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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.

SUBMITTER: Dunbar AB

PROVIDER: S-EPMC5520782 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Dunbar Amber B AB Taylor Jane R JR

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20170207 9

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 ...[more]

PMID: 28169286

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Project description:RATIONALE:Environmental stimuli, or cues, associated with the use of drugs such as cocaine are one of the primary drivers of relapse. Thus, identifying mechanisms to reduce the motivational properties of drug cues is an important research goal. OBJECTIVES:The purpose of this study was to identify cellular signaling events in the nucleus accumbens (NAc) that are induced when a cocaine cue memory is either extinguished through repeated cue presentation in the absence of drug, or when the memory is reactivated and reconsolidated by a brief cue re-exposure. Signaling events specific to extinction or reconsolidation represent potential targets for pharmacotherapeutics that may enhance extinction or disrupt reconsolidation to reduce the likelihood of relapse. METHODS:Male Sprague-Dawley rats were trained to self-administer cocaine paired with an audiovisual cue. Following a period of self-administration, the memory for the cocaine-associated cue was either extinguished, reactivated, or not manipulated (control) 15 min before sacrifice. Tissue from the NAc was subsequently analyzed using mass spectrometry based phosphoproteomics to identify cellular signaling events induced by each condition. RESULTS:Extinction and reconsolidation of the cocaine cue memory produced both common and distinct changes in protein phosphorylation. Notably, there were no significant changes in protein phosphorylation that were modulated in the opposite direction by the two behavioral conditions. Comparison of NAc phosphoproteomic changes to previously identified changes in the basolateral amygdala (BLA) revealed that cue extinction increases phosphorylation at serine (S) 883 of the GABAB receptor subunit 2 and on S14 of syntaxin 1a in both regions, while no common regional signaling events were identified in the reconsolidation group. CONCLUSIONS:Phosphoproteomics is a useful tool for identifying signaling cascades involved in different memory processes and revealed novel potential targets for selectively targeting extinction versus reconsolidation of a cocaine cue memory. Furthermore, cross region analysis suggests that cue extinction may produce unique signaling events associated with increased inhibitory signaling.

Dataset Information

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

Publications

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

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