Xie2-64, a novel CB2 receptor inverse agonist, reduces cocaine abuse-related behaviors in rodents

Copyright © 2020 Elsevier Ltd. All rights reserved..

Cocaine abuse remains a public health threat around the world. There are no pharmacological treatments approved for cocaine use disorder. Cannabis has received growing attention as a treatment for many conditions, including addiction. Most cannabis-based medication development has focused on cannabinoid CB1 receptor (CB1R) antagonists (and also inverse agonists) such as rimonabant, but clinical trials with rimonabant have failed due to its significant side-effects. Here we sought to determine whether a novel and selective CB2R inverse agonist, Xie2-64, has similar therapeutic potential for cocaine use disorder. Computational modeling indicated that Xie2-64 binds to CB2R in a way similar to SR144528, another well-characterized but less selective CB2R antagonist/inverse agonist, suggesting that Xie2-64 may also have CB2R antagonist profiles. Unexpectedly, systemic administration of Xie2-64 or SR144528 dose-dependently inhibited intravenous cocaine self-administration and shifted cocaine dose-response curves downward in rats and wild-type, but not in CB2R-knockout, mice. Xie2-64 also dose-dependently attenuated cocaine-enhanced brain-stimulation reward maintained by optical stimulation of ventral tegmental area dopamine (DA) neurons in DAT-Cre mice, while Xie2-64 or SR144528 alone inhibited optical brain-stimulation reward. In vivo microdialysis revealed that systemic or local administration of Xie2-64 into the nucleus accumbens reduced extracellular dopamine levels in a dose-dependent manner in rats. Together, these results suggest that Xie2-64 has significant anti-cocaine reward effects likely through a dopamine-dependent mechanism, and therefore, deserves further study as a new pharmacotherapy for cocaine use disorder.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:176

Enthalten in:

Neuropharmacology - 176(2020) vom: 01. Okt., Seite 108241

Sprache:

Englisch

Beteiligte Personen:

Jordan, Chloe J [VerfasserIn]
Feng, Zhi-Wei [VerfasserIn]
Galaj, Ewa [VerfasserIn]
Bi, Guo-Hua [VerfasserIn]
Xue, Ying [VerfasserIn]
Liang, Ying [VerfasserIn]
McGuire, Terence [VerfasserIn]
Xie, Xiang-Qun [VerfasserIn]
Xi, Zheng-Xiong [VerfasserIn]

Links:

Volltext

Themen:

Benzene Derivatives
CB(2) receptor
Cannabinoid
Cannabinoid Receptor Agonists
Cannabinoid Receptor Antagonists
Cocaine
Dopamine
Dopamine Uptake Inhibitors
I5Y540LHVR
Journal Article
Optogenetics
Receptor, Cannabinoid, CB2
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Self-administration
Sulfonamides
Xie2-64

Anmerkungen:

Date Completed 13.08.2021

Date Revised 02.10.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.neuropharm.2020.108241

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM312882106