Elsevier

Behavioural Brain Research

Volume 185, Issue 2, 28 December 2007, Pages 119-128
Behavioural Brain Research

Research report
The effects of extinction training in reducing the reinstatement of drug-seeking behavior: Involvement of NMDA receptors

https://doi.org/10.1016/j.bbr.2007.08.001Get rights and content

Abstract

Although the process of extinction has been well documented for various forms of behavioral responses, the effects of extinction on the reinstatement of drug-seeking behavior are relatively understudied. In this report, the effectiveness of an extinction training protocol to reduce primed reinstatement responses was compared with the effectiveness of an equivalent period of enforced abstinence. We found that extinction training performed in the drug taking environment significantly reduced reinstatement behavior subsequently primed by either contextual cues, conditioned cues, or cocaine infusion. The ability of extinction to reduce cocaine primed reinstatement was blocked by the systemic administration of the competitive NMDAR antagonist ((±)CPP, 5 mg/kg i.p.) administered prior to each extinction training session. Interestingly, this pharmacological intervention had no impact on the effectiveness of extinction to reduce drug-seeking behavior primed by either contextual cues or conditioned cues. These results suggest that an extinction training experience involves multiple mechanisms that can be dissociated into nonNMDAR and NMDAR dependent components with respect to the type of reinstatement (i.e. context-, conditioned stimuli (CS)-, or drug-induced) being assessed.

Introduction

The reinstatement of drug-seeking behavior in rodents as a model for relapse in humans has taken a prominent position in the preclinical field of addiction research [26]. In this model, exposure to various modes of priming stimuli (e.g. environmental context, conditioned cues, addictive drugs, stressors) following either abstinence or extinction can evoke, or reinstate, instrumental behaviors previously associated with the self-administration of an addictive substance [27]. An extinction training phase is typically incorporated into such protocols, in order to reduce instrumental responding to a low, stable baseline level from which the effectiveness of primed reinstatement can be assessed, although the resumption of drug-seeking behavior evoked by priming can also be assessed following periods of prolonged abstinence [28]. Much effort has been directed toward determining the neural substrates involved in the mechanisms of priming itself induced by various stimuli [24], however surprisingly little information is available concerning the mechanisms underlying the effectiveness of an extinction training experience to reduce instrumental responding following a priming event.

Using other behavioral models, evidence indicates that new learning is occurring during the extinction training experience [4], [20], [21]. This new learning may be dependent upon the activation of n-methyl-d-aspartate receptors (NMDARs), and either blocking NMDARs with antagonists or enhancing NMDAR activity with coagonists would be expected to affect the ability of an extinction training experience to alter the response to primed reinstatement. For example, conditioned fear has been used to demonstrate that NMDAR antagonists administered prior to extinction sessions can significantly inhibit extinction [2], [10], [22], and recent reports have indicated that treatment with d-cycloserine (an NMDAR coagonist) can facilitate extinction of conditioned fear [17], [35]. Together, these findings indicate an involvement of NMDARs in the learning process that occurs during an extinction training experience.

With respect to the various methods employed in previous studies to prime reinstatement of drug-seeking behavior, both diffuse (environmental context; [6]) and discrete (conditioned stimuli (CS); [7], [27]) cues have been evaluated, as well as the administration of the unconditioned stimulus (drug itself; [7], [27]). In addition, stress and anxiety have been suggested to be effective inducers of reinstatement behavior [8], [29]. Interestingly, different neural mechanisms appear to underlie the reinstatement induced by these priming stimuli, and several specific brain regions are involved in some of these events. For example, one early report identified that the basolateral region of the amygdala as being critical for the reinstatement response to conditioned stimuli priming [19]. Subsequently, Grimm and See [13] demonstrated that inactivation of the nucleus accumbens was effective in preventing drug (cocaine) induced drug seeking, but had no effect on CS-induced priming of reinstatement. The opposite relationship was found to exist for inactivation of the basolateral amygdala, as tetrodotoxin infusion did not affect drug primed reinstatement. This study established a basis for multiple, discrete neuronal mechanisms in mediating the primed reinstatement of drug-seeking behavior. Additional work has found that the dorsomedial prefrontal cortex is also involved in CS-induced reinstatement [18], and that inactivation of either the dorsomedial prefrontal cortex, the basolateral amygdala or the dorsal hippocampus can inhibit context induced reinstatement [11].

In this report we have tested the hypothesis that NMDARs may also be involved in the extinction of drug-seeking behavior. The efficacy of extinction was directly compared with the responses measured in another group of abstinent rats that remained in their home cage environments for an equivalent amount of time. The results demonstrate that extinction training is effective in reducing the reinstatement of drug-seeking behavior elicited by noncontingent exposure to contextual cues, conditioned stimuli, or cocaine infusion. Facilitating the activation of NMDARs during extinction training did not significantly affect the subsequent reinstatement, but inhibiting NMDAR activation resulted in the selective blockade of the extinction effects on drug primed reinstatement. These results indicate that diverse mechanisms participate in mediating the effects of extinction training on the expression of reinstatement of drug-seeking behavior.

Section snippets

Animals

Male Sprauge-Dawley rats (Harlan) weighed approximately 300 g at the beginning of the experiment and were housed individually in a temperature and humidity controlled vivarium having a 12-h light:12-h dark cycle (lights off at 7:00 p.m.). They were given access to food and water ad libitum and were handled daily for 5 days prior to the surgery in order to diminish stress associated with handling. The housing and experimental procedures followed the Guide for the Care and Use of Laboratory Animals

Cocaine self-administration and extinction of the drug-seeking behavior

Animals having indwelling jugular catheters were trained to self-administer cocaine in an operant chamber environment for 15 consecutive days. During the daily 90-min sessions, rats were initially trained on an FR-1 schedule for first 12 days and switched to an FR-3 schedule for the last 3 days of self-administration training. The transition to the FR-3 schedule was done to increase the number of active lever-pressing responses. Animals typically achieved stable self-administration by day 10 of

Discussion

In this report we have directly assessed the effectiveness of an extinction training protocol to reduce primed reinstatement as compared with an equivalent period of enforced abstinence. This was a prerequisite step for us in pursuing our intent to investigate the mechanisms underlying the effectiveness of extinction training to reduce reinstatement. We have found that in addition to reducing active lever responding when placed back into the drug paired environment (Fig. 2B), extinction

Acknowledgements

We thank R.E. See for helpful discussion and B.A. Gosnell for critiquing an earlier draft of the manuscript. This work was supported by National Institutes of Health Grant DA016302 to J.J.W.

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