α4β2 Nicotinic receptor desensitizing compounds can decrease self-administration of cocaine and methamphetamine in rats.

Published

Journal Article

Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a selective α4β2 nicotinic receptor desensitizing agent and partial agonist. Sazetidine-A has been shown in our previous studies to significantly reduce nicotine and alcohol self-administration in rats. The question arises whether sazetidine-A would reduce self-administration of other addictive drugs as well. Nicotinic receptors on the dopaminergic neurons in the ventral tegmental area play an important role in controlling the activity of these neurons and release of dopamine in the nucleus accumbens, which is critical mechanism for reinforcing value of drugs of abuse. Previously, we showed that the nonspecific nicotinic antagonist mecamylamine significantly reduces cocaine self-administration in rats. In this study, we acutely administered systemically sazetidine-A and two other selective α4β2 nicotinic receptor-desensitizing agents, VMY-2-95 and YL-2-203, to young adult female Sprague-Dawley rats and determined their effects on IV self-administration of cocaine and methamphetamine. Cocaine self-administration was significantly reduced by 0.3 mg/kg of sazetidine-A. In another set of rats, sazetidine-A (3 mg/kg) significantly reduced methamphetamine self-administration. VMY-2-95 significantly reduced both cocaine and methamphetamine self-administration with threshold effective doses of 3 and 0.3 mg/kg, respectively. In contrast, YL-2-203 did not significantly reduce cocaine self-administration at the same dose range and actually significantly increased cocaine self-administration at the 1 mg/kg dose. YL-2-203 (3 mg/kg) did significantly decrease methamphetamine self-administration. Sazetidine-A and VMY-2-95 are promising candidates to develop as new treatments to help addicts successfully overcome a variety of addictions including tobacco, alcohol as well as the stimulant drugs cocaine and methamphetamine.

Full Text

Duke Authors

Cited Authors

  • Levin, ED; Rezvani, AH; Wells, C; Slade, S; Yenugonda, VM; Liu, Y; Brown, ML; Xiao, Y; Kellar, KJ

Published Date

  • February 15, 2019

Published In

Volume / Issue

  • 845 /

Start / End Page

  • 1 - 7

PubMed ID

  • 30529197

Pubmed Central ID

  • 30529197

Electronic International Standard Serial Number (EISSN)

  • 1879-0712

Digital Object Identifier (DOI)

  • 10.1016/j.ejphar.2018.12.010

Language

  • eng

Conference Location

  • Netherlands