Compound Stimulus Presentation and the Norepinephrine Reuptake Inhibitor Atomoxetine Enhance Long-Term Extinction of Cocaine-Seeking Behavior

Abstract

Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002;O'Brien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drugpredictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies.

Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments

“…However, our results are consistent with prior findings in outbred rats showing that acute administration of methylphenidate did not alter cocaine seeking under a second-order schedule (Economidou et al, 2011). Notably, in outbred rats, NET plays an important role in regulating saliency of drug-associated cues (Economidou et al, 2011; Janak et al, 2012), and therefore be a critical regulator of cue reactivity in SHR.…”

The ontogeny of learned inhibition

“…In contrast, rats are able to learn the negative occasion setting task within 2 wk, well within the timeframe of even the most conservative definitions of adolescence. In addition, negative occasion setting has particular relevance for understanding the role of contextual cues in regulating the emission or omission of behavioral responses (e.g., extinction) (Bouton 1997), which has direct implications for drug seeking and addiction-related behavior (Bouton et al 1990;Conklin and Tiffany 2002;Janak et al 2012), both of which are prevalent during adolescence.…”

A comparison of therapies for the treatment of drug cues: Counterconditioning vs. extinction in male rats.

“…Very recent drug-cue extinction research suggests ways that this might be accomplished. For example, two studies (Janak, Bowers, & Corbit, 2012; Kearns, Tunstall, & Weiss, 2012) have found that applying a deepened extinction treatment – where the targeted cue is extinguished in compound with another drug cue – significantly enhances the effects of extinction by weakening the cue-drug association to a greater extent than standard extinction. Another recent study has shown that retrieving the cue-drug association (by briefly presenting the cue) during a sensitive window prior to an extinction session can virtually eliminate traces of the association (Xue et al, 2012).…”