Memory Destabilization and Cocaine-Cue Induced Reinstatement in Rat

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Drug-associated conditioned stimuli (CS), or cues, contribute to both the progression and persistence of addiction. We hypothesize, as have others, that blocking reconsolidation of cocaine-cue memories could prevent cue-induced relapse. Reconsolidation is a process whereby reactivation of a memory renders it labile and vulnerable to disruption. Our published data, and that of others, confirm that limbic-striatal dopamine (DA)- dependent and several plasticity-regulated signaling mechanisms are involved in cocaine-cue reconsolidation processes. In this new proposal we hypothesize that violation of cocaine-cue expectancy renders a memory labile by triggering memory destabilization, thereby making cocaine-cue memories more sensitive to subsequent disruption by amnestic agents. The ability to induce the destabilization of cocaine-cue memories may be a key factor in enabling the use of targeted pharmacotherapies to block cocaine-cue memory reconsolidation and treat maladaptive memories. We propose to investigate directly the role of expectancy in reconsolidation of cocaine-cue memories and their impact on subsequent relapse-like behaviors by varying the difference between what is expected and experienced during reactivation and by photo stimulation of midbrain DA-containing VTA neurons to neutralize or induce prediction error (PE)-like signals. In Aim 1 we will reactivate cocaine memories by violating expectations of a) US (i.e., cocaine) magnitude and b) CS-US temporal contiguity. These manipulations should generate PE-like signals at the time of memory retrieval. According to our hypothesis and preliminary data, both positive and negative PE-like signals should induce destabilization and make the cue memory susceptible to blockade (i.e., reconsolidation) by an amnestic agent to reduce subsequent relapse to drug-seeking behavior. Relapse-like behaviors will include cue-induced and drug-primed reinstatement, and other measures, in male and female rats subjected to weeks of long-access cocaine self-administration. Select agents that potently and selectively alter memory reconsolidation processes – the protein-synthesis inhibitor anisomycin (ANI) and the histone acetyltransferase (HAT) inhibitor garcinol – will be used to render the destabilized memory subject to amnestic blockade. In Aim 2 we will optogenetic-based photostimulation of midbrain VTA DA neurons (TH-Cre+ rats) during cocaine-cue memory reactivation a) to artificially produce a dip or b) a spike in DA signaling, to artificially act as a negative or positive PE-like signal, respectively, to destabilize the cue memory and render it susceptible to amnestic blockade, ultimately reducing measures of cocaine relapse-like behaviors. Together these studies will define novel behavioral conditions whereby destabilization mechanisms can be used to make memories more susceptible to amnestic agents, to block reconsolidation of cocaine-cue memories, to reduce relapse-like behaviors, and to inspire the development of innovative therapeutic strategies for maladaptive memories.