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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 α5GABAThrough 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. |
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