A novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking

Abstract

We recently reported that a conditioned stimulus (CS) memory retrieval-extinction procedure decreases reinstatement of cocaine and heroin seeking in rats and heroin craving in humans. Here we show that non-contingent cocaine or methylphenidate injections (UCS retrieval) 1 h before the extinction sessions decreases cocaine-priming-induced reinstatement, spontaneous recovery, and renewal of cocaine seeking in rats. Unlike the CS-based memory retrieval-extinction procedure, the UCS memory retrieval manipulation decreases renewal and reinstatement of cocaine seeking in the presence of cocaine cues that were not present during extinction training and also decreases cocaine seeking when the procedure commences after 28 days of abstinence. The inhibitory effect of the UCS retrieval manipulation on cocaine-priming-induced reinstatement is mediated by regulation of AMPA-receptor endocytosis in the basolateral amygdala. The UCS memory retrieval-extinction procedure has superior relapse prevention characteristics than the CS memory retrieval-extinction procedure and could be a promising method for decreasing relapse in human addicts.

Counterconditioning During Reconsolidation Prevents Relapse of Cocaine Memories

“…Recently, it has been demonstrated in several addictionrelated procedures that conducting extinction training following a brief memory retrieval session prevents relapse to drugs seeking (Luo et al, 2015;Ma et al, 2012;Millan et al, 2013;Sartor and Aston-Jones, 2014;Xue et al, 2012). Based on previous similar studies in fear conditioning procedures (eg, Liu et al, 2014;Monfils et al, 2009), it has been postulated that extinction training performed within the 'reconsolidation window' leads to incorporation of the new information (cue-nothing association) into the original cuereinforcement memory trace (eg, cue-drug) (Millan et al, 2013;Monfils et al, 2009;Sartor and Aston-Jones, 2014;Xue et al, 2012), rather than creating a competing memory as in regular extinction (Bouton, 2002;Milton and Everitt, 2012).…”

“…Based on previous similar studies in fear conditioning procedures (eg, Liu et al, 2014;Monfils et al, 2009), it has been postulated that extinction training performed within the 'reconsolidation window' leads to incorporation of the new information (cue-nothing association) into the original cuereinforcement memory trace (eg, cue-drug) (Millan et al, 2013;Monfils et al, 2009;Sartor and Aston-Jones, 2014;Xue et al, 2012), rather than creating a competing memory as in regular extinction (Bouton, 2002;Milton and Everitt, 2012). However, several studies on fear memories showed that postretrieval extinction did not always prevent reinstatement of fear behavior (Chan et al, 2010;Costanzi et al, 2011;Ishii et al, 2015;Soeter and Kindt, 2011), and studies on drug relapse showed attenuation, but not always prevention of relapse to drug seeking (Luo et al, 2015;Xue et al, 2012). Comparative studies have indicated that counterconditioning may have a stronger suppressive effect on relapse of memories, compared with extinction (Tunstall et al, 2012;Van Gucht et al, 2010).…”

Selective Inhibition of Amygdala Neuronal Ensembles Encoding Nicotine-Associated Memories Inhibits Nicotine Preference and Relapse

“…We recently hypothesized (22,23) that a potential reason for the limited translational utility of the classical CS-induced retrieval and reconsolidation interference procedure is that the neuropharmacological manipulations interfere only with reconsolidation of memories selectively associated with the reactivated CS without affecting memories associated with other CSs or the UCS (the drug) itself. In the case of nicotine addiction, smoking is associated with multiple CSs that vary across individuals (24).…”

“…Based on these considerations and results from threat (fear) conditioning studies showing that interference with memory reconsolidation after memory retrieval by the UCS (aversive shock) prevents subsequent threat conditioning induced by multiple CSs (25–27), we recently developed a UCS-induced memory retrieval–reconsolidation interference procedure and demonstrated its efficacy in decreasing cocaine relapse and craving in rat models (22). However, a limitation of the procedure we introduced in Luo et al .…”

“…However, a limitation of the procedure we introduced in Luo et al . (22), which is based on the memory retrieval–extinction memory reconsolidation procedure (28), is that it requires multiple exposures to the UCS (cocaine priming) and subsequent time-locked extinction training (22). Based on this procedural limitation, we recently developed a simpler UCS-induced memory retrieval–reconsolidation interference procedure in which UCS-induced memory reactivation occurs only once in a nondrug context (23).…”