Modeling cue-exposure therapy for alcohol use disorder in rhesus monkeys: Effects of putative cognitive enhancers

• Published in: Drug and alcohol dependence 2023-02, Vol.243, p.109735-109735, Article 109735
• Main Authors: Pareek, Tanya, Overton, John S., Nguyen, Luat T., Rahman, Md. Toufiqur, Sharmin, Dishary, Cook, James M., Platt, Donna M.
• Format: Article
• Language: English
• Subjects: Alcohol; Alcoholism - drug therapy; Alcoholism - psychology; Animals; Cue reactivity; Cue-exposure therapy; Cues; Cycloserine - pharmacology; Cycloserine - therapeutic use; Drug Inverse Agonism; Ethanol - pharmacology; Extinction; Extinction, Psychological; Implosive Therapy; Macaca mulatta; Male; Nootropic Agents - pharmacology; Nootropic Agents - therapeutic use; Rhesus monkey; Self Administration
• ISSN: 0376-8716; 1879-0046
• DOI: 10.1016/j.drugalcdep.2022.109735

Cue-exposure therapy (CET) is an effective approach for anxiety-related disorders, but its effectiveness for substance use disorders is less clear. One potential means of improving CET outcomes is to include a cognitive-enhancing pharmacotherapy. This study evaluated d-cycloserine (DCS) and RY-023, putative cognitive enhancers targeting glutamate and GABA systems, respectively, in a monkey model of CET for alcohol use disorder. Male rhesus monkeys (n = 4) underwent multiple cycles of the CET procedure. During baseline (Phase 1), monkeys self-administered an ethanol solution under a fixed-ratio schedule and limited access conditions such that every 5th response in a 3-h session resulted in 30-s access to a drinking spout and a change in ethanol-paired cue lights from white to red. Behavior then was extinguished (Phase 2) by omitting the ethanol solution yet retaining the ethanol-paired stimulus lights. Monkeys also received injections of vehicle, DCS (3 mg/kg), a partial agonist at the glycine modulatory site on glutamatergic NMDA receptors, or the α5GABAA receptor-selective inverse agonist RY-023 (0.03 or 0.3 mg/kg). Once responding declined, monkeys underwent a cue reactivity test (Phase 3), and then returned to self-administration the following day to assess reacquisition (Phase 4). Through multiple cycles, self-administration remained stable. Compared to vehicle, DCS facilitated extinction of ethanol seeking (Phase 2) and delayed reacquisition of ethanol self-administration (Phase 4). In contrast, RY-023 facilitated extinction (Phase 2) and reduced cue reactivity (Phase 3). Adjunctive pharmacotherapy can improve CET outcomes, but the choice of pharmacotherapy should be dependent on the outcome of interest. •Adjunctive pharmacotherapies may improve outcomes of cue-exposure therapy (CET).•D-cycloserine facilitated extinction and slowed resumption of self-administration.•RY-023 facilitated extinction and attenuated cue reactivity.•Glutamatergic and GABAergic compounds differentially enhance specific CET outcomes.