1. Catalog
  2. Citations
  3. PubMed:28391535

PubMed: 28391535

Title
Discriminative Stimulus Properties of S(-)-Nicotine: "A Drug for All Seasons".
Journal
Current topics in behavioral neurosciences
Volume
39
Issue
None
Pages
51-94
Date
2018-01-01
Authors
Young R | Rosecrans JA

Evidence 82a7292f44
JSON

Lobeline binds with high affinity to α4β2 nAChRs and displays mixed receptor agonist/antagonist actions (e.g., [150–154]).

a(CHEBI:"(-)-lobeline") increases complex(a(CHEBI:"(-)-lobeline"), a(MESH:"nicotinic receptor alpha4beta2")) View Subject | View Object

Appears in Networks:

Evidence 9e30d2705d
JSON

Lobeline has, however, been shown to antagonize partially the stimulus effects of (-)-nicotine and S(+)-methamphetamine ([64, 160]; but see [66]).

a(CHEBI:"(-)-lobeline") decreases act(a(CHEBI:nicotine)) View Subject | View Object

Appears in Networks:

a(CHEBI:"(-)-lobeline") decreases act(a(CHEBI:methamphetamine)) View Subject | View Object

Appears in Networks:

Evidence 128cc91658
JSON

In comparison, S(-)-nicotine was shown to be 7 times more toxic than R(+)-nicotine in rats injected intravenously

a(CHEBI:"(R)-nicotine") increases path(MESH:Death) View Subject | View Object

Appears in Networks:

a(CHEBI:"(S)-nicotine") increases path(MESH:Death) View Subject | View Object

Appears in Networks:

Evidence b63d1d1040
JSON

. It should be noted that hexamethonium, at relatively low doses, does not block the stimulus effects of (-)-nicotine but when administered at high doses has occasionally been reported to attenuate nicotine-like responding; probably the result of penetration into the CNS of a small proportion of the administered dose of drug (e.g., [35, 38, 64, 106, 146])

a(CHEBI:Hexamethonium) negativeCorrelation act(a(CHEBI:nicotine)) View Subject | View Object

Appears in Networks:

act(a(CHEBI:nicotine)) negativeCorrelation a(CHEBI:Hexamethonium) View Subject | View Object

Appears in Networks:

Evidence 49147eee12
JSON

This conclusion is based on the fact that the stimulus effects of nicotine are convincingly blocked by (a) mecamylamine, a voltage dependent noncompetitive channel blocker at nicotinic receptors (Fig. 3; Table 4) and (b) dihydro-β-erythrodine (DHβE), a nicotinic receptor antagonist that shows high affinity for the nAChR α4β2 subunit (Fig. 3; Table 5) but not by methyllycaconitine (MLA), a α7 nicotinic receptor antagonist (Table 5).

a(CHEBI:Mecamylamine) decreases act(a(CHEBI:nicotine)) View Subject | View Object

Appears in Networks:

a(MESH:"Dihydro-beta-Erythroidine") decreases act(a(CHEBI:nicotine)) View Subject | View Object

Appears in Networks:

a(MESH:"Dihydro-beta-Erythroidine") increases complex(a(MESH:"Dihydro-beta-Erythroidine"), a(MESH:"nicotinic receptor alpha4beta2")) View Subject | View Object

Appears in Networks:

a(MESH:"Dihydro-beta-Erythroidine") decreases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

Appears in Networks:

a(PUBCHEM:5288811) causesNoChange act(a(CHEBI:nicotine)) View Subject | View Object

Appears in Networks:

a(PUBCHEM:5288811) decreases act(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

Appears in Networks:

Evidence f025a71181
JSON

Mecamylamine (Inversine®, Vecamyl®; Fig. 3) was developed over 60 years ago and marketed as a ganglionic blocker for the treatment of hypertension (e.g., [127])

a(CHEBI:Mecamylamine) decreases path(MESH:Hypertension) View Subject | View Object

Appears in Networks:

Evidence 9cf4cbb599
JSON

In addition, mecamylamine can produce CNS effects that include tremor, mental confusion, seizures, mania, and depression but the mechanisms by which these effects are produced are unclear

a(CHEBI:Mecamylamine) increases path(MESH:Tremor) View Subject | View Object

Appears in Networks:

a(CHEBI:Mecamylamine) increases path(MESH:Confusion) View Subject | View Object

Appears in Networks:

a(CHEBI:Mecamylamine) increases path(MESH:Seizures) View Subject | View Object

Appears in Networks:

a(CHEBI:Mecamylamine) increases path(MESH:"Bipolar Disorder") View Subject | View Object

Appears in Networks:

a(CHEBI:Mecamylamine) increases path(MESH:Depression) View Subject | View Object

Appears in Networks:

Evidence 9b2ff9d7b3
JSON

Also, mecamylamine is sometimes used as an anti-addictive drug to help people stop smoking tobacco products (e.g.,[128, 129])

a(CHEBI:Mecamylamine) decreases path(MESH:Smoking) View Subject | View Object

Appears in Networks:

Evidence 1602dcf54a
JSON

Biochemical and pharmacological studies have characterized mecamylamine as a nonselective, voltage dependent and noncompetitive receptor antagonist of neuronal nAChRs and it is often referred to as a “nicotine receptor antagonist.”

a(CHEBI:Mecamylamine) decreases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

Appears in Networks:

Evidence 517b5ae271
JSON

For example, some biochemical studies suggest that mecamylamine is a channel blocker that inhibits most neuronal nAChRs (e.g., [131–133]).

a(CHEBI:Mecamylamine) decreases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

Appears in Networks:

Evidence c53dfad111
JSON

The release of epinephrine stimulates the body and causes a sudden release of glucose as well as an increase in blood pressure, respiration, and heart rate

sec(a(CHEBI:adrenaline)) increases sec(a(CHEBI:glucose)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Adrenal Glands

sec(a(CHEBI:adrenaline)) increases path(MESH:"Blood Pressure") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Adrenal Glands

sec(a(CHEBI:adrenaline)) increases bp(GO:"cellular respiration") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Adrenal Glands

sec(a(CHEBI:adrenaline)) increases bp(MESH:"Heart Rate") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Adrenal Glands

Evidence 2edb75b9a3
JSON

Bupropion [a.k.a. amfebutamone, (RS)-2-(tert-Butylamino)-1-(3-chlorophenyl)propan1-one, 3-Chloro tert-butylcathinone, 3-Chloro-N-tert-butyl-β-ketoamphetamine; Fig. 4] is a phenylaminoketone or cathinone derivative that is a weak central nervous system (CNS) stimulant

a(CHEBI:bupropion) increases act(a(MESH:"Central Nervous System")) View Subject | View Object

Appears in Networks:

Evidence 57c2bf04e0
JSON

It is prescribed as medication for the treatment of depression (Wellbutrin®) and/or as an adjunct in smoking cessation therapy (Zyban®).

a(CHEBI:bupropion) decreases path(MESH:Depression) View Subject | View Object

Appears in Networks:

Evidence d4d58950d0
JSON

Other studies have reported that bupropion blocked the acute effects of (-)-nicotine in a number of behavioral assays in mice (e.g., [171, 172])

a(CHEBI:bupropion) decreases act(a(CHEBI:nicotine)) View Subject | View Object

Appears in Networks:

Evidence ab58b0012a
JSON

Moreover, (-)-nicotine (indirectly) can produce a release of dopamine in brain regions that are thought to control pleasure and motivation; dopamine is thought to underlie the pleasurable sensations experienced by smokers (e.g., [14, 15] but see [16]).

a(CHEBI:dopamine) regulates path(MESH:Pleasure) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

a(CHEBI:dopamine) regulates path(MESH:Motivation) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

a(CHEBI:nicotine) increases sec(a(CHEBI:dopamine)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence cc54c9d837
JSON

For example, immediately after exposure to nicotine, there is a “stimulant-kick” caused, in part, by its stimulation of the adrenal glands and resultant discharge of epinephrine (adrenaline)

a(CHEBI:nicotine) increases act(a(MESH:"Adrenal Glands")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Adrenal Glands

a(CHEBI:nicotine) increases sec(a(CHEBI:adrenaline)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Adrenal Glands

Evidence b3be75c966
JSON

Nicotine also suppresses insulin output from the pancreas, which indicates that smokers are usually hyperglycemic (higher blood sugar level)

a(CHEBI:nicotine) decreases sec(a(CHEBI:"insulin (human)")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Pancreas

path(MESH:Smoking) increases a(MESH:"Blood Glucose") View Subject | View Object

Appears in Networks:

Evidence d58f388003
JSON

Centrally, (-)-nicotine has affinity for all brain nAChR subtypes, but binds preferentially and with high affinity to α4β2 nAChRs (e.g., [12, 13])

a(CHEBI:nicotine) increases complex(a(CHEBI:nicotine), a(MESH:"nicotinic receptor alpha4beta2")) View Subject | View Object

Appears in Networks:

Evidence 5a6e69084f
JSON

(-)-Nicotine activates all brain nAChR subtypes, but binds preferentially and with high affinity to α4β2 nAChRs (e.g., [12])

a(CHEBI:nicotine) increases complex(a(CHEBI:nicotine), a(MESH:"nicotinic receptor alpha4beta2")) View Subject | View Object

Appears in Networks:

a(CHEBI:nicotine) increases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

Appears in Networks:

Evidence 6216a3b3e2
JSON

For example, (-)-nicotine may increase dopamine activity at some brain sites such as the nucleus accumbens, an area thought to be important to drugs of abuse (e.g., [14, 101, 102]; but see [16, 103])

a(CHEBI:nicotine) increases act(a(CHEBI:dopamine)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Nucleus Accumbens

Evidence eaea15223a
JSON

For example, in rodents, administration of low doses of nicotine produced increased motor activity whereas high doses produced decreased motor activity (e.g.,[17, 18])

a(CHEBI:nicotine) negativeCorrelation path(MESH:"Motor Activity") View Subject | View Object

Appears in Networks:

path(MESH:"Motor Activity") negativeCorrelation a(CHEBI:nicotine) View Subject | View Object

Appears in Networks:

Evidence fb95c0f34e
JSON

. It is now well established that nicotine binds to nicotinic acetylcholine receptors (nAChRs) at the cellular level and is the prototype drug used to classify nAChRs

a(CHEBI:nicotine) increases complex(a(CHEBI:nicotine), a(MESH:"Receptors, Nicotinic")) View Subject | View Object

Appears in Networks:

Evidence 8aebf8e345
JSON

In antagonism tests, (-)-nicotine failed to block the stimulus effects of mecamylamine

a(CHEBI:nicotine) causesNoChange act(a(CHEBI:Mecamylamine)) View Subject | View Object

Appears in Networks:

Evidence 93bea9a618
JSON

Varenicline (Chantix®; Fig. 4) is prescribed as an adjunct medication in smoking cessation therapy and is thought to exert its effects as a partial agonist at α4β2 nAChRs and as a full agonist at α7 nAChRs [211, 212].

a(CHEBI:varenicline) increases act(a(MESH:"nicotinic receptor alpha4beta2")) View Subject | View Object

Appears in Networks:

a(CHEBI:varenicline) increases act(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

Appears in Networks:

Evidence fb09840ea8
JSON

Research results summarized in Table 5 indicate that DHβE effectively blocked the stimulus effects of (-)-nicotine in rats or mice (but see exceptions reported by [120, 121]).

a(MESH:"Dihydro-beta-Erythroidine") decreases act(a(CHEBI:nicotine)) View Subject | View Object

Appears in Networks:

Evidence daca6e1b8c
JSON

DHβE (Fig. 3) is an alkaloid found in plant seeds of Erythrina and is a competitive nAChR receptor antagonist with a preference for neuronal β2 subtypes

a(MESH:"Dihydro-beta-Erythroidine") decreases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

Appears in Networks:

a(MESH:"Dihydro-beta-Erythroidine") increases complex(a(MESH:"Dihydro-beta-Erythroidine"), p(HGNC:CHRNB2)) View Subject | View Object

Appears in Networks:

Evidence 7a4e4a98f3
JSON

For example, DHβE (at nM concentrations) blocks α4β2 and α3β2 nAChRs but is much less potent at α3β4 and α7 nAChRs expressed in Xenopus oocytes (e.g., [134–137]).

a(MESH:"Dihydro-beta-Erythroidine") decreases act(a(MESH:"nicotinic receptor alpha3beta4")) View Subject | View Object

Appears in Networks:

a(MESH:"Dihydro-beta-Erythroidine") decreases act(a(MESH:"nicotinic receptor alpha3beta2")) View Subject | View Object

Appears in Networks:

a(MESH:"Dihydro-beta-Erythroidine") decreases act(a(MESH:"nicotinic receptor alpha4beta2")) View Subject | View Object

Appears in Networks:

a(MESH:"Dihydro-beta-Erythroidine") decreases act(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

Appears in Networks:

Evidence c0cdf05111
JSON

In the body, nicotine is extensively metabolized and is susceptible to a significant first-pass effect during which 80–90% of it is metabolized by the liver. Also, the lung is able to metabolize nicotine, but to a much lesser degree [78, 79].

a(MESH:Liver) increases bp(GO:"nicotine metabolic process") View Subject | View Object

Appears in Networks:

a(MESH:Lung) increases bp(GO:"nicotine metabolic process") View Subject | View Object

Appears in Networks:

Evidence a942c4d0c7
JSON

Table 5 presents results of MLA/(-)-nicotine combination studies and shows that MLA failed to alter the stimulus effects of (-)-nicotine in rats or mice (but see partial antagonism reported by Quarta et al. [126])

a(PUBCHEM:5288811) causesNoChange act(a(CHEBI:nicotine)) View Subject | View Object

Appears in Networks:

Evidence 43328ce1e9
JSON

Its biochemical pharmacology indicates that it is a relatively potent competitive receptor antagonist that is selective for α7 nAChRs (e.g., [139–141]).

a(PUBCHEM:5288811) decreases act(a(MESH:"alpha7 Nicotinic Acetylcholine Receptor")) View Subject | View Object

Appears in Networks:

Evidence 339e938a36
JSON

In humans, about 70–80% of nicotine is converted to the primary metabolite (-)-cotinine, a lactam derivative (Fig. 2).

bp(GO:"nicotine metabolic process") increases a(CHEBI:"(-)-cotinine") View Subject | View Object

Appears in Networks:

Evidence d9692cf2a3
JSON

Lastly, S(-)-nornicotine is a minor metabolite of nicotine and, as mentioned previously, is considered a minor alkaloid of tobacco (Fig. 2)

bp(GO:"nicotine metabolic process") increases a(CHEBI:nornicotine) View Subject | View Object

Appears in Networks:

Evidence b39c8950d1
JSON

(-)-Nicotine withdrawal symptoms might begin within a few hours after the last nicotine product, and include irritability/anger/stress/anxiety, sleep disturbances, depressed mood, craving, cognitive and attention deficits, and increased appetite.

path(MESH:"Smoking Cessation") increases path(MESH:"Irritable Mood") View Subject | View Object

Appears in Networks:

path(MESH:"Smoking Cessation") increases path(MESH:Anger) View Subject | View Object

Appears in Networks:

path(MESH:"Smoking Cessation") increases path(MESH:"Stress, Psychological") View Subject | View Object

Appears in Networks:

path(MESH:"Smoking Cessation") increases path(MESH:Anxiety) View Subject | View Object

Appears in Networks:

path(MESH:"Smoking Cessation") increases path(MESH:"Sleep Wake Disorders") View Subject | View Object

Appears in Networks:

path(MESH:"Smoking Cessation") increases path(MESH:Depression) View Subject | View Object

Appears in Networks:

path(MESH:"Smoking Cessation") increases path(MESH:Craving) View Subject | View Object

Appears in Networks:

path(MESH:"Smoking Cessation") decreases bp(GO:cognition) View Subject | View Object

Appears in Networks:

path(MESH:"Smoking Cessation") decreases path(MESH:Attention) View Subject | View Object

Appears in Networks:

path(MESH:"Smoking Cessation") increases path(MESH:Appetite) View Subject | View Object

Appears in Networks:

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.