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: Comparison with the caudate-putamen

Neuropharmacology

(1990)

G Singer et al.

Effects of dopaminergic nucleus accumbens lesions on the acquisition of scheduleinduced self-injection of nicotine in the rat

Pharmacol Biochem Behav

(1982)

W Lichtensteiger et al.

Stimulation of nigrostriatal dopamine neurons by nicotine

Neuropharmacology

(1982)

P.B.S. Clarke

Nicotine and smoking: A perspective from animal studies

Psychopharmacology

(1987)

C.S. Pomerleau et al.

Euphoriant effects of nicotine in smokers

Psychopharmacology

(1992)

M.I. Damaj et al.

In vivo pharmacological effects of dihydro-β-erythroidine, a nicotinic antagonist, in mice

Psychopharmacology

(1995)

I.P. Stolerman et al.

Role of training dose in discrimination of nicotine and related compounds by rats

Psychopharmacology

(1984)

I.P. Stolerman et al.

Influencing cigarette smoking with nicotine antagonists

Psychopharmacology

(1973)

J.E. Rose et al.

Combined effects of nicotine and mecamylamine in attenuating smoking satisfaction

Exp Clin Psychopharmacol

(1994)

C. Lingle

Blockade of cholinergic channels by chlorisondamine on a crustacean muscle

J Physiol (Lord)

(1983)

W.A. Varanda et al.

Eldefrawi ME and Albuquerque EX, The acetylcholine receptor of the neuromuscular junction recognizes mecamylamine as a noncompetitive antagonist

Mol Pharmacol

(1985)

T.J. Martin et al.

Pharmacological evaluation of the antagonism of nicotine's central effects by mecamylamine and pempidine

J Pharmacol Exp Ther

(1990)

O. Peng et al.

Nicotine-induced increase in the neuronal nicotinic receptors results from a decrease in the rate of receptor turnover

Mol Pharmacol

(1994)

I.J. Reynolds et al.

[³H]MK801 binding to the N-methyl-d-aspartate receptor reveals drug interactions with the zinc and magnesium binding sites

J Pharmacol Exp Ther

(1988)

L.D. Snell et al.

Effects of nicotinic agonists and antagonists on $N- methyl - d - aspartate-induced$ ³H-norepinephrine release and ³H-[1-(2-thienyl)cyclohexyl]-piperidine) binding in rat hippocampus

Synapse

(1989)

S. Grady et al.

Characterization of nicotinic receptor-mediated [³H]dopamine release from synaptosomes prepared from mouse striatum

J Neurochem

(1992)

C. Vidai et al.

Pharmacological profile of nicotinic acetylcholine receptors in rat pre-frontal cortex: An electrophysiological study in a slice preparation

Neuroscience

(1989)

M. Alkondon et al.

Initial characterization of the nicotinic acetylcholine receptors in rat hippocampal neurons

J Recept Res

(1991)

C. Mulle et al.

Existence of different subtypes of nicotinic acetylcholine receptors in the rat habenulo-interpeduncular system

J Neurosci

(1991)

G.A. Kyerematen et al.

Metabolism of nicotine

Drug Metab Rev

(1991)

Cited by (110)

Varenicline but not cotinine increased the value of a visual stimulus reinforcer in rats: No evidence for synergy of the two compounds
2024, Pharmacology Biochemistry and Behavior
Smoking is the leading cause of preventable death worldwide, with <7 % of smoking cessation attempts being met with success. Nicotine, the main addictive agent in cigarettes, enhances the reinforcing value of other environmental rewards. Under some circumstances, this reward enhancement maintains nicotine consumption. Varenicline (i.e., cessation aid Chantix™) also has reward-enhancement effects via nicotinic acetylcholine receptor agonism (nAChRs) – albeit less robust than nicotine. Cotinine is the major metabolite of nicotine. Recent studies suggest that cotinine is a positive allosteric modulator (PAM) and/or a weak agonist at nAChRs. Thus, cotinine may enhance the behavioral effects of nAChR compounds such as varenicline and/or exert some behavioral effects alone. We used 20 (10M, 10F) Sprague-Dawley rats to assess reward-enhancement within-subjects by examining responding maintained by a reinforcing visual stimulus on a Variable Ratio 2 schedule of reinforcement. To assess the reward-enhancing effects of cotinine, rats received one injection of cotinine (saline, 0.1, 0.3, 1.0, 3.0, 6.0 mg/kg) before each 1 h session. To assess cotinine and varenicline interactions, rats received an injection of cotinine (saline, 0.1, 1.0, or 6.0 mg/kg) and of varenicline (saline, 0.1, 0.3, 1.0, or 3.0 mg/kg) before the session. While we replicated prior work identifying reward-enhancement by 0.1, 0.3, and 1.0 mg/kg varenicline, cotinine alone did not produce reward-enhancement nor augment the reward-enhancing effects of varenicline. Future studies may consider examining the reward-enhancing effects of cotinine with other reinforcers or co-administered with other smoking cessation aids such as bupropion.
Nicotine and its metabolite cotinine target MD2 and inhibit TLR4 signaling
2021, Innovation
Nicotine is the principal alkaloid of tobacco often manufactured into cigarettes and belongs to a highly addictive class of drugs. Nicotine attenuates the neuroinflammation induced by microglial activation. However, the molecular target(s) underlying anti-inflammatory action of nicotine has not been fully understood. Considering the psychoactive substances morphine, cocaine, and methamphetamine act as xenobiotic-associated molecular patterns and can be specifically sensed by the innate immune receptor Toll-like receptor 4 (TLR4), here we sought to delineate whether nicotine and/or its metabolite cotinine may be recognized by the innate immune system via myeloid differentiation protein 2 (MD2), an accessory protein of TLR4 that is responsible for ligand recognition. MD2-intrinsic fluorescence titrations, surface plasmon resonance, and competitive displacement binding assays with curcumin (MD2 probe) demonstrated that both nicotine and cotinine targeted the lipopolysaccharide (LPS; TLR4 agonist) binding pocket of MD2 with similar affinities. The cellular thermal shift assay indicated that nicotine binding increased, while cotinine binding decreased, MD2 stability. These biophysical binding results were further supported by in silico simulations. In keeping with targeting MD2, both nicotine and cotinine inhibited LPS-induced production of nitric oxide and tumor necrosis factor alpha (TNF-α) and blocked microglial activation. Neither a pan nicotinic acetylcholine receptor (nAChR) inhibitor nor RNAi for nAChRs abolished the suppressive effect of nicotine- and cotinine-induced neuroinflammation. These data indicate that TLR4 inhibition by nicotine and cotinine at the concentrations tested in BV-2 cells is independent of classic neuronal nAChRs and validate that MD2 is a direct target of nicotine and cotinine in the inhibition of innate immunity.
Nicotine and its derivatives in healthy brain aging
2021, Factors Affecting Neurological Aging: Genetics, Neurology, Behavior, and Diet
Aging is a multifaceted process affecting all aspects of the human psyche and body. Brain aging is one of the vital aspects of human aging manifested by memory and learning impairment. It is caused by impaired mitochondrial function, excessive production and scavenging of oxidants, diminished neurotrophic factors levels, and cholinergic hypofunction, eventually leading to neuroinflammation, excitotoxicity, and neuronal death. A myriad of therapeutic strategies has been tried to ameliorate at least partially age-induced cognitive decline. However, not all these options have yielded fruitful results in the clinic. Nicotine and its major cerebral metabolites, i.e., cotinine and nornicotine, have shown procognitive effects in disorders of cognition and healthy aging, in both experimental studies and clinical trials. These effects result from their antioxidant, antiapoptotic, antiinflammatory, and neuroprotective properties. A wider therapeutic window and lack of abuse potential make the latter a superior option over the former, though. This chapter tries to shed light on the procognitive impacts of nicotine and its major bioproduct cotinine on age-related cognitive decline.
Route of administration effects on nicotine discrimination in female and male mice
2019, Drug and Alcohol Dependence
Use of electronic cigarettes (e-cigarettes) has increased exponentially since their appearance on the U.S. market around 2007. To provide preclinical models of vaping that incorporate olfactory cues and chemosensory effects (including flavors) that play a role in human vaping behavior, the feasibility of using a modified e-cigarette device for delivery of aerosolized nicotine was examined in a nicotine discrimination procedure in mice.
Adult female and male C57BL/6 mice were trained to discriminate 0.75 mg/kg subcutaneous (s.c.) nicotine from saline. After determination of a s.c. nicotine dose-effect curve, aerosolized freebase nicotine and nicotine-containing tobacco products (i.e., non-flavored and Arctic Blast e-liquids) were evaluated.
Nicotine (s.c.) dose-dependently substituted in mice of both sexes, although females showed less sensitivity and greater variability. By contrast, aerosolized nicotine, regardless of formulation, produced concentration-dependent increases up to maximum of 46–62% nicotine-associated responding. Brain nicotine concentrations for each sex were similar for s.c. 0.75 mg/kg nicotine and 30 mg/ml freebase nicotine.
Mice of both sexes readily acquired s.c. nicotine discrimination, but females showed less sensitivity. Further, all three formulations of aerosolized nicotine produced increases in nicotine-like responding in mice of each sex. However, the maximum magnitude of these increases did not engender a similar degree of substitution as s.c. 0.75 mg/kg nicotine, despite similar brain concentrations of nicotine at 30 mg/ml aerosolized nicotine. Additional research is needed for determination of the reason(s); however, results here demonstrate initial feasibility for examination of the discriminative stimulus effects of vaped drugs such as nicotine.
Comparative study on the effects of cigarette smoke exposure, ethanol consumption and association: Behavioral parameters, apoptosis, glial fibrillary acid protein and S100β immunoreactivity in different regions of the rat hippocampus
2019, Alcohol
Exposure to cigarette smoke and ethanol are proposed to trigger neurotoxicity, apoptosis, and to impair neuronal signaling. However, it is little known how the combination of both might trigger astrogliosis and the morphological changes capable of affecting a differential susceptibility of hippocampal regions to these licit drugs. The present study investigated the chronic effects of exposure to cigarette smoke and/or ethanol on behavioral parameters, apoptosis, and alteration in immunoreactivity of glial fibrillary acid protein (GFAP) and S100β in the CA1, CA3, and dentate gyrus (DG) of the rat hippocampus. Adult male Wistar rats (n = 32) were divided into four groups: vehicle (VE, glucose 3% in water, 10 mL/kg), cigarette smoke (TOB, total 12 cigarettes per day), ethanol (ethanol, 2 g/kg), and cigarette smoke plus ethanol (TOB plus ethanol, total 12 cigarettes per day plus ethanol 2 g/kg) for 54 days. The groups were submitted to tail-flick, open-field, and inhibitory avoidance tasks. The results showed that ethanol per se worsened the short-term memory. The association between TOB and ethanol increased the immunoreactivity of cleaved caspase-3 in the CA3 and DG regions. The TOB plus ethanol group showed a lower immunoreactivity to GFAP in all regions of the hippocampus. In addition, ethanol and TOB per se also reduced the immunoreactivity for GFAP in the DG. Ethanol increased S100β immunoreactivity only in the DG. In conclusion, this study showed that only ethanol worsened short-term memory, and the DG became more susceptible to changes in the markers investigated. This evidence suggests that DG is more sensitive to neurotoxicity induced by cigarette smoke and ethanol.
Morphological changes in the cerebellum as a result of ethanol treatment and cigarette smoke exposure: A study on astrogliosis, apoptosis and Purkinje cells
2018, Neuroscience Letters
The link between Ethanol (EtOH) and tobacco (TOB) has potentially important implications for people involved in alcohol treatment; many alcoholics smoke, putting them at high risk of tobacco-related complications. The present study investigates the effect of chronic exposure to cigarette smoke, EtOH consumption and the combination of both on astrogliosis and apoptosis in the cerebellum of rats. Adult male Wistar rats were divided into 4 groups (8 animals per group): vehicle (glucose 3%, 10 mL/kg, twice a day), EtOH treated (EtOH 2 g/kg, twice a day), exposure to cigarette smoke (TOB, smoke of 6 cigarettes, twice a day) and a combination of EtOH and cigarette smoke (TOB + EtOH, twice a day). The treatment period was 57 days, after which the animals were euthanized, the cerebellum removed and subjected to immunohistochemical studies focusing on glial fibrillary acidic protein (GFAP), cleaved caspase-3, and S100. We also counted the number of Purkinje cells (PC) present following treatment. The combination of both EtOH and TOB exposure induced an increase in GFAP immunoreactivity, whilst TOB alone increased apoptosis in the white matter of the cerebellum. In addition, EtOH consumption reduced the number of PC and TOB tempered this effect. Overall, the present study opens up relevant perspectives for the consequences on human health of the combined use of alcohol and smoking, by demonstrating the biological mechanisms and cerebellar function vulnerabilities to combined use and dependence of licit drugs.

View all citing articles on Scopus

^☆: The work of the authors discussed in this commentary was supported by a grant from the Tobaco and Health Research Institute, Lexington, KY. The authors would also like to thank Dr. John Littleton for his insightful comments regarding this commentary.

View full text

CommentaryContribution of CNS nicotine metabolites to the neuropharmacological effects of nicotine and tobacco smoking☆

Abstract

Pharmacol Biochem Behav

Biochem Pharmacol

Neuropharmacology

Neurosci Lett

Brain Res

Neuropharmacology

Essays Toxicol

Trends Pharmocol Sci

Curr Opin Neurobiol

Curr Opin Neurobiol

Mol Brain Res

J Biol Chem

Neuron

Neuron

FEBS Lett

Life Sci

Pharmocol Biochem Behav

Eur J Pharmacol

Pharmocol Biochem Behav

Pharmacol Biochem Behav

Pharmocol Biochem Behav

Biochem Pharmocol

Brain Res Bull

Neuropharmacology

Eur J Pharmacol

Eur J Pharmacol

Eur J Pharmacol

Eur J Pharmacol

Neuropharmacology

Pharmacol Biochem Behav

Neuropharmacology

Nicotine and smoking: A perspective from animal studies

Psychopharmacology

Euphoriant effects of nicotine in smokers

Psychopharmacology

In vivo pharmacological effects of dihydro-β-erythroidine, a nicotinic antagonist, in mice

Psychopharmacology

Role of training dose in discrimination of nicotine and related compounds by rats

Psychopharmacology

Influencing cigarette smoking with nicotine antagonists

Psychopharmacology

Combined effects of nicotine and mecamylamine in attenuating smoking satisfaction

Exp Clin Psychopharmacol

Blockade of cholinergic channels by chlorisondamine on a crustacean muscle

J Physiol (Lord)

Eldefrawi ME and Albuquerque EX, The acetylcholine receptor of the neuromuscular junction recognizes mecamylamine as a noncompetitive antagonist

Mol Pharmacol

Pharmacological evaluation of the antagonism of nicotine's central effects by mecamylamine and pempidine

J Pharmacol Exp Ther

Nicotine-induced increase in the neuronal nicotinic receptors results from a decrease in the rate of receptor turnover

Mol Pharmacol

[3H]MK801 binding to the N-methyl-d-aspartate receptor reveals drug interactions with the zinc and magnesium binding sites

J Pharmacol Exp Ther

Effects of nicotinic agonists and antagonists on N-methyl-d-aspartate-induced3H-norepinephrine release and 3H-[1-(2-thienyl)cyclohexyl]-piperidine) binding in rat hippocampus

Synapse

Characterization of nicotinic receptor-mediated [3H]dopamine release from synaptosomes prepared from mouse striatum

J Neurochem

Pharmacological profile of nicotinic acetylcholine receptors in rat pre-frontal cortex: An electrophysiological study in a slice preparation

Neuroscience

Initial characterization of the nicotinic acetylcholine receptors in rat hippocampal neurons

J Recept Res

Existence of different subtypes of nicotinic acetylcholine receptors in the rat habenulo-interpeduncular system

J Neurosci

Metabolism of nicotine

Drug Metab Rev

Commentary
Contribution of CNS nicotine metabolites to the neuropharmacological effects of nicotine and tobacco smoking☆

[³H]MK801 binding to the N-methyl-d-aspartate receptor reveals drug interactions with the zinc and magnesium binding sites

Effects of nicotinic agonists and antagonists on $N- methyl - d - aspartate-induced$ ³H-norepinephrine release and ³H-[1-(2-thienyl)cyclohexyl]-piperidine) binding in rat hippocampus

Characterization of nicotinic receptor-mediated [³H]dopamine release from synaptosomes prepared from mouse striatum