Garcinol Blocks the Reconsolidation of Multiple Cocaine-Paired Cues after a Single Cocaine-Reactivation Session

Abstract

Manipulations of memory reconsolidation can interfere with the ability of a drug-paired cue to drive drug-seeking behavior. However, the typical reconsolidation paradigm that reactivates the memory through the presentation of the cue (conditioned stimulus (CS)) only interferes with the memory of the reactivated CS while leaving other drug-paired CSs intact and able to continue driving drug-seeking behavior. Here, we used a novel unconditioned-stimulus (US) reactivation paradigm to interfere with the ability of multiple cues to drive drug-seeking behavior after just one reactivation and treatment session. Rats were trained to self-administer cocaine, during which time each active lever press resulted in an i.v. cocaine infusion paired with one of two cues that alternated within each session. The drug memory was later reactivated with either i.v. or i.p. cocaine presentation in the absence of any cue. The histone acetyltransferase (HAT) inhibitor garcinol or vehicle was injected following US reactivation to impair reconsolidation. Rats were later tested on cue-induced reinstatement to both cues. Garcinol administered after either i.v. or i.p. cocaine reactivation significantly decreased cue-induced reinstatement to both cues, indicative of reconsolidation impairment. In addition, garcinol administered in the absence of reconsolidation or at a 6 h delay when the memory should be restabilized had no effect on reinstatement, further suggesting that garcinol's effects on reinstatement are through reconsolidation-based mechanisms. Our results demonstrate that a US-reactivation paradigm may be preferable to traditional CS-reactivation paradigms for treating disorders that involve multiple CS-US associations and support investigations of garcinol as a therapeutic pharmacological agent.

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

“…Together, the results from the current study and other studies (22,23,29) support the idea that UCS memory retrieval–reconsolidation interference procedures have superior relapse-prevention characteristics compared with the classical CS memory retrieval–reconsolidation interference procedures.…”

“…We showed that in rats our procedure prevented both nicotine preference and nicotine relapse after both short and prolonged abstinence and that in humans the procedure prevented craving induced by diverse smoking-associated CSs (23). Dunbar and Taylor also recently reported that a drug named garcinol blocks the reconsolidation of multiple cocaine-paired cues after UCS reactivation (29). …”

Reconsolidation and psychopathology: Moving towards reconsolidation-based treatments

“…For example, a single US-reactivation session followed by pharmacological treatment in a rodent model of cocaine self-administration blocks cue-induced reinstatement to multiple CSs paired with the drug (Dunbar and Taylor Under Review). The pharmacological agent used was garcinol, a naturally-occurring histone acetyltransferase inhibitor that can safely be given to humans and also blocks reconsolidation after CS reactivation (Monsey et al 2016; Maddox et al 2013).…”

“…Based on preclinical studies of drug memories, the pharmacological approach may be more advantageous as compared to retrieval-extinction, as it requires only one short treatment session (Dunbar and Taylor Under Review; Luo et al 2015). Developing an effective clinical treatment that requires fewer sessions and less time will increase patient retention, decrease costs, and improve treatment outcomes.…”

“…Developing an effective clinical treatment that requires fewer sessions and less time will increase patient retention, decrease costs, and improve treatment outcomes. An exciting candidate to examine for the pharmacological approach is garcinol, which can be given safely to humans and which blocks reconsolidation in rodents (Dunbar and Taylor Under Review; Maddox et al 2013; Monsey et al 2016). …”