Therearenopharmacotherapiesforstimulantabuse,includingmethamphetamine(METH)andrelapserates arehigh.Relapsetriggeredbyremindersofdruguseisaparticularchallengetoprevent,astheunderlying memoriesexertapowerfulmotivationalinfluenceoverbehaviorandrepresentalifelongrelapseriskfactor. Learningissupportedbystructuralplasticityindendriticspines,drivenbytraining-inducedactinpolymer- ization.Memorystabilityissubsequentlyachievedbyarrestingactindynamics,stabilizingthecytoskeleton.As aresult,memoryisimpervioustoactindepolymerizationwithinminutesoflearning.However,priorworkinthe labdiscoveredthattheactincytoskeletonsupportingMETHmemoriesremainsuniquelydynamicinthe amygdalalongaftertraining.Thisenablesselective,retrieval-independentdisruptionofMETH-associated memoriesanddrugseekingwithasingleadministrationofanactindepolymerizer.Becauseactin?scritical rolesinthebodylimititstherapeuticpotential,focusshiftedtononmusclemyosinII(NMII),adirectdriverof learning-stimulatedactinpolymerizationinspines.TheeffectofNMIIinhibitionisspecifictotheamygdalaand METH.Indeed,NMIIinhibitionhasnoeffectonMETHmemorieswhenotherregionsofthedrug-memory neuralcircuitaretargetedandthereisnosimilarretrieval-independenteffectonmemoriesforfear,food rewardorotherdrugsofabuse,includingopioids.GeneticandpharmacologictargetingofNMIIestablishedit isaviabletherapeutictargetandanNIH-fundedmedicationdevelopmentprojectforaclinicallysafeNMII inhibitorisunderway(UH3NS096833).However,fundamentalknowledgeneededtounderstandandfurther leveragethisspecificityislacking.Thiswillbeaddressedthroughthecentralhypothesisinthisnewproject: thatMETH-associatedmemoriesareuniquelysupportedintheamygdalabyNMII,leavingthosememories selectivelyvulnerabletodisruptionlongafterlearning,evenwhenotherassociativelearningisintroduced.The focusofthisapplicationistwo-fold:(1)Thekeymechanisticquestionregardingthespecificrequirementof theamgydala,actin-NMIIandMETHforselectivememorystoragedisruptionwillbeaddressed.Forthis,the impactofMETH-relatedneuromodulators(Aim1),aswellasNMIIphosphorylationandinteractingpartners (Aim2)willbestudiedonNMII-dependentBLAsynapticactindynamicsandMETH-associatedmemory,witha focusonfactorsthatareuniquetoMETHandtheBLA.Onceidentified,themechanism(s)responsiblecould beharnessedtorenderrelapse-inducingmemoriesforotherdrugsofabusevulnerabletodisruption.(2) BecausemostindividualswithMETHusedisorderusemultiplesubstances,includingopioids,itisnecessary todeterminetheimpactofpolydrugadministrationonMETHmemorysusceptibilitytoNMIIinhibition. PreliminarydataindicatethatMETHconferssusceptibilitytopreviouslyimperviousopioidassociations. Technicallyinnovativeapproacheswillbeemployedthroughouttheproject,spanningfromsinglesynapse manipulationsinlivetissueslicestomemory-basedself-administrationstudies.

Public Health Relevance

The public health relevance of the proposed research is two-fold: (1) The work is expected to identify novel therapeutictargetsforthepreventionofsubstanceabuserelapsetriggeredbydrug-associatedmemorythatmay also be applicable to other forms of aberrant amygdala-dependent memory, such as post-traumatic stress disorder. (2) This work is further expected to profoundly impact our fundamental understanding of the mechanisms governing amygdala plasticity. Taken together, this will significantly contribute to the missions of bothNIDAandNIMH.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA049544-02
Application #
10071155
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Satterlee, John S
Project Start
2019-12-15
Project End
2024-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458