Table Of Content^
^^ •^wtS' ^yf^
a
101^^ f^^i^> /i0i/^ \f/^e^y^ xf 11^^^1//'i f\/f^^y\ f\^^
., -^ -
,.^ ,^ •..
% ^'
^. ^>^^
V V V V
V
*o. .^^ ^O^ .^^^ .^"^ .^"^ .<i>^ .^^
^' SoTy "^^/'i^*
%
,™. ^. .^ .»,^ .# .«., %. ,# ..,^ %. ,# .nrc %, .#" «»r,„ %. ,
^lS=y« •3^1 f^'j
1/ ./- ^
.•^
n
NATIONAL INST!^'
NIH LIB;
4
BLDGIO, 10CENTEROft
BETHESDA, MD 20892-1150
DEPARTMENTOFHEALTHANDHUMANSERVICES-PUBLICHEALTHSERVICE PROJECTN'JMBER
NOTICEOFINTRAMURALRESEARCH PROJECT
Z01 DA00001-10 BPGS
PERIODCOVERED
October1 1993 to September30 1994
TITLEOFPROJECT
ControlofBehaviorbyDrug Injection
PRINCIPALINVESTIGATOR
PI StevenGoldberg, Ph.D. Chief Preclinical Pharmacology Laboratory
ChristineSannerud, Ph.D. Sr. StaffFellow Preclinical Pharmacology Laboratory
CharlesSchindier, Ph.D. Research Psychologist Preclinical PharmacologyLaboratory
CharlesSchuster, Ph.D. SeniorScientist Officeofthe Director
Stephen Heishman, Ph.D. Research Psychologist Clinical Pharmacology Branch
JosePrada Research Psychologist Preclinical PharmacologyLaboratory
COOPERATINGUNITS
LAB/BRANCH
PreclinicalPharmacologyLaboratory
SECTION
Behavioral Pharmacology
INSTITUTEANDLOCATION
National Instituteon DrugAbuse,Addiction ResearchCenter, Baltimore, MD 21224
TOTALSTAFFYEARS: PROFESSIONAL:
4.5 2 25
CHECKAPPROPRIATEBOXES
n
d(A)Human LJ (b)HumanTissue (c)Neither
(a1)Minors
LJ (a2)Interviews
SUMMARYOFWORK
Drugsserveaspositivereinforcerstomaintain andstrengthen behaviorleadingtotheiradministration and
cancontrol behaviorthroughtheirabilitytofunction asdiscriminativestimuli. In manysituations, drugsof
abusefunctionthrough phanmacological and behavioral mechanismstopersistentlysustain longsequences
ofdrugseeking behaviorthatareveryresistanttoextinction. These longsequencesofdrug-seeking
behavior can beanalyzed using schedule-controlled performancesinthesamewayasoperantbehavior
maintained byothereventssuch asfood orshock. Using avarietyofintravenousself-administration
procedures in ratsand primates, ongoing experimentsare being conductedto evaluate behaviormaintained
bydrugsandtheabilityofpharmacologicaltreatments, (i.e., antagonistadministration orthedevelopmentof
dependence) and/orbehavioral manipulationsto modifydrug self-administration behaviorand/orfood-
maintained behavior. Thesestudieswill compare responding maintained underfixed-ratio, fixed interval and
complexsecond-orderschedules, byvariousdrugsincluding cocaine, nicotineand otherpsychomotor
stimulants, benzodiazepinesandothersedative/anxiolytics, morphineand otheropioidsanddelta-9THC (the
active ingredientofmarijuana). Forexample, sinceserotonergicmechanismsappearto underiie
psychomotorstimulantaction, recentstudiesevaluatedtheeffectsofsertraline, aselectiveserotonergic
uptakeinhibitorthatiseffectiveasan antidepressant, onthe reinforcing effectsofi.v. nicotine insquirrel
monkeys. Inadditiontodifferencesinthe pharmacological efficacyofdrugstocontrol ormodifybehavior, it
isclearthatbehavioral andenvironmentalfactorsplayan importantroleinthecontrolthateven highly
efficaciousdrugsexerton behavior. Thefocusofexperimentsintherhesusself-administration labareto
studythepharmacological, behavioral, andenvironmentalvariablesinvolved in initiating and maintaining
drugself-administration. Recentstudiesassessed ratesofacquisition ofcocaineself-injection in rhesus
monkeysfounda relationshipwith behavioral history, butnotactivitylevel. Additionalstudiesareevaluating
theeffectsofserotonergicantagonistsondelta-amphetamineself-injection and noradrenergicantagonists
and uptakeinhibitorson cocaineself-injection. In anotherstudy,weareevaluatingthereinforcing efficacyof
thestereoisomersofl-deprenyl (selegiline) incomparisonto methamphetamineand itsl-stereoisomer, as
wellasevaluatingtheabilityofdeprenyl pretreatmenttoalterself-administrationofcocaine,
methamphetamineorbeta-phenylethylamine
PHS6040(Rev.5/92)
PUBLICATIONS
Goldberg SR, YasarS. Behavioral pharmacologyofselegiline (l-deorenvl) and its metabolitesand interactions
with E-phenylethylamine, Progressin Brain Research: in press.
Goldberg SR, Youdim MBH. Clinical and preclinical experiencewith l-deprenyi (selegiline)with regardto abuse
liability, Clinical PharmacologyandTherapeutics 1994; in press.
WingerG, YasarS, NegusSS, Goldberg SR. Intravenousself-administration studieswith l-deprenyl (selegiline)
in monkeys. Clinical PharmacologyandTherapeutics 1994; in press.
YasarSY, BergmanJ. Amphetamine-likeeffectofl-deprenyl in drug discrimination studies. Clinical
PharmacologyandTherapeutics 1994; in press.
Sannerud CA,AtorNA, GriffithsRR. Behavioral pharmacologyofabecamil in baboons. In: StephensDN, ed.
AnxiolyticS-carboiines: from molecularbiologytotheclinic. PsychopharmacologySeries II. Berlin: Springer-
Verlag, 1993;113-20.
MumfordGK, Evans, SM, Kaminski BJ, Preston KL, Sannerud CA, Silverman,K, GriffithsRR. Discriminative
stimulusandsubjectiveeffectsoftheobromineand caffeine in humans, Psychopharmacology 1994;115:1-8.
SannerudCA, Kaminski BJ, GriffithsRR. MaintenanceofHI antagonistsself-injection in baboons,
Experimental and Clinical Psychopharmacology 1994; in press.
SannerudCA, Kaminski BJ, GriffithsRR. Self-injectionofphenethylamine"designerdrugs" in baboons.
Behavioral Pharmacology 1994; in press.
DEPARTMENTOFHEALTHANDHUMANSERVICES-PUBLICHEALTHSERVICE PROJECTNUMBER
NOTICEOFINTRAMURALRESEARCH PROJECT
Z01 DA00002-09CDM
PERIODCOVERED
October1 1993 to September30 1994
TITLEOFPROJECT
ValidityStudiesofCommercial Drug ScreeningAssays
PRINCIPALINVESTIGATOR
PI. E.J. Cone, Ph.D. Chief Clinical Pharmacology Branch
W.D. Darwin Chemist Clinical PharmacologyBranch
A.Jenkins IRTA Clinical PharmacologyBranch
D.Yousefnejad Chemist Clinical PharmacologyBranch
COOPERATINGUNITS
LAB/BRANCH
Clinical PharmacologyBranch
SECTION
Chemistry
INSTITUTEANDLOCATION
National InstituteonDrugAbuse,Addiction Research Center, Baltimore, MD 21224
TOTALSTAFFYEARS: PROFESSIONAL OTHER:
0.5 0.3 0.2
CHECKAPPROPRIATEBOXES
13 n(A)Human [J (b)HumanTissue LJ (c)Neither
n (a1)Minors
(a2)Interviews
SUMMARYOFWORK
Commercialassaysforthedetection ofdrugsofabusein urinechangeperiodicallyand mustbe reevaluated
forperformance. Studiesaredesignedtotestthevalidityofnewassayswith clinicalspecimensobtained
fromdrug usersundercontrolled conditions.
Healthymalevolunteerswith a historyofchemicalsubstanceabuse participate inthesestudies. Informed
consent isobtained and all proceduresareapproved bythe hospital Institutional ReviewBoard. Commercial
assaysfordetection ofdrugsofabuse in urinearetested forvaliditywith specimenscollected under
controlleddosing conditions. Avarietyofdrugsofabusewerestudied atvariousdose levels. The resultsof
theassayswerecomparedtoGC/MSanalysis.
Thesestudiestestthevalidityofcommercialassaysonclinicalsamplesinstead of"spiked"samplesand
provideuniqueandvaluable informationtothemilitaryand industryconcerningtheirtimecourseof
detection, specificityand accuracy.
PHS6040(Rev.5/92)
rUDl_IV-<MIHwlINO
Cone, E.J., Dickerson. S.L, Paul. B.D. and Mitchell. J.M.. Forensic Drug Testing ForOpiates V UrineTesting
ForHeroin. MorphineAnd Codeine With Commercial Opiate Immunoassays. J. Anal. Toxicol.. 17: 156-164.
Jenkins,A.J., Mills, LC, Darwin, W.D., Huestis. M. A. and Cone, E. J. ValidityTesting OfThe EZ-Screen-
Cannabinoid Test. J. Anal. Toxicol.. 17:292-298. 1993.
Joseph, T., Dickerson, S.L, Willis, R., Frankenfield. D., Cone. E.J. and Smith. D.R. Interference by
NonsteroidalAnti-inflammatoryDrugsin EMITand TDxAssaysforDrugsofAbuse. J. Anal. Toxicol., In Press
1994.
Jenkins. A.J., Dan^/in, W.D., Huestis, M.A., Cone, E.J. and Mitchell. J.M. ValidityTesting ofthe accu/PINCH
THCTest. J.Anal. Toxicol., In Press, 1994.
DEPARTMENTOFHEALTHANDHUMANSERVICES-PUBLICHEALTHSERVICE PROJECTNUMBER
NOTICEOFINTRAMURALRESEARCH PROJECT
Z01 DA00003-09 BPGS
PERIODCOVERED
October11993 to September30 1994
TITLEOFPROJECT
EffectsofDrugson Schedule-Controlled BehaviorofExperimentalAnimals
PRINCIPALINVESTIGATOR
PI StevenGoldberg, Ph.D. Chief Preclinical Pharmacology Laboratory
CharlesSchindler, Ph.D. Research Psychologist Preclinical PharmacologyLaboratory
ChristineSannerud, Ph.D. Sr. StaffFellow Preclinical Pharmacology Laboratory
SevilYasar, M.D. GuestScientist Preclinical Pharmacology Laboratory
EricThomdike Research Psychologist Preclinical PharmacologyLaboratory
MohammedShoaib. Ph.D. Visiting Fellow Preclinical PharmacologyLaboratory
COOPERATINGUNITS
JohnsHopkinsSchoolofMedicine
LAB/BRANCH
Preclinical PhanmacoloqyLaboratory
SECTION
Behavioral Phannacoloqv
INSTITUTEANDLOCATION
National Instituteon DrugAbuse, Addiction ResearchCenter, Baltimore, MD 21224
TOTALSTAFFYEARS: PROFESSIONAL:
3.3 2 1.3
CHECKAPPROPRIATEBOXES
n
n(A)Human LJ (b)HumanTissue (c)Neither
n (a1)Minors
(a2)Interviews
SUMMARYOFWORK
Thebehavioral pharmacological profileofadrug ina pertinentspeciesisnecessarytoevaluate
quantitativelyhowthedrugfunctionsasa reinforcerora punisheraswell astoestablish itsstimuluseffects.
Schedulesoffood presentationwith bothfixed-interval andfixed-ratiocomponentshave been used most
frequentlyinthistypeofstudysincetheygenerate awide rangeofratesand patternsofrespondingwithin a
session and providestable, long-term baselinesforchronicstudies in individual animals. The present project
involvesthe assessmentofboththeacuteand chroniceffectsofavarietyofdrugsonschedule-controlled
behavior. We have recentlyshownthattheenhancedsensitivityobservedtothe behavioral effectsofthe
opioid antagonistnaltrexone isinfluenced byGABAergicprocesses, and in particularbyan action atthe
GABAassociated chloridechannel. Further, thissensitivity maybe associatedwith changesin both mu and
delta opioid receptors. Geneticfactorsareknownto influencethe behavioral effectsofa numberofdifferent
drugs, andstudiesofthe interactionsbetween environmental andgeneticcomponentsthatpotentiallyaffect
thedevelopmentofbehavioraltoleranceandsensitivityare being initiated. Behaviorallyactivedrugscan
alsoserveasdiscriminativestimulitoguide behavioralchoice. Two-andthree-leverdrugdiscrimination
projectsinthelaboratoryhavehelpedtodefineand characterizethespectrum ofbehavioral effects
produced bythedrug,tocomparea rangeofothercompounds, such ascocaine, l-deprenyl, morphine,
midazolam, and caffeinetocharacterizethe relative potencyand efficacyto producedrug-likeeffects, andto
evaluatethedrug'smechanismsofaction atthereceptorlevel. Since mosthumandrug-taking behavior
involveschroniclong-term useofan illicitdrugornon-medical abuseofa prescribed medication,the
consequencesofchronicadministration ofdrugsonschedule-controlled behaviorandthediscriminative
functionsofdrugsarebeingevaluated. Althoughthedevelopmentoftoleranceanddependenceare related
topharmacologicalfactors,tolerancecan alsobemodified byenvironmentalfactors. Forexample, the
interaction betweendrugadministrationandtheabilitytoperformthetaskcan result indifferentialtolerance
thatisafunctionofchronicdailydoseandduration oftreatment.
PHS6040(Rev.5/92)
PUBLICATIONS
Sannemd CA, MarleyRJ, SerdikoffSL.AlastraAJG. Cohen C. Goldberg, SR. Tolerancetothe behavioral
effectsofchlordiazepoxide: pharmacological and biochemical selectivity, Journal ofPharmacologyand
ExperimentalTherapeutics 1993;267:1311-20.
Gauvin DV, Sannerud CA, YoungAM. Lackofacutetolerancetothediscriminativestimuluseffectsof
morphine in pigeons, Life Sciences 1994; in press.
Sannerud CA,AtorNA. Drugdiscrimination analysisofmidazolam underathree-leverprocedure I: dose-
dependentdifferencesingeneralization and antagonism.Journal ofPharmacology and Experimental
Therapeutics 1994; in press.
PersicoAM, SchindlerCW, O'Hara BF, BrannockMT, Uhl GR. Braintranscnption factorexpression: effectsof
acute and chronicamphetamineand injectionstress, MolecularBrain Research 1993;20:91-100.
SchindlerCW, PersicoAM, Uhl GR, Goldberg SR. Behavioral assessmentofhigh-dose amphetamine
withdrawal: importanceoftraining andtestingconditions, Pharmacology, Biochemistryand Behavior1994; in
press.
YasarSY, SchindlerCW, Thomdike EB, Goldberg SR. Evaluation ofdeprenylforcocaine-likediscriminative
stimuluseffectsin rats, EuropeanJournalofPharmacology 1994;259:243-250.
GewissMV, MarleyRJ,Thomdike EB, Goldberg SR, SchindlerCW. GABA-receptorlinked chloridechannels
andthebehavioraleffectsofnaltrexonein rats. Pharmacology, Biochemistryand Behavior1994; in press.
PersicoAM, SchindlerCW, ZaczekR, BrannockMT, Uhl GR. Braintranscriptionfactorgeneexpression,
neurotransmitterlevelsand noveltyresponse behaviors: alterationsduring ratamphetaminewithdrawaland
followingchronicinjectionstress. Synapse 1994; in press.
0-Hara BF, Donovan DM, Lindberg I, BrannockMT, RickerDD, MoffattCA, Klaunberg BA, SchindlerCW,
ChangTS, Nelson RJ, Uhl GR. Proenkephalintransgenicmice: a short promoterconfershightestisexpression
and reducedfertility. MolecularReproduction and Development 1994;38:275-84.
