The effects of varied extinction procedures on contingent cue-induced reinstatement in Sprague-Dawley rats

Abstract

Rationale Cue exposure therapy, which attempts to limit relapse by reducing reactivity to cocaine-paired cues through repeated exposures, has had limited success. Objectives The current experiments examined cocaine cue-induced anxiogenesis, and investigated whether a model of cue-exposure therapy would reduce reinstatement of cocaine seeking in rats with a history of cocaine self-administration. Methods Male rats experienced daily intravenous cocaine self-administration. Rats then experienced exposure to either the self-administration context or the context plus noncontingent presentations of cocaine-paired cues. Immediately following exposure, anxiety-like behavior was measured using elevated plus maze and defensive burying tests. In a second group of rats, self-administration was followed by seven days of exposure to the context, context + noncontingent cue exposure, lever extinction, or cue + lever extinction. All animals then underwent two contingent cue-induced reinstatement tests separated by 7 days of lever extinction. Results Exposure to noncontingent cocaine-paired cues in the self-administration context increased anxiety-like behavior on the defensive burying test. Animals that experienced lever + cue extinction displayed the least cocaine seeking on the first reinstatement test, and lever extinction reduced cocaine seeking below context exposure or context + noncontingent cue exposure. All animals had similar levels of cocaine seeking on the second reinstatement test. Conclusions Noncontingent cue exposure causes anxiety, and noncontingent cue and context exposure are less effective at reducing contingent cue-induced reinstatement than lever or lever + cue extinction. These data indicate that active extinction of the drug-taking response may be critical for reduction of relapse proclivity in former cocaine users.

Extinction of a cocaine-taking context that protects against drug-primed reinstatement is dependent on the metabotropic glutamate 5 receptor

“…This may be due to the absence of any discrete cue paired with cocaine self‐administration, because a beneficial effect of context extinction was not found in a study that utilized discrete cues (Buffalari et al . ). Consistent with this idea, Holland () proposed that the drug‐taking context indirectly acts as an ‘occasion setter’ in situations where associations with drug taking are ambiguous.…”

“…Interestingly, Pearce & Hall () demonstrated that two exposure sessions to the context previously associated with food self‐administration were enough to significantly reduce food‐seeking behavior in the absence of any instrumental extinction. However, this effect was not replicated when cocaine was used as the reward (Buffalari, Feltenstein & See ). A critical difference between the two studies is that during the self‐administration sessions, no discrete cues were presented contingently upon lever pressing in the former, whereas lever pressing was paired with a light + tone compound cue in the latter.…”

Recent developments in the behavioural and pharmacological enhancement of extinction of drug seeking

“…In contrast, Buffalari et al . () showed greater cue‐induced reinstatement in rats exposed to context extinction than to lever extinction. Differences may arise in the involvement of context or lever extinction between these two studies because of the use of different reinstatement paradigms (cue versus cocaine primed), particularly when Kim et al .…”

“…Extinction of both a cocaine‐paired lever and cocaine cues in rats reduces cue‐induced reinstatement, compared with the lever or context alone (Feltenstein & See ; Buffalari et al . ). In addition, Torregrossa et al .…”

Outcome specificity in deepened extinction may limit treatment feasibility: Co-presentation of a food cue interferes with extinction of cue-elicited cocaine seeking

“…Likewise, while some studies have found that interspersing extinction trials within a retrieval-reconsolidation window enhanced the extinction of cue-elicited drug seeking (Xue et al, 2012), others have found increased drug seeking (Millan et al, 2013). Thoroughly testing cue-targeted treatments and optimizing procedural parameters within pre-clinical models (e.g., as in Buffalari et al, 2013) will be essential for maximizing the benefits, and minimizing potential risks, of such treatments before they are used in humans.…”