Predictive validity of the extinction/reinstatement model of drug craving

Abstract

The effects of chronic desmethylimipramine (DMI) treatment on measures of incentive motivation for cocaine were assessed in order to investigate the predictive validity of the extinction/reinstatement model of drug craving. Rats were trained to respond for cocaine infusions (0.75 mg/kg per 0.1 ml i.v.) or received yoked-saline infusions during daily 3-h sessions. A light and tone were presented with the infusions. Following self-administration training, each group received daily injections of either saline or DMI (10 mg/kg, i.p.) for 21 days of withdrawal from the self-administration regimen. On days 12-21 of withdrawal, rats were allowed to respond in the absence of cocaine reinforcement (extinction phase). After reaching an extinction criterion of no responses for 1 h, the cocaine-paired stimuli were repeatedly presented to reinstate responding (reinstatement phase). In the control group, DMI treatment did not alter responding during either test phase, but increased the response latency during the extinction phase. In contrast, DMI treatment in the cocaine group decreased responding and increased the response latency during both test phases, and decreased the extinction latency during the extinction phase. Overall, the effects of DMI were consistent with a reduction of incentive motivation for cocaine, lending support for the predictive validity of the extinction/reinstatement model of drug craving.

Enduring Resistance to Extinction of Cocaine-Seeking Behavior Induced by Drug-Related Cues

“…Consistent with a role of conditioning factors in the resumption of drug abuse habits, several studies in animals have demonstrated that drug-associated stimuli can elicit a transient recovery of extinguished responding at a lever previously associated with cocaine selfadministration (e.g., deWit and Stewart 1981; Fuchs et al 1998). However, little information is available, to date, about the persistence of cue-induced drug-seeking behavior.…”

“…A wealth of clinical studies point towards drug-related stimuli or events as a critical factor in the long-lasting compulsion to abuse drugs. This literature suggests that environmental stimuli repeatedly paired with the subjective actions of cocaine throughout an individual's history of drug abuse can produce intense drug craving (Childress et al 1988;Ehrman et al 1992;Kilgus and Pumariega 1994;Robbins et al 1997;Satel et al 1995;Wallace 1989) or elicit automatic behavioral responses (Miller and Gold 1994;Tiffany and Carter 1998) that may lead to relapse.Consistent with a role of conditioning factors in the resumption of drug abuse habits, several studies in animals have demonstrated that drug-associated stimuli can elicit a transient recovery of extinguished responding at a lever previously associated with cocaine selfadministration (e.g., deWit and Stewart 1981;Fuchs et al 1998). However, little information is available, to date, about the persistence of cue-induced drug-seeking behavior.…”

Novel Cues Reinstate Cocaine-Seeking Behavior and Induce Fos Protein Expression as Effectively as Conditioned Cues

“…Further evidence supporting the construct validity of the model are that neuroimaging studies in human addicts and examination of immediate early gene (IEG) expression in animals that reveal the same brain regions are activated by cocaine-paired cues (Childress et al, 1999;Garavan et al, 2000;Grant et al, 1996;Kufahl et al, 2009;Wang et al, 1999;Zavala et al, 2008). In addition, compounds found to decrease self-reports of craving in humans have been shown to attenuate cue-elicited drug-seeking behavior in animals (Fuchs et al, 1998;Yahyavi-FirouzAbadi and See, 2009), demonstrating predictive validity and overall utility of the cue reinstatement model. Fos protein expression is an established method for identifying brain circuits associated with cocaine-induced conditioning effects (Brown et al, 1992;Crawford et al, 1995;Neisewander et al, 2000).…”

Cue-Induced Cocaine Seeking and Relapse Are Reduced by Disruption of Drug Memory Reconsolidation

“…Such drug-associated stimuli evoke memories of the effects of the drug, induce craving in abstinent addicts, and precipitate relapse to a drug-taking habit (Gawin and Kleber, 1986;O'Brien et al, 1998;Childress et al, 1999). In experimental animals, a conditioned stimulus (CS) paired repeatedly with the self-administration of cocaine similarly induces relapse to, or reinstatement of, drug seeking (de Wit and Stewart, 1981;Meil and See, 1996;Fuchs et al, 1998;Grimm et al, 2001), while also supporting prolonged periods of cocaine seeking, for example under second-order schedules of reinforcement (Arroyo et al, 1998;. Through association with the effects of cocaine, the CS acquires powerful conditioned reinforcing and other properties that are not easily diminished by nonreinforced presentations of the CS (Di Ciano and Everitt, 2004), and this may explain why cue exposure therapy in a clinical setting has not generally been a successful treatment strategy for drug addiction (Conklin and Tiffany, 2002).…”