journal of pharmacology and experimental therapeutics fuentes de información i

8/9/2019 Journal of Pharmacology and Experimental Therapeutics Fuentes de Informacin I

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Journal of Pharmacology And Experimental Therapeutics

J Pharmacol Exp Ther January 2004 308:156-167

ENDOCRINE AND REPROD CTI!E

O"arian #teroid $ormone %odulation of the Acute Effects ofCocaine on &uteini'ing $ormone and Prolactin &e"els inO"ariectomi'ed Rhesus %on(eys

Nancy )* %ello+ Jac( $* %endelson+ #* #te"ens Negus+ and %aureen )elly

Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont,Massachusetts

Address correspondence to:Dr. Nancy K. Mello, Alcohol and Drug Abuse Research Center, Harvard Medical School-McLean Hos ital,!!" Mill St., #el$ont, MA %&'(). *-$ail+ $ello $clean.org

Received Jul !", #$$%& accepted September #', #$$%(

A,stract

Cocaine stimulates signi)icant increases in luteini*ing hormone +LH and decreases prolactin levels ingonadall intact rhesus mon e s, but cocaine did not alter plasma levels o) these anterior pituitarhormones in ovariectomi*ed )emales( .hese )indings suggested that ovarian steroid hormones macontribute to the endocrine e))ects o) acute cocaine administration( .o test this h pothesis, the acutee))ects o) cocaine and placebo-cocaine on plasma LH and prolactin levels /ere e0amined in )iveovariectomi*ed rhesus )emales during three chronic hormone replacement conditions1 ! estradiol +2 #treatment +$($$!3-$($$' mg4 g4da i(m( , # progesterone treatment +$(%# mg4 g4da i(m( , and %combinations o) progesterone +$(%# mg4 g4da i(m( and 2 # +$($$# and $($$5 mg4 g4da i(m( ( Cocaine+$(6 mg4 g i(v( did not alter prolactin or LH in ovariectomi*ed mon e s /ithout ovarian steroidreplacement( During chronic estradiol treatment, cocaine produced an estradiol dosedependent decrease in

prolactin( Cocaine also decreased prolactin during treatment /ith progesterone alone and progesterone 72 # +$($$5 mg4 g4da i(m( ( Cocaine stimulated a signi)icant increase in LH during treatment /ith

progesterone alone, but not during treatment /ith progesterone 7 2 # , or three o) )our estradiol treatmentdoses( Cocaine pharmaco inetics did not di))er as a )unction o) hormone replacement conditions(.ogether, these data suggest that both 2 # and progesterone modulate cocaine8s e))ects on prolactin,/hereas 2 # alone and in combination /ith progesterone, do not )acilitate LH release in response tococaine in ovariectomi*ed rhesus )emales(

.here is increasing evidence that ovarian steroid hormones ma modulate some biological and behaviorale))ects o) cocaine, but the nature o) these interactions is poorl understood +)or revie/, see Mello andMendelson, #$$# ( 9n behavioral studies, estradiol ma enhance the rein)orcing and locomotor e))ects o)cocaine in rats +Roberts et al(, !:6: & L nch et al(, #$$$ & Sell et al(, #$$$ ( 9n endocrine studies, cocaine

stimulates

a rapid increase in estradiol in )emale rhesus mon e s during

the )ollicular phase o) themenstrual c cle /hen ovarian steroid hormone levels are lo/, but not during the luteal phase /hen

ovarian steroid hormone levels are high +Mello et al(, #$$$ ( Moreover, there is general agreement thatcocaine stimulates release o) some anterior pituitar hormones +Mello and Mendelson, #$$# ( ;or
mailto:[email protected]:[email protected]://jpet.aspetjournals.org/cgi/content/full/308/1/156#REF24%23REF24http://jpet.aspetjournals.org/cgi/content/full/308/1/156#REF29%23REF29http://jpet.aspetjournals.org/cgi/content/full/308/1/156#REF43%23REF43http://jpet.aspetjournals.org/cgi/content/full/308/1/156#REF20%23REF20http://jpet.aspetjournals.org/cgi/content/full/308/1/156#REF40%23REF40http://jpet.aspetjournals.org/cgi/content/full/308/1/156#REF24%23REF24mailto:[email protected]


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e0ample, acute cocaine administration stimulates signi)icant increases in luteini*ing hormone +LH andadrenocorticotropin hormone +AC.H in humans +Mendelson et al(, !::# , #$$! & Sholar et al(, !::6and in rhesus mon e s +Mello et al(, !::$a , !::% & Sarn ai et al(, !::' & Broadbear et al(, !:::a ,b (

.he in)luence o) the ovarian steroid hormone milieu on the hormonal e))ects o) cocaine has not beens stematicall e0amined( Ho/ever, the potential importance o) gonadal steroid hormones in modulating

the e))ects o) cocaine on anterior pituitar hormones is suggested b the observation that cocaine did not

stimulate LH or AC.H

in ovariectomi*ed rhesus mon e s as it did in gonadall intact

male and )emalerhesus mon e s +Mello et al(, !::3 & Sarn ai et al(, !::3 ( .his )inding /as surprising, because theovariectomi*ed )emales, gonadall intact males, and )ollicular and luteal phase )emales /ere given thesame dose o) cocaine +$(6 mg4 g i(v( and /ere studied under identical conditions +Mello et al(, !::$a ,

!::% & Sarn ai et al(, !::' ( ne ma?or di))erence bet/een gonadall intact and ovariectomi*ed rhesus )emales is the basallevels o) ovarian steroid and gonadotropin hormones( A)ter ovariectom , estradiol and progesteronedecrease to ver lo/ levels, and in the absence o) tonic inhibition b ovarian steroid hormones, LHincreases to periovulator levels +Hotch iss and @nobil, !::5 (

9n contrast to cocaine-induced stimulation o) LH and AC.H, acute administration o) cocaine signi)icantldecreases prolactin levels in gonadall intact rhesus mon e s +Mello et al(, !::$a , !::5 & )or revie/, seeMello and Mendelson, #$$# ( .his e))ect o) cocaine is consistent /ith its pharmacological actions as anindirect dopamine agonist because prolactin release is under inhibitor dopaminergic control +Ben-Jonathan, !:63 & Ben-Jonathan and Hnas o, #$$! ( et in ovariectomi*ed )emale rhesus mon e s, acutecocaine administration did not decrease prolactin as it did in gonadall intact rhesus males and )emalesstudied under identical conditions +Mello et al(, !::$b , !::% , !::3 ( .ogether, these )indingssuggested that the ovarian steroid milieu ma be an important modulator o) cocaine8s e))ects on anterior

pituitar hormones(

.he goal o) the present stud /as to test the h pothesis that ovarian steroid hormone levels are onedeterminant o) cocaine8s e))ects on anterior pituitar hormones( >variectomi*ed mon e s /ere givensteroid hormone replacement regimens that /ere designed to produce ph siological levels o) estradiol and

progesterone(


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hormone treatment conditions, and successive endocrine stud da s /ere separated b at least ' to 6/ee s(

Animal maintenance and research /ere conducted in accordance /ith the guidelines provided b theCommittee on Care and se o) Laborator Animals o) the 9nstitute o) Laborator Animal Resources,

ational Research Council( .he )acilit is licensed b the (S( Department o) Agriculture( .his protocol/as approved b the McLean Hospital 9nstitutional Animal Care and se Committee( Mon e s had

visual, auditor , and ol)actor contact /ith other

mon e s throughout the stud ( 2nrichment /as provided b to s +pu**le )eeders, mirrors, che/ to s , )ood treats, television, and music( .he health o) the mon e s/as monitored periodicall b a consultant veterinarian trained in primate medicine(

O"arian #teroid $ormone Administration.he e))ects o) cocaine on anterior pituitar hormones /ere studied during chronic saline administration,and during chronic administration o) estradiol ben*oate +2 # , progesterone and combinations o) 2 # and

progesterone( Successive doses o) each hormone /ere separated b a hormone-)ree interval to preventan carr over e))ects )rom the previous hormone treatment condition( 9n preliminar studies, /e measured

basal levels o) !" -estradiol to veri) the hormonal status o) each ovariectomi*ed mon e ( A)terovariectom , !" -estradiol levels decreased /ithin ' to !# da s and )luctuated bet/een $ and #% pg4ml(./o mon e s /ere observed )or !53 da s a)ter ovariectom, and samples )or !" -estradiol anal sis /ere collected ever 3 or " da s( .he lo/est detectable !" -estradiol values averaged bet/een !#(' E !(% and!5(! E !(" pg4ml over the period o) observation( >n the basis o) these data, /e de)ined baseline estradiollevels as less than #$ pg4ml in ovariectomi*ed )emales( .his empiricall derived criterion also provided a

basis )or evaluating the e))ect o) the estradiol replacement regimens on basal levels o) !" -estradiol( .herationale )or hormone dose selection and the details o) hormone administration are described belo/(

Estradiol Administration* Dail intramuscular in?ections o) 2 # +$($$!3, $($$#, $($$5, and $($$'mg4 g4da /ere given )or at least 6 da s be)ore each endocrine stud da ( 2 # doses /ere administered inan ascending order( 2 # /as administered at !$1%$ ever morning to unanestheti*ed mon e s( .he dailin?ection procedure ielded relativel stable and predictable levels o) estradiol at the doses studied( Bloodsamples )or estradiol anal sis /ere collected % times a /ee to )ollo/ !" -estradiol levels during 2 # replacement( A single sample )or estradiol anal sis /as also collected on each endocrine stud da ( At theend o) each 2 # dose condition, samples )or estradiol anal sis /ere collected ever 3 to " da s )or ' to 6/ee s( .he ne0t estradiol replacement condition did not begin until a)ter basal !" -estradiol levelsreturned to baseline levels(

9n gonadall intact )emales, estradiol and LH )eedbac relationships control levels o) each hormoneacross the menstrual c cle +Hotch iss and @nobil, !::5 ( 2stradiol inhibits LH e0cept at the peri-ovulator phase /hen estradiol stimulates an LH surge +Hotch iss and @nobil, !::5 ( A)ter ovariectomor natural menopause, the loss o) estradiol inhibitor )eedbac results in high levels o) LH( 9n the present

stud , the lo/est doses o) 2 # /ere e0trapolated )rom transdermal

estradiol doses used to treatmenopausal s mptoms +$($3-$(!$ mg4da )or a 3$- g /oman is the eFuivalent o) $($$!-$($$# mg4 g4da+c)( Carr, !::6 ( .hese doses /ere selected to mimic estradiol levels during the )ollicular phase o) thenormal menstrual c cle( .he highest doses o) 2 # studied /ere selected to mimic estradiol levels duringthe peri-ovulator phase o) the menstrual c cle +Hotch iss and @nobil, !::5 ( 2 # /as administeredchronicall because acute 2 # administration can stimulate an LH surge in ovariectomi*ed mon e s that iscomparable to the peri-ovulator LH surge in normal )emales + ama?i et al(, !:"# &


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Progesterone Administration* 9n preliminar studies, a range o) i(m( progesterone doses /ere evaluatedto identi) a dose that provided progesterone levels characteristic o) the earl luteal and mid-luteal phaseso) a normal ovulator menstrual c cle in )emale rhesus mon e s( >vulation is usuall in)erred )rom aluteal phase increase in progesterone to 6(3 ng4ml or above +;ilicori et al(, !:65 ( 9n our previous studiesin rhesus mon e s, pea progesterone levels during ovulator menstrual c cles averaged bet/een !# and!' ng4ml +Mello et al(, !::" ( 9n ovariectomi*ed )emales in the present stud , a progesterone dose o) $(%#mg4 g4da administered intramuscularl resulted in progesterone plasma levels that ranged bet/een : and

#! pg4ml(

Administration of Progesterone and Estradiol Com,inations* .o stud the e))ect o) progesterone and2 # in combination, the same dose o) progesterone +$(%# mg4 g i(m( /as administered /ith $($$# and$($$5 mg4 g4da o) 2 # (


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and /ithin 5 to 6 min in humans +Mendelson et al(, !:::b ( .he duration o) sampling /as determined in part, b the hal)-li)e o) cocaine in )emale rhesus mon e s, /hich averages bet/een 5$ and '$ min a)ter ani(v( bolus in?ection o) $(6$ mg4 g cocaine +Mendelson et al(, !:::a ( .he duration o) sampling /aslimited b the volume o) blood that can be sa)el e0)used )rom a rhesus mon e ( 9n the present stud ,

bet/een '$ and '#(3 ml o) blood /as collected over !#$ min( .he !!$-min postcocaine sampling period permitted measurement o) hormonal changes during and a)ter the period o) ma0imal cocaineconcentrations in plasma(

!enous Catheteri'ation and 2lood #ample Collection ProceduresMon e s /ere anestheti*ed /ith etamine h drochloride +3-!$ mg4 g i(m( , /hich does not alter pituitargonadotropins in rhesus mon e s +;erin et al(, !:"' & ;uller et al(, !:65 ( A Sur-;lo 9ntracath containinga #$-gauge needle +i(d( $(6$ x 3! mm +.erumo Medical Corporation, 2l ton, MD /as inserted into thesaphenous vein o) each leg using aseptic procedures( A)ter removal o) the needle st let, each catheter /as

?oined to heparin-impregnated sterile silicon tubing and secured /ith sutures( >ne catheter /as used )orin?ection o) cocaine solutions, and one catheter /as used )or /ithdra/al o) blood samples to measure

plasma levels o) cocaine and anterior pituitar hormones( .he mon e /as placed in a standard primatechair )or at least :$ min be)ore collection o) baseline samples( Mon e s /ere adapted to chair-restraint onseveral occasions be)ore this stud began(

Blood samples )or cocaine anal sis /ere collected in tubes containing potassium o0alate and sodium)luoride +#(3 ng4ml to prevent cocaine h drol sis b serum esterases +Jatlo/ and Baile , !:"3 ( Bloodsamples )or LH and prolactin anal sis /ere collected in heparini*ed tubes( Samples /ere centri)uged, andaliFuots o) plasma /ere dra/n and stored at -"$IC until anal sis(

Drug and $ormone PreparationCocaine* Cocaine h drochloride /as obtained )rom the ational 9nstitute on Drug Abuse, and solutions/ere prepared b dissolving cocaine in sterile saline )or in?ection (S( ( .he solution /as )iltersterili*edusing a $(!!- g Millipore )ilter +Millipore Corporation, Bed)ord, MA ( Cocaine +$(6 mg4 g or an eFualvolume vehicle control solution /as in)used into the saphenous vein o) the leg opposite the e0)usioncatheter in a single bolus in?ection over !$ s(

Estradiol and Progesterone* -2stradiol %-ben*oate +!,%,3-G!$ -estratriene-%,!" -diol and progesterone/ere purchased )rom the Sigma-Aldrich +St( Louis, M> ( 2stradiol ben*oate and progesterone /eresuspended in sesame oil and diluted to the appropriate milligram per ilogram dose )or individual animals(AliFuots o) less than ! ml /ere in?ected intramuscularl at the same time each da ( 2stradiol and

progesterone po/der and stoc solutions /ere stored in the dar at room temperature(

Plasma $ormone and Cocaine AnalysesData are reported )or the anal sis o) LH, prolactin, and plasma cocaine levels using the )ollo/ing assa

procedures(

&$ Radioimmunoassay* lasma LH concentrations /ere measured in duplicate b a double-antibodradioimmunoassa procedure similar to that described b Midgle +!:'' using rhesus pituitar LHre)erence preparation + 9CHD-rhLH, also no/n as < -K -#$ , prepared b


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!ie. larger"ersion +!$@ 1

Gin this /indo/Gin a ne/ /indo/

0ig* 3* Standard R9A curves )or prolactin +top and LH +bottom ( 2ach standardcurve /as generated b plotting the percentage o) B4Bo versus the log o) theconcentration o) RL or LH( ercentage o) B4Bo represents the binding o) thestandards relative to the *ero calibrator( 2ach data point )or RL is the average

o) !# determinations( 2ach data point )or LH is the average o) #!determinations +mean E S(2( (

Prolactin Radioimmunoassay* lasma prolactin concentrations /ere measured using a double antibodR9A it purchased )rom ante0, Santa Monica, CA( Results are e0pressed in nanograms per milliliter interms o) the re)erence preparation( .he RL assa sensitivit /as #(# ng4ml( 9ntra- and interassacoe))icients o) variance /ere :(6 and !#($N, respectivel ( .he standard R9A curve is sho/n in ;ig( ! (

Estradiol Radioimmunoassay* lasma concentrations o) !" -estradiol /ere determined in duplicateusing a double antibod R9A it purchased )rom 9C Biomedicals 9nc( +Cosa Mesa, CA ( A modi)ication

/as made to the protocol( Be)ore anal sis, the plasma samples /ere e0tracted and then reconstituted in*ero standard( .he estradiol assa sensitivit /as 6(# pg4ml( 9ntra- and interassa coe))icients o) variance/ere "(# and !#("N, respectivel (

Progesterone Radioimmunoassay* lasma progesterone concentrations /ere determined in duplicateusing a direct, double-antibod R9A it purchased )rom 9C Biomedicals 9nc( .he progesterone assasensitivit /as $(!# ng4ml, and the intra- and interassa coe))icients o) variance /ere 3(: and !$(!N,respectivel (

Plasma Cocaine Analysis* lasma cocaine levels /ere measured in duplicate using a solid phasee0traction method described b Spec 9nstructions Manual b Ans s /ith a He/lett ac ard model 36:$

Series 99 gas chromatograph eFuipped /ith a capillar

column and a He/lett ac ard 3:"! Series massselective detector +Abusada et al(, !::% ( .he assa sensitivit /as !$ ng4ml, and the intra-assacoe))icient o) variance /as #(#N(

Pharmaco(inetic Analysis* 2stimates o) cocaine8s primar inetic parameters +i(e(, pea plasma cocaineconcentrations and time to pea plasma concentration /ere calculated, and secondar parameters +i(e(,area under the curve, initial and terminal phase hal)-lives /ere obtained directl )rom a nonlinearregression estimation so)t/are program based upon the Manual o) harmacologic Calculations /ithComputer rograms using HARM4 CS, version 5(# +MicroComputer Specialist MCS, hiladelphia, A (lasma drug concentrations /ere )itted to a single-dose, one-compartment model /ith bolus input, )irstorder output, and elimination( lasma concentrations /ere /eighted b the reciprocal o) the predicted

concentrations( 2stimates o) the elimination hal)-li)e +t !4# /ere obtained )rom the computer-)itted model(A one-compartment model /as used, because the duration o) sampling /as !!$ min(
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#tatistical Analysis* .he e))ects o) cocaine and its placebo on anterior pituitar hormones /ere evaluated/ith anal sis o) variance +A > A Abacus Concepts, 9nc(, Ber ele , CA( 9) A > A )or repeatedmeasures sho/ed a signi)icant main e))ect, contrast tests /ere used to determine /hich mean values /ere

statisticall di))erent )rom each other /ithin each treatment condition( A > A /as used to comparetreatment groups and the signi)icance o) group mean values at each sample period /ere compared /ith

baseline means using contrast tests )or comparison o) multiple e0perimental groups /ith a single controlgroup( H undt-;eldt epsilon ad?ustments /ere used in all contrast tests( robabilit levels o) P O $($3 to

$($$$! are reported as

statisticall signi)icant(

Results

.hree studies /ere conducted to characteri*e the interactions bet/een ovarian steroid hormones and theacute e))ects o) cocaine on LH and prolactin in ovariectomi*ed rhesus )emales( 9n the )irst stud , the dose

range over /hich dail 2 # administration

produced ph siologicall relevant levels o) !" -estradiol /as

evaluated( 2 # /as studied up to doses that signi)icantl decreased LH levels in ovariectomi*ed mon e s(9n the second stud , the e))ect o) cocaine on anterior pituitar hormones /as studied in ovariectomi*edmon e s /ithout estradiol replacement( .hese control data provided a basis )or comparison /ith thee))ects o) estradiol replacement( 9n the third stud , the e))ects o) cocaine on prolactin and LH /ere studiedduring chronic administration o) 2 # alone +$($$!3-$($$' mg4 g4da , progesterone alone +$(%#

mg4 g4da , and the same dose o) progesterone in combination /ith t/o doses o) 2 # +$($$# and $($$5mg4 g4da (

#tudy 3/ Effects of Chronic E 4 Administration on 2asal &e"els of 35 6Estradiol+ &$+ and Prolactin70ig* 48

35 6Estradiol* Basal !" -estradiol levels averaged ##(" E

#(! pg4ml +data not sho/n ( ;igure # sho/s thata)ter 2 # replacement, the average levels o) !" -estradiol increased /ith increasing doses o) 2 # dose +r P$("::& P P $($$$! ( .he lo/est doses o) 2 # +$($$!-$($$!3 mg4 g4da did not increase !" -estradiollevels signi)icantl above baseline levels( Higher 2 # doses +$($$5-$($$' mg4 g4da each producedsigni)icant increases in !" -estradiol levels in comparison to baseline + P O $($!-$($$3 ( .he time reFuiredto reach stable estradiol levels at each 2 # dose varied across mon e s and averaged bet/een % and 'da s( A)ter maintenance on 2 # /as discontinued, estradiol returned to base-line levels /ithin % to ' da s(

!ie. larger "ersion +#5@ 1Gin this /indo/

Gin a ne/ /indo/

0ig* 4* 2))ects o) 2 # on LH +nanograms per milliliter and !"estradiol +picograms per milliliter in ovariectomi*ed rhesusmon e s( Doses o) 2 # are sho/n on the abscissae, and !" -estradiol +picograms per milliliter levels +closed circles and LH+nanograms per milliliter levels +open circles are sho/n on thele)t and right ordinates( At 2 # doses o) $($$! and $($$# mg4 g4da ,each data point is the average +E S(2( o) three or )our mon e s( At2 # doses o) $($$5 and $($$' mg4 g4da , each data point is theaverage +ES(2( o) )ive mon e s(
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&$* Be)ore estradiol replacement, baseline LH levels e0ceeded !$$ ng4ml and these levels arecharacteristic o) ovariectomi*ed )emales in this laborator +Mello et al(, !::3 ( .he relationship bet/eenLH and !" -estradiol during 2 # treatment is sho/n in ;ig( # ( As !" -estradiol levels increased, there /asa corresponding decrease in LH( Average LH levels decreased signi)icantl )rom !#3 E !" to #6(# E #ng4ml during maintenance on $($$! to $($$5 mg4 g 2 # + P O $($#-$($$$! ( Ho/ever, LH did not decrease)urther during maintenance on the highest dose o) 2 # studied +$($$' mg4 g4da and averaged #%(' E !("

ng4ml( During maintenance on estradiol doses o) $($$5 and $($$' mg4 g4da , LH levels /ere in the

normal range )or the mid-)ollicular

phase o) the menstrual c cle in gonadall intact mon e s +Mello

et al(,!::" (

Prolactin* Baseline prolactin levels /ere in the lo/ normal range and averaged bet/een 5 and !$ ng4ml(Average prolactin levels increased as a )unction o) increasing doses o) 2 # , but these changes /ere notsigni)icantl di))erent )rom baseline +data not sho/n ( rolactin levels remained /ithin the normal range+!$(% E #('-!6(% E %(3 ng4ml during maintenance on $($$! to $($$5 mg4 g4da 2 # ( During treatment/ith the highest dose o) 2 # studied +$($$' mg4 g4da , basal prolactin levels increased to #!(5 E #(!ng4ml, and this level approaches the h perprolactinemic range de)ined as da time levels Q#3 ng4ml+Martin and Reichlin, !:6" (

#tudy 4/ Effects of Cocaine and #aline on Anterior Pituitary $ormones in O"ariectomi'ed %on(eys.ithout $ormone Replacement 7 0ig* 9 8Basal levels o) !" -estradiol and progesterone on the stud da are sho/n in .able ! ( Baseline prolactinand LH levels did not di))er signi)icantl be)ore $(6 mg4 g i(v( cocaine and saline administration inovariectomi*ed )emale rhesus mon e s /ithout hormone replacement( Baseline prolactin levels averaged3(6# E !(% ng4ml be)ore saline administration and "(!" E !(' ng4ml be)ore cocaine administration( BaselineLH levels averaged !#! E !" ng4ml be)ore saline administration and !!3 E !: ng4ml be)ore cocaineadministration( Cocaine reached pea plasma levels o) #$5 E 53 ng4ml /ithin 5 min a)ter i(v(administration( ;igure % sho/s that neither saline nor cocaine +$(6 mg4 g i(v( produced signi)icantchanges in basal levels o) prolactin or LH over the !!$-min sampling period(

!ie. larger"ersion +#!@ 1


0ig* 9* 2))ects o) saline or cocaine on prolactin, LH, and plasma cocaine inovariectomi*ed rhesus mon e s /ithout hormone replacement( retreatment

baseline levels o) prolactin +ro/ ! and LH +ro/ # are sho/n above baseline+BL and time +minutes a)ter saline or cocaine in?ection is sho/n on theabscissae( lasma hormone and cocaine levels +nanograms per milliliter aresho/n on the le)t ordinates( .he vertical dotted line above time $ indicates/hen saline +open circles or cocaine +closed circles /as in?ected( 2ach data

point be)ore and a)ter saline administration is the average +ES(2( o) threemon e s, and each point be)ore and a)ter cocaine +$(6 mg4 g i(v( is the average+ES(2( o) )ive mon e s( lasma cocaine levels +nanograms per milliliter aresho/n as open sFuares in ro/ %, and each data point is the average o) threemon e s because o) problems /ith sample handling(

#tudy 9/ Cocaine Effects on Prolactin and &$ during O"arian #teroid $ormone ReplacementCocaine Effects on Prolactin during Chronic Administration of E 4 Alone 7 0ig* : + ro. 38* .he e))ectso) cocaine on prolactin during dail maintenance on $($$!3 to $($$' mg4 g4da 2 # are sho/n in ;ig( 5 ,ro/ !( .hese doses o) 2 # produced average estradiol levels o) 6' E %" to ##! E %" pg4ml on the stud da
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+.able ! ( At lo/ estradiol doses, baseline prolactin levels /ere in the normal range and averaged !$(%5 E#(' to !5(!6 E %(3 ng4ml( Ho/ever, at the highest estradiol dose, baseline prolactin levels increased toaverage #%(5 E :(' ng4ml( During chronic treatment /ith all doses o) 2 # , cocaine administration /as)ollo/ed b a signi)icant decrease in prolactin levels + P O $($3-$($$! ( rolactin decreased signi)icantl

belo/ baseline /ithin 6 min a)ter i(v( cocaine administration during maintenance on $($$!3, $($$#, and$($$' mg4 g4da 2 # ( During maintenance on $($$5 mg4 g4da 2 # , prolactin decreased more slo/l and)ell signi)icantl belo/ baseline levels /ithin #$ to %3 min a)ter cocaine administration( .he signi)icant

decreases

in prolactin )rom baseline levels /ere sustained throughout

the !!$-min postcocaine sampling period + P O $($3-$($$! (

!ie. larger "ersion+#6@ 1


0ig* :* 2))ects o) cocaine on prolactin levels in ovariectomi*ed rhesusmon e s during ovarian steroid hormone replacement( .ime +minutes a)teradministration o) $(6 mg4 g i(v( cocaine is sho/n on the abscissae( BL is the

precocaine baseline prolactin level( rolactin levels +nanograms permilliliter are sho/n on the le)t ordinate( Ro/ ! sho/s prolactin levels

be)ore and a)ter cocaine administration during dail maintenance on 2 # +$($$!3-$($$' mg4 g i(m( ( Ro/ # sho/s prolactin levels be)ore and a)tercocaine administration during dail administration o) progesterone +$(%#mg4 g i(m( ( Ro/ % sho/s prolactin levels during dail administration o)

progesterone /ith 2 # +$($$# or $($$5 mg4 g i(m( ( 2ach data point in ro/ !is the average +ES(2( o) )our or )ive mon e s( 2ach data point in ro/s # and% is the average +ES(2( o) )our mon e s( s mbols, daggers, asteris s, anddiamonds sho/n above the 2 # doses indicate the points at each dose thatdi))er signi)icantl )rom the precocaine baseline + , P O $($3& , P O $($!&

, P O $($$! (

Cocaine Effects on Prolactin during Chronic Administration of Progesterone Alone 7 0ig* : + ro. 48* Be)ore progesterone replacement, basal progesterone levels averaged less than !(3 ng4ml( .able ! sho/sthat a)ter chronic treatment /ith $(%# mg4 g4da progesterone, basal progesterone levels /erecharacteristic o) earl luteal phase values measured in )emale rhesus mon e s during a normal ovulatormenstrual c cle +Mello et al(, !::" ( >n the stud da , baseline prolactin levels averaged :($3 E #(%'ng4ml be)ore cocaine administration( ;igure 5 +ro/ # sho/s that prolactin decreased signi)icantl /ithin!' min a)ter cocaine administration + P O $($$! ( rolactin remained signi)icantl belo/ precocaine

baseline levels )or the remainder o) the sampling period + P O $($3-$($$! (

Cocaine Effects on Prolactin during Chronic Administration of E 4 and Progesterone Com,inations70ig* : + ro. 98* .able ! sho/s basal progesterone and estradiol levels on the stud da a)ter chronictreatment /ith a combination o) progesterone and 2 # ( A)ter chronic treatment /ith progesterone and$($$# mg4 g4da 2 # , baseline prolactin levels averaged !#('# E '(#3 ng4ml, and there /ere no signi)icantchanges in prolactin levels a)ter cocaine administration + ;ig( %, ro/ % ( A)ter chronic treatment /ith

progesterone and $($$5 mg4 g4da 2 # , baseline prolactin levels averaged 5: E #5 ng4ml on the stud da (A)ter cocaine administration, prolactin levels decreased and remained belo/ baseline throughout thesample period + P O $($$! ( .here /ere no statisticall signi)icant di))erences in prolactin values at eachtime point bet/een the t/o progesterone 7 estradiol treatment conditions(

Cocaine Effects on &$ during Chronic Administration of E 4 Alone 70ig* ; + ro. 38* .he e))ect o)cocaine on LH during maintenance on $($$!3 to $($$' mg4 g4da 2 # is sho/n in ;ig( 3 +ro/ ! ( BaselineLH levels decreased as doses o) 2 # increased( LH averaged 66(' E !$, "%(5 E !$, #6(# E #(#, and #%(' E!(" ng4ml during maintenance on 2 # at doses o) $($$!3 to $($$' mg4 g4da ( Cocaine stimulated a small
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but signi)icant increase in LH /ithin !' min in mon e s maintained on $($$# mg4 g4da 2 # + P O $($3 (Ho/ever, during maintenance on both lo/er and higher doses o) 2 # , LH levels did not changesigni)icantl )rom precocaine baseline levels throughout the sampling period a)ter cocaine administration(

!ie. larger "ersion+#6@ 1


0ig* ;* 2))ects o) cocaine on LH levels in ovariectomi*ed rhesus mon e sduring ovarian steroid hormone replacement( .ime +minutes a)teradministration o) $(6 mg4 g i(v( cocaine is sho/n on the abscissae( BL is the

precocaine baseline LH level( LH levels +nanograms per milliliter aresho/n on the le)t ordinate( Ro/ ! sho/s prolactin levels be)ore and a)tercocaine administration during dail maintenance on 2 # +$($$!3-$($$'mg4 g i(m( ( Ro/ # sho/s LH levels be)ore and a)ter cocaine administrationduring dail administration o) progesterone +$(%# mg4 g i(m( ( Ro/ % sho/sLH levels during dail administration o) progesterone +$(%# mg4 g i(m( incombination /ith 2 # +$($$# or $($$5 mg4 g i(m( ( 2ach data point in ro/ !is the average +ES(2( o) )our or )ive mon e s( 2ach data point in ro/s # and% is the average +E S(2( o) )our mon e s( Daggers +$($# mg4 g4da andasteris s indicate points that di))er signi)icantl )rom the precocaine baseline+ , P O $($3& , P O $($!& , P O $($$! (

Cocaine Effects on &$ during Chronic Administration of Progesterone Alone 7 0ig* ; + ro. 48* >n thestud da , a)ter dail administration o) $(%# mg4 g progesterone alone, baseline LH levels averaged ::(6 E!'(#" ng4ml be)ore cocaine administration( ;igure 3 +ro/ # sho/s that LH increased signi)icantl /ithin6 min a)ter cocaine administration and remained elevated )or #$ min + P O $($3-$($! (

Cocaine Effects on &$ during Chronic Administration of E 4 and Progesterone Com,inations 7 0ig*; + ro. 98* >n the stud da , baseline LH levels averaged #6(# E "(# and #'(% E !(# ng4ml during chronictreatment /ith $(%# mg4 g progesterone in combination /ith $($$# or $($$5 mg4 g 2 # , respectivel (Basal 2 # and progesterone levels are sho/n in .able # ( During chronic maintenance on a combination o)$($$# mg4 g estradiol 7 $(%# mg4 g progesterone, cocaine stimulated a nonsigni)icant increase in LH/ithin 6 min, and LH remained elevated )or #$ min( .here /as considerable variabilit bet/eenmon e s( LH increased b !%$ to over !3$N /ithin 6 to !' min in t/o mon e s, but did not changeappreciabl in t/o other mon e s( During chronic maintenance on $(%# mg4 g progesterone incombination /ith $($$5 mg4 g 2 # , LH levels increased progressivel across the sampling period and

averaged 53(6 E !!(6 ng4ml at !!$ min a)ter

cocaine administration( Ho/ever, there /ere no statisticall

signi)icant changes in LH a)ter cocaine administration(

!ie. thista,le/Gin this

/indo/Gin a ne//indo/

.ABL2 # harmaco inetics o) cocaine +$(6 mg4 g4i(v( in ovariectomi*ed )emaleRhesus mon e s /ith and /ithout ovarian steroid hormone replacement
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Plasma Cocaine &e"els during $ormone Replacement 7 Ta,le 4 8* .able # sho/s average plasmacocaine levels during chronic treatment /ith 2 # alone +$($$#-$($$' mg4 g4da , progesterone alone +$(%#mg4 g4da alone, and 2 # +$($$# mg4 g 7 progesterone +$(%# mg4 g4da in combination( lasmacocaine levels a)ter treatment /ith $($$5 mg4 g4da 2 # , in combination /ith $(%# mg4 g4da

progesterone and $($$!3 mg4 g4da 2 # alone are not reported because o) problems /ith sample handling(A pharmaco inetic anal sis o) plasma cocaine levels in these ovariectomi*ed )emales /ithout hormonereplacement and during each hormone condition /as per)ormed, and the results are summari*ed in .able

#( .here

/ere no signi)icant di))erences in an pharmaco inetic parameter

as a )unction o) chronichormone treatment in comparison /ith control conditions( .he time to reach ma0imum plasma cocaine

concentrations + T ma0 /as 5 to 3(% min a)ter intravenous cocaine administration during chronicadministration o) 2 # , progesterone and 2 # 7 progesterone combinations( .he pea plasma cocaine

concentration + C ma0 averaged bet/een !"5 E !:(% and #%6 E %%(5 ng4ml, and there /ere no signi)icantdi))erences across treatment conditions( .he average hal)-li)e o) plasma cocaine +t !4# /as bet/een %'(:and 33 min and also did not var signi)icantl as a )unction o) the hormone treatment condition(

Discussion

>ne ma?or )inding o) this stud is that dail administration o) ph siologicall relevant doses o) estradiolor progesterone to ovariectomi*ed rhesus mon e s signi)icantl in)luenced the e))ects o) cocaine on

prolactin( nder control conditions /ithout hormone replacement, cocaine did not alter prolactin&ho/ever, during chronic treatment /ith estradiol or progesterone, cocaine signi)icantl decreased

prolactin( Hormone replacement had less consistent e))ects on cocaine8s interactions /ith LH( Cocaine didnot stimulate LH release in untreated ovariectomi*ed mon e s, and it also did not reliabl increase LHrelease during treatment /ith ovarian steroid hormones( .he onl e0ceptions to this general )inding /ere

that cocaine signi)icantl increased plasma LH

levels during treatment /ith an intermediate dose o) $($$5mg4 g4da 2 # alone and /ith $(%# mg4 g4da progesterone alone( Ho/ever, these e))ects /ere relativelsmall, and an modulation o) cocaine e))ects on LH b 2 # /as not monotonicall related to the 2 # dose(.here /ere no statisticall signi)icant di))erences in plasma cocaine levels or cocaine pharmaco inetics

bet/een control conditions and hormone replacement conditions, /hich suggest that an hormone-associated changes in the endocrine e))ects o) cocaine could not be attributed to changes in the

pharmaco inetics o) cocaine(

Effects of O"arian #teroid $ormone replacement on &$ and Prolactin &e"els* .he present studmanipulated ovarian steroid hormone levels in ovariectomi*ed rhesus mon e s to test the h pothesis thatovarian steroid hormone levels ma in)luence cocaine8s endocrine e))ects( 9n accordance /ith previousstudies, dail treatment /ith 2 # +$($$!3-$($$' mg4 g4da and progesterone +$(%# mg4 g4da produced

ph siological plasma levels o) estradiol and progesterone( Speci)icall , doses o) $($$!3-$($$# mg4 g4da

2 # produced estradiol levels similar to those observed during the )ollicular and luteal phases o) themenstrual c cle, and higher doses o) $($$5 to $($$' mg4 g4da 2 # produced estradiol levels similar tothose observed during the peri-ovulator phase( 9n addition, $(%# mg4 g4da progesterone producedsustained levels o) progesterone similar to those observed during the luteal phase o) an ovulatormenstrual c cle +Mello et al(, !::" (

.hese ovarian hormone treatment regimens also produced e0pected changes in basal LH and prolactinlevels( 2 # produced a dose-dependent decrease in LH and an increase in prolactin levels( .hese )indings

are consistent /ith the e))ects o) estradiol treatment in postmenopausal /omen +Carr, !::6 andovariectomi*ed rats +Ben-Jonathan, !:63 & DeMaria et al(, #$$$ ( 9n contrast, the dose o) progesterone

used in this stud +$(%# mg4 g4da had little e))ect on either LH or prolactin levels(
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12/21

Cocaine


13/21

LH prevented the commonl observed stimulation o) LH b cocaine +Mendelson et al(, #$$! & Mello andMendelson, #$$# ( Consistent /ith this h pothesis, /hen the inhibitor e))ect o) estradiol on LH /as

absent during treatment /ith progesterone alone, cocaine stimulated LH release /ithin 6 min( .his timecourse /as similar to that observed in gonadall intact, luteal phase rhesus )emales a)ter $(6 mg4 gcocaine +!$ min +Mello et al(, !::% and in luteal phase human )emales a)ter $(5 mg4 g i(v( cocaine +!#min +Mendelson et al(, #$$! ( Cocaine stimulation o) LH release during chronic progesterone treatmentalso is consistent /ith reports that acute progesterone administration can stimulate an LH surge in

ovariectomi*ed mon e s +.erasa/a, !:63 (

Basal LH levels did not seem to in)luence cocaine8s e))ects, because cocaine did not stimulate LH /hen basal LH levels /ere lo/ +#%-#6 ng4ml or high +"%-66 ng4ml ( .he time course o) LH stimulation during progesterone treatment /as most similar to that previousl observed in mid-luteal )emales, inso)ar as LHincreased signi)icantl /ithin !$ to #$ min +Mello et al(, !::% ( Ho/ever, LH remained elevated )or 3$min in mid-luteal )emales but returned to baseline /ithin %$ min in these ovariectomi*ed )emales( 9n)ollicular phase )emales, the onset o) signi)icant LH increases occurred more slo/l , /ithin #$ min, butremained above baseline )or 5$ to 3$ min +Mello et al(, !::$a (

Cocaine Interactions .ith O"arian #teroid $ormones* .a en together, these )indings are consistent/ith the h pothesis that ovarian steroid hormones ma modulate cocaine8s e))ects on anterior pituitarhormones +Mello et al(, #$$$ & Mello and Mendelson, #$$# ( Moreover, it seems that ovarian steroidhormone replacement restored cocaine8s abilit to decrease prolactin levels more e))ectivel than itrestored cocaine8s abilit to increase LH levels( .hese )indings are also o) interest in vie/ o) theconsiderable evidence that ovarian steroid hormones ma in)luence some o) cocaine8s behavioral e))ects+)or revie/, see Mello and Mendelson, #$$# ( ;or e0ample, high levels o) estradiol be)ore estrus /ere

associated /ith higher levels o) cocaine-induced locomotor e))ects than at other stages o) the estrous c clein rats, and ovariectom decreased cocaine-induced locomotion +Sell et al(, #$$$ ( 9n ovariectomi*edrats, replacement o) estradiol, and estradiol and progesterone in combination, increased cocaine-inducedlocomotor activit signi)icantl above levels measured during replacement o) progesterone alone or nohormone replacement +Sell et al(, #$$$ & @uhn et al(, #$$! ( 9n cocaine sel)-administration studies, therein)orcing e))ects o) cocaine /ere greatest /hen estradiol levels /ere high +Roberts et al(, !:6: & L nchet al(, #$$$ ( 9n)ormation about the in)luence o) ovariectom on cocaine8s abuse-related e))ects is lessconsistent( 9n rats trained to sel)-administer cocaine, neither ovariectom nor estradiol replacement

signi)icantl altered cocaine sel)-administration dose-e))ect curves +S( B( Caine, C( A( Bo/en, ( u, D(Tu*ga, S( S( egus, and ( @( Mello, submitted ( Rats learned to sel)-administer cocaine a)terovariectom +S( B( Caine, C( A( Bo/en, ( u, D( Tu*ga, S( S( egus, and ( @( Mello, submitted , andadministration o) estradiol tended to decrease cocaine sel)-administration + rimm and See, !::' ( .hee0tent to /hich these interactions bet/een cocaine and ovarian steroid hormones ma have implications

)or some cocaine-related behavioral e))ects remains to be determined +)or revie/, see Mello andMendelson, #$$# (

Ac(no.ledgements


14/21

hormone serum +rabbit +A; %5#::5 ( reliminar data /ere presented to the College on roblems o)Drug Dependence at the #$$# annual meeting(

References!(

Abusada GM, Abukhalaf IK, Alford DD, Vinzon-Bautista I, Pramanik AK, Ansari A, Manno !",and Manno B# $%&&'( )olid-*has+ + traction and GC M) .uantitation of cocain+, +c/onin+m+th0l +st+r, b+nzo0l+c/onin+, and coca+th0l+n+ from m+conium, 1hol+ blood and *lasma2 ! Anal To icol %3 : '4'-'452

#(

B+n-!onathan $%&54( Do*amin+6 a *rolactin-inhibitin/ hormon+2 "ndocr #+7 8 : 489-45&2

Abstract 4;R22 ;ull .e0t

%(

B+n-!onathan and :nasko # $;


15/21

Carr B# $%&&5( Disord+rs of th+ o7ari+s and f+mal+ r+*roducti7+ tract, in ?ilson s T+ t Book of "ndocrinolo/0 $?ilson !D2, ost+r D?, Kron+nb+r/ :M, and =ars+n P# +ds( * 83, ?2 B2)aund+rs Com*an0, Philad+l*hia2

6(

D+Maria !", a/0 GM, =+rant AA, +k+t+ MI", =+7+nson C?, and r++man M" $;


16/21

:otchkiss ! and Knobil " $%&&9( Th+ m+nstrual c0cl+ and its n+uro+ndocrin+ control, in Th+ Ph0siolo/0 of #+*roduction, ;nd +d2 $Knobil " and +ill !D +ds( ** 3%%-39&, #a7+n Pr+ss, +1Eork2

!'(

!atlo1 PI and Bail+0 DI $%&34( Gas-chromato/ra*hic anal0sis for cocain+ in human *lasma, 1ith

us+ of a nitro/+n d+t+ctor2 Clin Ch+m ;% : %&%5-%&;%2

Abstract

!"(

Kuhar M! $%&&'( +urotransmitt+r trans*ort+rs as dru/ tar/+ts6 r+c+nt r+s+arch 1ith a focus onth+ do*amin+ trans*ort+r2 Pharmacolo/ist '4 : ;5-''2

!6(

Kuhn CM, ?alk+r FD, Ka*lan KA, and =i )T $;


17/21

CrossRe) Medline

#5(

M+llo K and M+nd+lson !: $;


18/21

%!(

M+llo K, )arn0ai , M+nd+lson !:, Dri+z+ !M, and K+ll0 M $%&&'( Acut+ +ff+cts of cocain+ onant+rior *ituitar0 hormon+s in mal+ and f+mal+ rh+sus monk+0s2 ! Pharmacol " * Th+r ;88 : 5


19/21

Misra A=, Giri VV, Pat+l M , Alluri V#, and Mul+ )! $%&33( Dis*osition and m+tabolism of $ ' :(cocain+ in acut+l0 and chronicall0 tr+at+d monk+0s2 Dru/ Alcohol D+*+nd ; : ;8%-;3%2

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Articles citing this article Histologic and $$unohistoche$ical Characteri/ation o0 S ontaneous 1ituitary Adeno$as in

2ourteen Cyno$olgus Maca3ues 4Macaca 0ascicularis5 6eterinary 1athology 7uly !, &%%8 '9+')'-':9o Abstracto Full Texto Full Text (PDF)
http://vet.sagepub.com/cgi/content/abstract/43/4/484http://vet.sagepub.com/cgi/content/full/43/4/484http://vet.sagepub.com/cgi/reprint/43/4/484http://vet.sagepub.com/cgi/content/abstract/43/4/484http://vet.sagepub.com/cgi/content/full/43/4/484http://vet.sagepub.com/cgi/reprint/43/4/484

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