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.
Highlights
One commonality among substance use disorders is the tendency to relapse to drug-seeking behaviors that is a major detrimental factor for long-term abstinence
In our first experiment we examined whether the intra-LA infusion of garcinol impairs the reconsolidation of a cocaineassociated memory following either memory reactivation or in no reactivation controls
We found that post-reactivation intra-LA garcinol decreased active lever pressing during the reinstatement test when compared to vehicle controls [p < 0.05]; no differences were observed between groups on the last day of extinction
Summary
One commonality among substance use disorders is the tendency to relapse to drug-seeking behaviors that is a major detrimental factor for long-term abstinence. Administration of a histone deacetylase (HDAC) inhibition in the LA following memory reactivation enhances reconsolidation of an auditory fear memory, while use of a HAT inhibitor, like the amnestic agent garcinol, impairs memory reconsolidation (Maddox et al, 2013a,b). These epigenetic mechanisms are thought to play an important role in the reconsolidation of auditory fear memories, yet little is known about their involvement in the reconsolidation of appetitive memories and drug-associated memories in particular. We explore the effect of the HAT inhibitor garcinol, on reconsolidation of cocaine-associated cue memories
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