Potentiation of (α4)2(β2)3, but not (α4)3(β2)2, nicotinic acetylcholine receptors reduces nicotine self-administration and withdrawal symptoms.
Allosteric Regulation
Animals
Behavior, Animal
/ drug effects
Hydrocarbons, Brominated
/ pharmacology
Indole Alkaloids
/ pharmacology
Isoxazoles
/ pharmacology
Mice
Nicotine
/ administration & dosage
Nicotinic Agonists
/ administration & dosage
Protein Isoforms
Pyrazoles
/ pharmacology
Receptors, Nicotinic
/ drug effects
Self Administration
Substance Withdrawal Syndrome
/ etiology
Tobacco Use Disorder
/ metabolism
Acute thermal nociception
Nicotine self-administration
Nicotine withdrawal symptoms
Nicotine-induced hypothermia
Nicotinic acetylcholine receptors
Positive allosteric modulators
Journal
Neuropharmacology
ISSN: 1873-7064
Titre abrégé: Neuropharmacology
Pays: England
ID NLM: 0236217
Informations de publication
Date de publication:
01 06 2021
01 06 2021
Historique:
received:
21
12
2020
revised:
28
02
2021
accepted:
10
04
2021
pubmed:
21
4
2021
medline:
12
1
2022
entrez:
20
4
2021
Statut:
ppublish
Résumé
The low sensitivity (α4)3(β2)2 (LS) and high sensitivity (α4)2(β2)3 (HS) nAChR isoforms may contribute to a variety of brain functions, pathophysiological processes, and pharmacological effects associated with nicotine use. In this study, we examined the contributions of the LS and HS α4β2 nAChR isoforms in nicotine self-administration, withdrawal symptoms, antinociceptive and hypothermic effects. We utilized two nAChR positive allosteric modulators (PAMs): desformylflustrabromine (dFBr), a PAM of both the LS and HS α4β2 nAChRs, and CMPI, a PAM selective for the LS nAChR. We found that dFBr, but not CMPI, decreased intravenous nicotine self-administration in male mice in a dose-dependent manner. Unlike dFBr, which fully reverses somatic and affective symptoms of nicotine withdrawal, CMPI at doses up to 15 mg/kg in male mice only partially reduced nicotine withdrawal-induced somatic signs, anxiety-like behavior and sucrose preference, but had no effects on nicotine withdrawal-induced hyperalgesia. These results indicate that potentiation of HS α4β2 nAChRs is necessary to modulate nicotine's reinforcing properties that underlie nicotine intake and to reverse nicotine withdrawal symptoms that influence nicotine abstinence. In contrast, both dFBr and CMPI enhanced nicotine's hypothermic effect and reduced nicotine's antinociceptive effects in male mice. Therefore, these results indicate a more prevalent role of HS α4β2 nAChR isoforms in mediating various behavioral effects associated with nicotine, whereas the LS α4β2 nAChR isoform has a limited role in mediating body temperature and nociceptive responses. These findings will facilitate the development of more selective, efficacious, and safe nAChR-based therapeutics for nicotine addiction treatment.
Identifiants
pubmed: 33878302
pii: S0028-3908(21)00122-2
doi: 10.1016/j.neuropharm.2021.108568
pmc: PMC8169606
mid: NIHMS1695162
pii:
doi:
Substances chimiques
3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)isoxazole
0
Hydrocarbons, Brominated
0
Indole Alkaloids
0
Isoxazoles
0
Nicotinic Agonists
0
Protein Isoforms
0
Pyrazoles
0
Receptors, Nicotinic
0
desformylflustrabromine
0
nicotinic acetylcholine receptor alpha4 subunit
0
nicotinic receptor beta2
0
Nicotine
6M3C89ZY6R
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
108568Subventions
Organisme : NIDA NIH HHS
ID : DP1 DA039658
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA032246
Pays : United States
Organisme : NIGMS NIH HHS
ID : R25 GM090084
Pays : United States
Organisme : NIDA NIH HHS
ID : U01 DA045299
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.
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