ADX106772, an mGlu2 receptor positive allosteric modulator, selectively attenuates oxycodone taking and seeking.

Autor: Illenberger JM; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: jillenberger@scripps.edu., Flores-Ramirez FJ; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Matzeu A; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Lütjens R; Addex Therapeutics, Geneva, Switzerland., Martin-Fardon R; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2023 Nov 01; Vol. 238, pp. 109666. Date of Electronic Publication: 2023 Jul 16.
DOI: 10.1016/j.neuropharm.2023.109666
Abstrakt: Opioid abuse and overdose have risen to epidemic proportions in the United States. Oxycodone is the most abused prescription opioid. Treatments for opioid use disorder (OUD) seek to reduce vulnerability to relapse by reducing sources of reinforcement to seek drug (i.e., acute drug effects or drug withdrawal/craving). Accumulating evidence that glutamate release elicits drug-seeking behaviors has generated interest in pharmacotherapies targeting the glutamate system. Agonists and positive allosteric modulators of the metabotropic glutamate 2 (mGlu2) receptor decrease glutamate activity, reducing drug taking and seeking. The present study tested whether the mGlu2 receptor positive allosteric modulator ADX106772 reduces oxycodone self-administration and the conditioned reinstatement of oxycodone seeking without affecting behaviors directed toward a highly palatable nondrug reinforcer (sweetened condensed milk). Male Wistar rats were trained to self-administer oxycodone (0.15 mg/kg/infusion, i.v., 12 h/day) or sweetened condensed milk (SCM; diluted 2:1 v/v in H 2 O, orally, 30 min/day) for 13 days in the presence of a contextual/discriminative stimulus (S D ), and the ability of ADX106772 (0, 0.3, 1, 3 and-10 mg/kg, s. c.) to decrease self-administration was tested. The rats then underwent extinction training, during which oxycodone, SCM, and the S D were withheld. After extinction, the ability of ADX106772 to prevent S D -induced conditioned reinstatement of oxycodone and SCM seeking was tested. ADX106772 reduced oxycodone self-administration and conditioned reinstatement without affecting SCM self-administration or conditioned reinstatement. ADX106772 reduced oxycodone taking and seeking and did not affect the motivation for the palatable conventional reinforcer, SCM, suggesting that activating mGlu2 receptors with a positive allosteric modulator is a potential approach for prescription OUD treatment.
Competing Interests: Declaration of competing interest None
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: