Dataset Information

Regulation of Garcinol on Histone Acetylation in the Amygdala and on the Reconsolidation of a Cocaine-Associated Memory.

ABSTRACT: Exposure to drug-related cues often disrupts abstinence from cocaine use by triggering memories of drug effects, leading to craving and possible relapse. One prospective method of treatment is weakening cocaine-associated memories via impairment of memory reconsolidation. Previous experiments have shown that systemic injection of the amnestic agent garcinol impairs the reconsolidation of cocaine-cue memories in a temporally constrained, cue-specific, and persistent manner. Here, we investigated garcinol's effect on cocaine-cue memory reconsolidation when administered to the lateral nucleus of the amygdala (LA), as well as its epigenetic activity following systemic garcinol administration and also when given in conjunction with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor. Rats received 12 days of cocaine self-administration training during which time an active lever press resulted in an i.v. cocaine infusion that was concurrently paired with the presentation of a light/tone cue. After 8 days of lever extinction, rats received a memory reactivation session followed by a cue-induced reinstatement test. Intra-LA garcinol following memory reactivation significantly impaired reconsolidation only if the memory was reactivated. Additional studies revealed a significant reduction in histone H3 K27 acetylation and reduced expression of the immediate-early genes Arc and Egr-1 in the LA. When administered alone, TSA enhanced the reinstatement of a cocaine-cue memory, an effect that was prevented when garcinol was concurrently administered. These data indicate the LA is a key structure responsive to garcinol, suggest that one of garcinol's mechanisms of action is through the reduction of memory-related gene expression in the LA, implicate changes in histone acetylation in memory reconsolidation, and support garcinol as a potential therapeutic tool for sustaining abstinence.

SUBMITTER: Monsey MS

PROVIDER: S-EPMC6961612 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Regulation of Garcinol on Histone Acetylation in the Amygdala and on the Reconsolidation of a Cocaine-Associated Memory.

Monsey Melissa S MS Ruiz Sonia G SG Taylor Jane R JR

Frontiers in behavioral neuroscience 20200108

Exposure to drug-related cues often disrupts abstinence from cocaine use by triggering memories of drug effects, leading to craving and possible relapse. One prospective method of treatment is weakening cocaine-associated memories <i>via</i> impairment of memory reconsolidation. Previous experiments have shown that systemic injection of the amnestic agent garcinol impairs the reconsolidation of cocaine-cue memories in a temporally constrained, cue-specific, and persistent manner. Here, we invest ...[more]

PMID: 31998092

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Project description:Environmental stimuli elicit drug craving and relapse in cocaine users by triggering the retrieval of strong cocainerelated contextual memories. Retrieval can also destabilize drug memories, requiring reconsolidation, a protein synthesis-dependent storage process, to maintain memory strength. Corticotropin-releasing factor (CRF) signaling in the basolateral amygdala (BLA) is necessary for cocainememory reconsolidation. We have hypothesized that a critical source of CRF in the BLA is the dorsal raphe nucleus (DR) based on its neurochemistry, anatomical connectivity, and requisite involvement in cocaine-memory reconsolidation. To test this hypothesis, male and female Sprague-Dawley rats received adeno-associated viruses to express Gi-coupled designer receptors exclusively activated by designer drugs (DREADDs) selectively in CRF neurons of the DR and injection cannulae directed at the BLA. The rats were trained to self-administer cocaine in a distinct environmental context then received extinction training in a different context. They were then briefly reexposed to the cocaine-predictive context to destabilize (reactivate) cocaine memories. Intra-BLA infusions of the DREADD agonist deschloroclozapine (DCZ; 0.1 mM, 0.5 μL/hemisphere) after memory reactivation attenuated cocaine-memory strength, relative to vehicle infusion. This was indicated by a selective, DCZ-induced and memory reactivation-dependent decrease in drug-seeking behavior in the cocaine-predictive context in DREADD-expressing males and females at test compared to respective controls. Notably, BLA-projecting DR CRF neurons that exhibited increased c-Fos expression during memory reconsolidation co-expressed glutamatergic and serotonergic neuronal markers. Together, these findings suggest that the DRCRF → BLA circuit is engaged to maintain cocaine-memory strength after memory destabilization, and this phenomenon may be mediated by DR CRF, glutamate, and/or serotonin release in the BLA.

Project description:Re-exposure to a cocaine-associated context triggers craving and relapse through the retrieval of salient context-drug memories. Upon retrieval, context-drug memories become labile and temporarily sensitive to modification before they are reconsolidated into long-term memory stores. The effects of systemic cannabinoid type 1 receptor (CB1R) antagonism indicate that CB1R signaling is necessary for cocaine-memory reconsolidation and associated glutamatergic plasticity in the basolateral amygdala (BLA); however, the contribution of BLA CB1R signaling to cocaine-memory reconsolidation is unknown. Here, we assessed whether intra-BLA CB1R manipulations immediately after cocaine-memory retrieval alter cocaine-memory strength indexed by subsequent drug context-induced cocaine-seeking behavior in an instrumental rodent model of drug relapse. Administration of the CB1R antagonist, AM251 (0.3 µg/hemisphere) into the BLA increased subsequent drug context-induced cocaine-seeking behavior in a memory retrieval-dependent and anatomically selective manner. Conversely, the CB1R agonist, WIN55,212-2 (0.5 or 5 µg/hemisphere) failed to alter this behavior. In follow-up experiments, cocaine-memory retrieval elicited robust hypothalamic-pituitary-adrenal axis activation, as indicated by a rise in serum corticosterone concentrations. Intra-BLA AM251 administration during memory reconsolidation selectively increased this cocaine-memory retrieval-induced corticosterone response. Intra-BLA corticosterone administration (3 or 10 ng/hemisphere) during memory reconsolidation did not augment subsequent cocaine-seeking behavior, suggesting that CB1R-dependent effects of corticosterone on memory strength, if any, are mediated outside of the BLA. Together, these findings suggest that CB1R signaling in the BLA gates cocaine-memory strength, possibly by diminishing the impact of cue-induced arousal on the integrity of the reconsolidating memory trace or on the efficacy of the memory reconsolidation process.

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

Regulation of Garcinol on Histone Acetylation in the Amygdala and on the Reconsolidation of a Cocaine-Associated Memory.

Publications

Regulation of Garcinol on Histone Acetylation in the Amygdala and on the Reconsolidation of a Cocaine-Associated Memory.

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