The Scripps Research
Institute
National Institute
on Drug Abuse
For Information:
Mona Brown, NIDA
(301) 443-1124
Robin B. Goldsmith,TSRI
(6le) ss4-8134
#06t893
Embargoedby ScienceMagazine:
For wire servicesand broadcastnews,June17, 1993,3p.m. PacificTime
For print media,June 18, 1993
Scripps ScientistsDiscover Involvementof New Receptorin CocaineAbuse
La Jolla, CA. June L8, 1993-- Scientistsat The ScrippsResearchInstitute(TSRI) have
discoveredthe role of a new classof brain receptorsin cocaineabuse,a finding that could
lead to the developmentof more selectiveand more effectivepharmacologictherapiesto
weanaddictsfrom cocaineas well as strategiesfor the preventionof addiction.
The work was announcedin the June 18 issueof Science,the journal of the American
Associationfor the Advancementof Science,by S. BarakCaineand GeorgeF. Koob, Ph.D.,
a memberof the Departmentof Neuropharmacology
at TSRI, in an article entitled,
"Modulation of CocaineSelf-Administrationin the Rat ThroughD-3 DopamineReceptors.
"
It was fundedby grantsfrom the NationalInstituteon Drug Abuse.
"The value of this study is that we have uncoveredinformation about thesereceptorsthat has
increasedour understandingof how to modulatethe reinforcing propertiesof cocaineand
to counterits effects," saidKoob, in whose
therebydesignsafeand appropriatetherapeutics
laboratorythe work was conducted.
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Page2 -- Involvement of Brain Receptorin CocaineAbuse
Overwhelming evidencesuggeststhat cocaineproducesits behavioraleffects by increasing
the activity of dopamine-- a neurotransmitteror chemicalthat passesbetweenbrain cells for
communication-- that is believedto be a critical part of one of the brain's pleasuresystems.
Further, dopaminethen stimulatescell proteinscalled receptors,to produceits effects.
Neurotransmitterscan be viewed as keys to the receptors'locks; they are able to open
severallocks that can then perform a variety of functions. Dopaminereceptorsare thought
to regulatebrain activitiesrelatedto movement,arousaland motivation,and possibly
emotionsas well as other thoughtprocesses.
For nearly 15 years, investigationof the effectsof dopamineon the brain hasbeenbasedon
D-1 and D-2 receptors,two of the five dopaminereceptorscurrently identified. While they,
too, are involved in cocaine'sreinforcingeffects,they are widely distributedin areasof the
brain that affect other functional activities, most notably motor movements.
In recentyears,the FrenchscientistsJean-Charles
Schwartz,Daniel kvesque, and
colleaguesin the laboratory of Pierre Sokoloff clonedthe D-3 receptorand identified the
selectivity of compoundsfor thesereceptors,allowing for the experimentalwork in this
study. An important factor in the involvementof this receptorin cocaineabuse-- and its
significancein developingtherapiesto lessenits effects - is its restrictedlocalization to the
'limbic" dopaminergicprojectionareain the brain that hasbeenimplicatedas an interface
betweenemotion, motivation and behavior - areasimportant in drug reward - possibly
leaving areasresponsiblefor motor function unaffected.
The authorsnote that addictive substancesseemto sharemany coilrmon featuresin their
actions in the brain, engagingbrain circuits relatedto emotions,motivation and behavior.
This, in part, explainshow drugscan gain control over one'sbehaviorby playing on basic
biological drives and motives.
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Page3 -- Involvement of Brain Receptorin CocaineAbuse
In this study, rats, connectedto a cocainesupplyby intravenoustubes,are allowedto
administeras much cocaineas they like for three hours eachday. When limited to that time
period, eachrat quickly establishes
a baselinestability, taking almostexactlythe same
amount of cocaineeachday. When self-administeringcocainein combinationwith very
small quantitiesof the drugs that bind to the D-3 receptor, "they take up to 60 percentless
than their normal daily amount," accordingto co-authorCaine. He notesthat theselow
dosesof the compoundswere not by themselvesreinforcing.
In the past, scientistshavetried to lessenthe cravingsfor cocaineby blocking the dopamine
receptors,therebyblocking the effectsof cocaine.However,in the presenceof these
compounds,rats tend to increasetheir cocaineintake, presumablyto compensatefor the
antagonist'seffects.Likewise in humans,this approachhaslost favor becauseefforts to
block cocaine'seffectsusing dopamineantagonists
seemto exacerbate
symptomsof
depressionand craving, he remarked.
"In contrastto this methodology,what we're interestedin achieving," Cainecontinued,"is a
meansof regulating the dopaminesystemand by so doing, finding compoundsthat reduce
thesesymptomswithout producing dependenceon the compoundsthemselves. The drugs we
have used in this study bind directly to the D-3 dopaminereceptors,and producethe desired
effect of reducingthe amountof cocaineself-administered.
However,we still don't know
whether theseD-3 selectivedrugs can reducesymptomsof craving and withdrawal."
In 1987Dr. Koob and his associates
testeda drug widely usedto treat infertility and
Parkinson'sdiseaseas a tool to reducethe addictiveeffectsof cocaine. Bromocriptine,
known then to bind to the D-2 receptor, but now known to bind to D-3 receptorsas well,
reducescocaineintake by the samemechanismof interactingwith the chemical "pleasure
center" in the brain that is stimulatedby cocaine. This drug hasbeen availablefor more
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Page4 -- Involvement of Brain Receptorin CocaineAbuse
than a decade. It was initially studiedto overcomefemaleinfertility causedby
overproductionof the hormoneprolactinand is alsousedto relievesymptomsof Parkinson's
disease.
While it was shownto reducethe cravingfor cocainein animalmodels,the utility of
bromocriptinein cocaineabusetreatmentis still unclear.Theremay be advantages
in using
compoundsthat bind selectivelyto D-3 receptorsratherthan D-2 receptorsbecauseof their
localizationonly to areasthoughtto affect cognition,emotionand motivation,but not motor
function, therebyreducingsideeffects. To date,thesecompoundsare experimentaldrugs
usedin basicbiomedicalresearch. While the researchers
note that they were usedbecauseof
their binding affinity to thesereceptors,more work must be doneto studytheir safety;the
abusepotentialof the compoundsis as yet unknown.
Koob remarksthat one can generalizesomewhatfrom the animal model to the human
condition, and postulatesthat the next stepsin their researchwill be to test the effectsof D-3
selectivedrugs with animalmodelsof withdrawaland craving. "We will continueto explore
the neurobiologicalmechanisms
of D-3 receptorswhich could leadus to a better
understandingof the cellular mechanisms
underlyingcocaine'seffects," he said. "This
information could lead us to the developmentof highly selectivedrugs and to breakthroughs
in prevention.In addition,the informationmay ultimatelyprovide insight into the
neurobiologicalmechanismsof debilitatingpsychiatricdisorderssuchas maniaand
depression.Theseare importantgoals."
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