Abstract

Twinstudiessuggestthatapproximately50%ofthevulnerabilitytococaineusedisorderisdeterminedby geneticfactors,butgenome-wideassociationstudies(GWAS)inhumanshaveonlybeguntoidentifyspecific genesthatconferthisrisk.Onemajorimpedimenttostudiesofcocaineusedisorderisthecomplexityofthe phenotypeandthelackofcontrolofenvironmentalvariables.Weproposeacomplementaryapproachthat leveragesamultidisciplinary,highlycollaborativeconsortiumthatcombinesnext-generationsequencingwith state-of-the-artbehavioralscreeninginaunique,geneticallydiverse,nonhumananimalmodel.Theprimary goalofthisproposalistoidentifygenevariantsthatareassociatedwithincreasedvulnerabilitytocompulsive cocaineusebyperformingaGWASinN/NIHheterogeneousstockrats.Wewillusethemostrelevantanimal modelofcocaineusedisorder(i.e.,escalationofintravenouscocaineself-administration)andhighly standardizedmeasuresofcontrolledandcompulsivecocaineself-administration.Toincreasetheimpactof thesefindingsandfacilitatetranslationalandbasicresearchstudiesonthemechanismsunderlyingcompulsive cocaineuse,wewillalsoestablishadata/tissuerepository(CocaineBioBank.org)frombehaviorallyand geneticallycharacterizedanimalsthatwillallowresearcherstofurtherinvestigatethecellularandmolecular mechanismsunderlyingcompulsivecocaineuseandidentifythebiologicalchangesassociatedwiththe expressionofspecificgenevariants.Thisprojectislikelytohaveasustainedandpowerfulimpactonthefield becauseitwill(1)characterizethetransitionfromcontrolledtocompulsivecocaineuseinmaleandfemale outbredrats,(2)identifygenesassociatedwithcompulsivecocaineuse,(3)createtheCocainBioBankwhich willprovidefreeaccesstobrain,kidney,liver,spleen,ovary,testis,adrenal,andbloodsampleswithavariety oftissuepreservationprotocolsthatwillallowthegenerationofinducedpluripotentstemcellsaswellas neuroanatomical,molecular,biochemical,andpharmacologicalstudiesonbehaviorally/genetically characterizedanimals.

Public Health Relevance

Thisisamultidisciplinary,highlycollaborativeconsortiumthatcombinesnext-generationsequencingwith state-of-the-artbehavioralscreeninginaunique,geneticallydiverse,nonhumananimalmodel.Thegoalsof thisconsortiumaretoidentifygenevariantsthatareassociatedwithcompulsivecocaineintakeusinggenome- wideassociationstudies(GWAS)inbehaviorallycharacterizedheterogeneousstockrats,andtoestablisha data/tissuerepository(CocaineBioBank.org)accessibletoallresearcherstostudythecellularandmolecular mechanismsofcocaineaddiction.Resultsfromthesestudieshavethepotentialtohaveasustainedand powerfulimpactonthefieldofaddictionbecausetheywillidentifynoveldruggabletargets,providea comprehensiveanalysisofcompulsivecocaineuseinmalesandfemales,andcreateauniquedata/tissue repositorythatwillfacilitatefollow-upandreplicationstudies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DA043799-05
Application #
9873956
Study Section
Special Emphasis Panel (ZDA1)
Program Officer
Lossie, Amy C
Project Start
2017-04-01
Project End
2022-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
University of California, San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Kononoff, Jenni; Melas, Philippe A; Kallupi, Marsida et al. (2018) Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood. Sci Rep 8:13893
George, Olivier; Koob, George F (2017) Individual differences in the neuropsychopathology of addiction. Dialogues Clin Neurosci 19:217-229
George, Olivier; Hope, Bruce T (2017) Cortical and amygdalar neuronal ensembles in alcohol seeking, drinking and withdrawal. Neuropharmacology 122:107-114