Abstract

Dopaminergicneuronsoriginatingfromtheventraltegmentalarea(VTA)regulateavarietyofrewardanddrug- relatedbehaviors.However,upto20%ofVTAneuronsareGABAergicinterneurons,and~5%areGABA projectionneurons(GPNs)thatsendprojectionstoseveralbrainregionsinvolvedindrugreward,includingthe nucleusaccumbens(NAc).RecentlytheroleofVTAGABAneuronsandGPNsinreinforcementhasbeen exploredusingtransgenicmicethatallowforselectivemanipulationofVTAGABAneurons.However,therole oftheseGABAergicneuronsindrug-relatedbehaviorsismuchlessunderstood.Weproposetouseanovel combinatorialadeno-associatedviral(AAV)vectorsystemtotargetgeneexpressiontoeitherVTAGABA neuronsorVTA?NAccoreGPNsinwildtyperatsthathavebeentrainedtoself-administercocaine.The targetedGABAneuronswillexpressDREADDs(designerreceptorsexclusivelyactivatedbydesignerdrugs) whichwillallowustoselectivelystimulatetheseneuronalsubtypesduringextinctionofcocaineself- administration,andreinstatementofcocaine-seekingbehavior,aratmodelofrelapse.Wehypothesizethat VTAGABAneuronswillenhancerespondingduringextinctionlearningandcocaine-andcue-induced reinstatementbydisruptinglearnedcue-rewardassociations.Furthermore,webelievethatVTA?NAccore GPNactivationwillselectivelyenhancecue-inducedreinstatement,buthavelittleinfluenceoncocaine-induced reinstatementorextinction.
In aim1 ofthisproposal,wewilldeterminetheroleofVTAGABAneuronsin extinctionlearningandreinstatementofcocaine-seeking.Wewillalsoundertakeapilotstudyinfemaleratsto determineifsexdifferencesexist.
In aim2 wewillselectivelytargettheVTAGPNsprojectingtotheNAccore. Bycontrastingtheseresultsofaim1and2,wewilldetermineiftheVTA?NAccoreGPNeffectsdiffer substantiallyfromstimulatingallVTAGABAneurons,andwhetherthesespecificprojectionsalonemayserve asapotentialtargetfortherapeuticintervention.TheseexperimentswillestablishtheroleofVTAGABA neuronsindrug-seekingbehaviors,andwillprovidethenecessarygroundworkforfutureexplorationintothe mechanismsunderlyingVTAGABAneuroneffectsonrespondingtodrugcuesandtheprocessesunderlying relapse.

Public Health Relevance

Relapseisapersistentproblemfacingcocaineaddicts?amorethoroughunderstandingofthebrainsystems responsibleforrelapseisneededinordertodevelopnewtherapeuticstrategies.Thisprojectexaminesthe roleofGABAergicneuronsinthebrain?sventraltegmentalarea(VTA)inaratmodelofrelapse,usinganovel combinatorialviralvectorsystemtoselectivelydeliverDREADDs(designerreceptorsexclusivelyactivatedby designerdrugs)toVTAGABAneurons,orasubsetofGABAneuronsthatprojecttothenucleusaccumbens core.DREADDactivationofVTAGABAneurons,willdeterminewhetherVTAGABAisinvolvedinregulating thebehavioralresponsestococaine-associatedcues,thusestablishingitasapotentialefficacioustargetfor treatingcocainecravingsandrelapseincocaineaddicts.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA043190-02
Application #
9552131
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Sorensen, Roger
Project Start
2017-09-01
Project End
2019-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
State University of New York at Buffalo
Department
Pharmacology
Type
Schools of Medicine
DUNS #
038633251
City
Amherst
State
NY
Country
United States
Zip Code
14228

  Publications

Bernosky-Smith, Kimberly A; Qiu, Yan-Yan; Feja, Malte et al. (2018) Ventral tegmental area D2 receptor knockdown enhances choice impulsivity in a delay-discounting task in rats. Behav Brain Res 341:129-134