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Principal Investigator: Jane R Taylor
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $330,750
Funding agency: National Institute on Drug Abuse
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.
Terms: <Anisomycin><Behavior><Behavior Control><Behavioral><Behavioral Manipulation><Cell Communication and Signaling><Cell Signaling><Chronic><Cocaine><Cocaine Addiction><Cocaine Dependence><Common Rat Strains><Corpus Striatum><Corpus striatum structure><Cue-induced relapse><Cues><DA Neuron><Data><Development><Disease><Disorder><Dopamine><Dopamine neuron><Dose><Drug Therapy><Drug usage><Drugs><Expectancy><Exposure to><Female><Histone Acetylase><Human><Hydroxytyramine><Intracellular Communication and Signaling><Learning><Measures><Medication><Memory><Mesencephalon><Methods><Mid-brain><Midbrain><Midbrain structure><Modeling><Modern Man><Nerve Cells><Nerve Unit><Neural Cell><Neurobiology><Neurocyte><Neurons><Outcome><Pharmaceutical Preparations><Pharmacotherapy><Population><Predisposition><Preventative strategy><Prevention strategy><Preventive strategy><Process><Protein Synthesis Antagonists><Protein Synthesis Inhibitors><Publishing><Rat><Rats Mammals><Rattus><Relapse><Research><Retrieval><Role><Signal Transduction><Signal Transduction Systems><Signaling><Stimulus><Striate Body><Striatum><Susceptibility><Techniques><Therapeutic><Time><addicted to cocaine><addiction><addiction to cocaine><addictive disorder><attenuation><behavioral control><biological signal transduction><camboginol><cocaine addicted><cocaine cue><cocaine relapse><cocaine self-administration><craving><design><designing><developmental><dopaminergic neuron><drug abstinence><drug seeking behavior><drug treatment><drug use><drug/agent><expectation><experience><experiment><experimental research><experimental study><experiments><garcinol><histone acetyltransferase><inhibitor><innovate><innovation><innovative><male><memory retrieval><neural><neurobiological><neuronal><new approaches><novel><novel approaches><novel strategies><novel strategy><optogenetics><pharmacologic><prevent><prevent relapse><preventing><relapse against cocaine><relapse prevention><self-administer cocaine><social role><striatal><therapeutic target><tool><translational study>