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.
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.
