Addictive disorders are a huge burden on both the individual and on society. Unfortunately, there are few effective treatments, partially due to the persistence of drug-associated memories that drive craving and relapse. Therefore, recent research has focused on finding ways to reduce the strength of drug-associated memories to prevent relapse. Memory strength can be reduced by either disrupting the association between a cue and a drug via extinction or by inhibiting the reconsolidation of the memory after a reminder event. Both strategies have been effective in preclinical and clinical models, but in some cases, a memory meant to be weakened, is instead strengthened due to unintentional enhancement of reconsolidation or inhibition of extinction. In order to address this problem, we have analyzed changes in protein phosphorylation after a memory undergoes extinction vs. reconsolidation to identify signaling cascades that are selective to either memory process, or that ideally regulate the two processes in opposite directions. Identification of opposing signaling events could allow the development of treatments that both enhance extinction and inhibit reconsolidation, reducing the strength of the drug-associated memories that drive relapse. Our preliminary data strongly suggest that opposing Ca2+-related signaling events in the basolateral amygdala (BLA) mediate the reconsolidation vs. extinction of a memory associated with self-administered cocaine. We will expand our identification of opposing signaling events in Aim 1 of the proposed studies, including increasing the number of proteins analyzed, expansion of the time course of analysis, and extending the analysis to females. Moreover, we will follow-up on the exciting findings from our initial study, which include 1) identification of a novel phosphorylation event on Ca2+ -calmodulin-dependent kinase 2 alpha (CaMKII?, phospho-serine 331) induced by extinction and reduced during reconsolidation that functions to inhibit kinase activity, and 2) a general decrease in protein phosphorylation after extinction, implicating activation of a phosphatase, such as calcineurin. Our data led us to hypothesize that extinction training, in addition to involving new learning mechanisms, can also oppose normal reconsolidation processes. We propose that this occurs within the same circuits via Ca2+-regulated synaptic depotentiation mechanisms. Extinction-induced synaptic depotentiation and differences in CaMKII and calcineurin signaling have been reported for conditioned fear memories, but have not been examined for cocaine-associated memories. Thus, using a combination of approaches in Aims 2 & 3, we will determine if CaMKII? inhibition via S331 phosphorylation, and activation of calcineurin phosphatase, can reduce cocaine memory strength to decrease cue-induced reinstatement via enhancement of extinction AND inhibition of reconsolidation. We will also determine if these signaling pathways directly regulate each other and synaptic strength in the same or different pathways. Determination of the mechanisms regulating cocaine memories will lead to novel targets for relapse prevention treatment development.

Public Health Relevance

The proposed project aims to determine the molecular and physiological mechanisms underlying the maintenance of cocaine-associated memories. We will specifically explore the role of Ca2+-related signaling events in the opposing regulation of memory reconsolidation vs. extinction. Identifying the mechanisms underlying whether a cocaine memory is stabilized during reconsolidation or is weakened by extinction training will help researchers develop novel ways to treat addiction through the prevention of relapse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA042029-02S1
Application #
9408065
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Satterlee, John S
Project Start
2016-07-01
Project End
2021-04-30
Budget Start
2017-07-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Torregrossa, Mary M; MacDonald, Matthew; Stone, Kathryn L et al. (2018) Phosphoproteomic analysis of cocaine memory extinction and reconsolidation in the nucleus accumbens. Psychopharmacology (Berl) :
Logan, Ryan W; Hasler, Brant P; Forbes, Erika E et al. (2018) Impact of Sleep and Circadian Rhythms on Addiction Vulnerability in Adolescents. Biol Psychiatry 83:987-996
Bertholomey, Megan L; Torregrossa, Mary M (2017) Gonadal hormones affect alcohol drinking, but not cue+yohimbine-induced alcohol seeking, in male and female rats. Physiol Behav :