Cognitive enhancers for facilitating drug cue extinction: insights from animal models

Abstract

Given the success of cue exposure (extinction) therapy combined with a cognitive enhancer for reducing anxiety, it is anticipated that this approach will prove more efficacious than exposure therapy alone in preventing relapse in individuals with substance use disorders. Several factors may undermine the efficacy of exposure therapy for substance use disorders, but we suspect that neurocognitive impairments associated with chronic drug use are an important contributing factor. Numerous insights on these issues are gained from research using animal models of addiction. In this review, the relationship between brain sites whose learning, memory and executive functions are impaired by chronic drug use and brain sites that are important for effective drug cue extinction learning is explored first. This is followed by an overview of animal research showing improved treatment outcome for drug addiction (e.g. alcohol, amphetamine, cocaine, heroin) when explicit extinction training is conducted in combination with acute dosing of a cognitive-enhancing drug. The mechanism by which cognitive enhancers are thought to exert their benefits is by facilitating consolidation of drug cue extinction memory after activation of glutamatergic receptors. Based on the encouraging work in animals, factors that may be important for the treatment of drug addiction are considered.

Figure 1. Decrease in active lever responses from day 1 to day 2 of extinction training during acquisition of cocaine cue extinction learning

Rats were trained to self-administer 1.0 mg/kg cocaine under an FI 5 min (FR5:S) second-order schedule before undergoing two 1 hr extinction training sessions on consecutive days for which cocaine delivery was suspended, but the cocaine-paired discrete light cue was presented upon completion of each FR5. Rats received infusion of vehicle or lidocaine into the rBLA of both hemispheres (bilateral rBLA/rBLA); infusion of vehicle or lidocaine into the DH of both hemispheres (bilateral DH/DH); infusion of vehicle or lidocaine into the DH of one hemisphere and the rBLA of the contralateral hemisphere (asymmetric DH/rBLA); infusion of vehicle or lidocaine into the DH of one hemisphere with infusion of only vehicle into the contralateral rBLA (unilateral DH/rBLA); infusion of vehicle or lidocaine into the rBLA of one hemisphere with infusion of only vehicle into the contralateral DH (unilateral rBLA/DH); infusion of vehicle or lidocaine into the DH and rBLA of the same hemisphere (ipsilateral DH/rBLA). n=4–8 rats per treatment group. * p<0.05 compared to the corresponding vehicle/vehicle (V/V) control treatment. The figure is adapted from Table 1, reported in Szalay et al. in press.

Figure 2. Cocaine cue extinction and reacquisition of cocaine self-administration after treatment with CDPPB

Rats were trained to self-administer 0.3 mg/kg cocaine under an FI 5 min (FR5:S) second-order schedule paired with a 2-sec light cue before undergoing three 1 hour weekly extinction training sessions. Lever responses were extinguished by substituting saline for cocaine delivery while maintaining response contingent presentation of the cocaine-paired discrete light cue upon completion of each FR5. Rats received i.p. injections of either 0 mg/kg (n=6) or 10 mg/kg CDPPB (n=6) 15 min prior to the weekly extinction (a) or self-administration sessions (b). Reacquisition of cocaine self-administration began 7 days after the last extinction or self-administration session (c and d, respectively) under conditions identical to self-administration training. Values are the mean ± SEM percent of baseline lever responses (last five cocaine self-administration sessions). * p<0.03 compared to the vehicle control.

Figure 3. Time course of drug cue extinction

Rats were trained to self-administer 0.3 mg/kg cocaine (n=8) or passively receive yoked saline (n=4) under an FR5 schedule before undergoing a single 2 hr extinction training session for which cocaine delivery was suspended, but the cocaine-paired discrete light cue was presented upon completion of each FR5. The number of active lever responses during the extinction session was divided into 30 min bins. * p<0.05 compared to the corresponding saline control.