ERIC EJ913381: Effects of Daily Morphine Administration and Deprivation on Choice and Demand for Remifentanil and Cocaine in Rhesus Monkeys

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by  ERIC

JOURNALOFTHEEXPERIMENTALANALYSISOFBEHAVIOR 2011,95,75–89 NUMBER1(JANUARY)
EFFECTS OF DAILY MORPHINE ADMINISTRATION AND DEPRIVATION ON CHOICE AND
DEMAND FOR REMIFENTANIL AND COCAINE IN RHESUS MONKEYS
TAMMY WADE-GALUSKA1,2, CHAD M. GALUSKA3, AND GAIL WINGER1
1UNIVERSITYOFMICHIGAN
2UNIVERSITYOFSOUTHCAROLINA-SALKEHATCHIE
3COLLEGEOFCHARLESTON
Choiceprocedureshaveindicatedthattherelativereinforcingeffectivenessofopioiddrugsincreases
duringopioidwithdrawal.Thedemandcurve,anabsolutemeasureofreinforcervalue,hasnotbeen
appliedtothisquestion.Thepresentstudyassessedwhethermildmorphinewithdrawalwouldincrease
demandfororchoiceofremifentanilorcocaine.Fourrhesusmonkeyschosebetweenremifentaniland
cocaineduringdailysessions.Demandcurvesforbothdrugsweresubsequentlyobtained.Theeffectsof
dailyinjectionsof3.2mg/kgmorphineonbothchoiceanddemandforthesedrugswasassayed3and
20.5hraftereachmorphineinjection,andthenduringapostmorphineperiod.Threehoursfollowing
morphineinjections,choiceofremifentanilovercocainedecreasedanddemandforremifentanil—but
not cocaine—became more elastic. During morphine withdrawal (20.5 hr postinjection), choice of
remifentanil increased and remifentanil demand became more inelastic in 3 of 4 monkeys. Cocaine
demand also became more inelastic during this period. Four to five weeks following the morphine
regimen,demandforbothdrugswas moreinelasticrelativetotheinitialdetermination.Theresults
suggestthatboththerelativeandabsolutereinforcingeffectivenessofremifentanildecreasedfollowing
morphine administration and increased during morphine withdrawal. The absolute reinforcing
effectivenessofcocainealsoincreasedduringmorphinewithdrawal.Inaddition,extendedexposureto
drugself-administrationand/orexposuretothemorphineregimenproducedlong-termincreasesin
demandforbothdrugs.
Keywords: drugself-administration,behavioraleconomics,choice,remifentanil,cocaine,leverpress,
rhesusmonkeys
_______________________________________________________________________________
Studiesofwhetherthereinforcingeffectsof is the possibility that withdrawal-induced in-
opioids are increased as the result of opioid creases in the reinforcing effects of opioids,
withdrawal are important for several reasons. particularly if they are long-term, may contrib-
First, in dependent individuals, opioids may ute to relapse to opioid abuse in recovering
servenotonlyaspositivereinforcers, buttheir opioid abusers. Two procedures frequently
self-administration also may be maintained by have been employed to reflect withdrawal-
negative reinforcement. Opioid withdrawal induced increases in the reinforcing effective-
has been characterized as an aversive condi- ness of opioids: the measurement of changes
tion (Downs & Woods, 1975), which is quickly in rates of responding and number of injec-
ameliorated by opioid self-administration tions self-administered, and the measurement
(Gerak,Galici,&France,2009).Second,there of changes in choice of an opioid over a non-
opioid option.
The University of Michigan is accredited by the Gerak et al. (2009) evaluated the effects of
AmericanAssociationfortheAccreditationofLaboratory chronic,noncontingentmorphineadministra-
AnimalCare(AAALAC).Assuch,proceduresusedinthis tion on the self-administration of a range of
experiment were conducted in accordance with the
heroin and cocaine doses in rhesus monkeys.
National Research Council’s (1996) Guide for the Care
and Use of Laboratory Animals and approved by the Theirregimenoftwice-dailymorphineadmin-
UniversityCommitteeonCareandUseofAnimals. istration,whichinvolvedincreasingthedoseof
SupportfromtheNationalInstituteonDrugAbuse,DA morphine over a period of several weeks,
015449 and DA 023992 is gratefully acknowledged. The
resulted in dependence as measured by signs
authorsalso thankAmyHall andGrahamFloryfor their
of withdrawal. Heroin and cocaine self-admin-
technical assistance with this research, and Dr. James H.
Woodsforhiscommentsonthemanuscript. istration then was assessed following varying
Correspondence may be addressed to Tammy Wade- durationsofmorphinedeprivation.Fivehours
Galuska, University of South Carolina-Salkehatchie, 807
after an injection of morphine, rates of
Hampton St. Walterboro, SC 29488 (e-mail: twadegal@
responding maintained by both heroin and
mailbox.sc.edu).
doi:10.1901/jeab.2011.95-75 cocaine were decreased relative to baseline.
75
76 T. WADE-GALUSKA et al.
However,17hrofmorphinedeprivationledto tion of heroin. The authors suggested that
increases in the number of injections of small morphine and naloxone had altered choice
cocaine doses (less than 10 mg/kg/infusion) behavior by interacting with the reinforcing
and 29 hr of morphine deprivation led to properties of heroin. Given the large dose of
increases in the number of injections of all heroin the baboons obtained (1.0 mg/kg/
heroin doses tested (ranging from 5.6 to injection), it is likely that naloxone produced
560 mg/kg/infusion). Following the comple- increasesinchoiceofheroininpartbecauseit
tion of chronic morphine administration, the elicited opioid withdrawal.
number of injections of small heroin doses, Another way to evaluate changes in the
particularly 5.6 mg/kg/infusion and smaller, effectiveness of a reinforcer is demand-curve
remained markedly elevated relative to injec- analysis (e.g., Bickel, DeGrandpre, Higgins, &
tions earned before and during morphine Hughes 1990; Hursh & Silberberg, 2008;
administration. The authors attributed this Hursh & Winger, 1995). Here, the consump-
effect to conditioned reinforcement; specifi- tion of a commodity, or reinforcer, is mea-
cally,theypostulatedthatthecuespairedwith sured as its price (response requirement) is
heroin and cocaine infusions became more altered. Initially as the price (defined here as
effective in maintaining responding during the response requirement / dose) of a
opioidwithdrawalthantheyhadbeenpriorto reinforcer is increased, consumption is de-
morphine exposure. These cues then main- fended by increases in responding and re-
tainedtheirreinforcingeffectivenessformany mains relatively unchanged. With further
weeks following withdrawal. increases in price, consumption decreases.
Studies in rats support this conclusion; for Whenplottedonlog–logcoordinates,therate
example,ratstrainedtoself-administerheroin at which consumption decreases as a function
show marked increases in responding for cues of price is termed elasticity of demand.
that were previously paired with heroin. This Generally speaking, a reinforcer that is more
occurred for rats that had been heroin effective at maintaining behavior engenders a
abstinent for 4 weeks as well as for those that less elastic demand curve, with consumption
hadbeenheroinabstinentfor1week(Zhouet decreasing at a slower rate as a function of
al. 2004). price,whencomparedwithareinforcerthatis
An alternative evaluation of opioid-main- less effective at maintaining behavior.
tained responding during opioid withdrawal In the present experiment, both a choice
involves measuring changes in choice of an procedureandademandprocedurewereused
opioid versus a non-opioid reinforcer during to assess the effects of mild morphine with-
opioid withdrawal. Negus (2006) assessed drawal on the reinforcing effectiveness of the
choice between a range of heroin doses and ultrashort-acting m-opioid agonist remifentanil
food in nondependent and heroin-dependent and the psychostimulant cocaine in rhesus
rhesus monkeys. At small or zero doses of monkeys. After (premorphine) measures of
heroin, the monkeys showed a near-exclusive choice and demand for cocaine and remifen-
preference for food; as the dose of heroin was tanil were obtained, 4 monkeys were given
increased, preference shifted from food to daily injections of 3.2 mg/kg morphine. This
heroin. When the monkeys were given suffi- method of morphine administration has been
cient access to heroin to produce opioid used previously to produce mild opioid de-
dependence and were then heroin-restricted, pendence in rhesus monkeys (France &
opioidwithdrawalwasobservedandthechoice Woods,1989;Winger&Woods,2001).Choice
ofheroinoverfoodwasincreasedsubstantially betweencocaineandremifentanilwasassessed
at all but the largest dose. foratleast2weeksinsessionsconducted3and
Earlier findings regarding choice between 20.5 hr after each morphine injection. When
heroin and food are consistent with those of choice of cocaine and remifentanil was stable,
Negus (2006). Griffiths, Wurster, and Brady demand for each self-administered drug was
(1981) found that infusions of morphine reassessed while daily morphine injections
produced dose-dependent decreases in selec- continued. The morphine injections were
tion of heroin over food in baboons whereas then stopped; 4 to 5 weeks following the final
infusions of the opioid antagonist naloxone morphine injection, demand for cocaine and
produced dose-dependent increases in selec- remifentanil was assessed for a third time. It
CHOICE AND DEMAND FOR REMIFENTANIL AND COCAINE 77
was predicted that, while overall responding catheter exited the tether at the rear of the
would be suppressed 3 hr following morphine cage,itultimatelywasconnectedtothreestock
administration, responding for remifentanil solutions, one with cocaine, one with remifen-
would be affected to a greater extent than tanil, and one with saline. The tubing that
respondingforcocaineatthistime.At20.5hr connected the catheter with each stock solu-
following morphine, choice and demand for tion passed through an infusion pump (one
remifentanil was expected to increase relative per stock solution) which delivered 0.2 ml of
to choice and demand for cocaine. It also was solution per second. Each delivery lasted 5 s
expected that the latter changes would be (totaling a 1-ml injection volume). Control of
maintained, at least to some extent, beyond experimentalsessionswasprovidedbyMed-PC
the period of daily morphine administration. (Med-Associates, Georgia, VT) interfacing and
software (Version IV) installed on computers
located in an adjacent room.
METHOD
Subjects Procedure
Subjects were 4 adult rhesus monkeys Drug-dose selection. The monkeys in the
(Macaca mulatta), 3 male and 1 female. All present experiment were previously employed
monkeys had a history of self-administering inanexperimentconductedbyWade-Galuska,
drugs, including cocaine and remifentanil, Winger,andWoods(2007).Thedosesselected
according to fixed-ratio (FR) schedules. Ex- for 3 of the monkeys in the present experi-
ment (30 mg/kg/inf cocaine and 0.3 mg/kg/
perimental sessions were conducted in the
inf remifentanil) were based on data obtained
home cages. The monkeys were fed high-
by Wade-Galuska et al. that demonstrated that
protein monkey biscuits twice daily and fruit
these doses maintained comparable levels of
once daily to maintain their adult body
behavior across a variety of response require-
weights. Water was continuously available and
ments. When these doses were used in the
environmental enrichment was provided on a
choice phase of the present study, 2 of the 3
rotating basis.
monkeyschoseremifentanilnearlyexclusively.
Therefore, the 4th monkey (3506) was tested
Apparatus
with a smaller dose of remifentanil (0.03 mg/
Monkeyswerehousedandtestedinstainless
kg/inf) so that the effects of morphine
steelcagesthatmeasured83.3cm376.2cm3
administration and deprivation could be ob-
91.4 cm. Each cage was equipped with a
served in an animal that initially preferred
response panel located on the left wall,
cocaine.
approximately 10 cm from the front and
Drug infusions. So that cocaine and remifen-
19cmfromthebottomofthecage.Thepanel
tanil could be administered within the same
contained three horizontally aligned levers,
session through the same catheter, the follow-
each of which could be activated by approxi-
ing procedure was employed: At the start of
mately 10-15 g of force. Three stimulus lights, each session, approximately 1 ml saline was
each one of which was centered above a lever, infused into the portion of the catheter
were 2.5 cm in diameter and spaced 1.5 cm externaltothemonkey(hereafter,theexternal
apart. Each light consisted of a circular catheter).Duringeachreinforcerdelivery,a10-
opening that was covered with translucent s infusion occurred consisting of two compo-
plastic and capable of being illuminated from nents. During the first component the drug
behind by 5-W colored bulbs. pump operated for 5 s, pushing the saline
Monkeys were implanted withanindwelling (infused into the external catheter at the start
intravenous catheter that passed subcutane- of the session) into the monkey while filling
ously from the implanted vein to an exit site the externalcatheter with1 ml of the selected
on the monkey’s back. The catheter was fed drug. The second component of an infusion
through a stainless steel tether that was consisted of the 5-s operation of the saline
attachedtothebackoftheTeflonmeshjacket pump which pushed the drug into the
(Lomir, Quebec, Canada) worn by each monkey, while filling the external catheter
monkey. The other end of the tether was with saline in preparation for the next
attachedtothebackwallofthecage.Oncethe reinforcer delivery.
78 T. WADE-GALUSKA et al.
Drug infusions were characterized by the Table1
same stimulus changes in all phases of the Order in which drugs were tested in demand conditions
study. When an infusion was earned, the occurring before (Pre), during (Daily), and following
stimulus lights above the center and right (Post)dailymorphineadministration.
levers were turned off and the light above the
Condition
left lever turned green for the duration of the Drug
infusion. Following each infusion there was a Monkey (lever) Pre Daily Post
45-s timeout in which all stimuli were turned 3956 Coc(C) 1 2 –
off and lever presses had no consequence. Coc(R) 4 – –
Left-lever holding. This procedure, used in Remi(C) 3 – –
Remi(R) 2 1 –
Wade-Galuska et al.’s 2007 experiment as well
3953 Coc(C) 2 1 1
as in the present study, was implemented so Coc(R) 1 – –
that the monkeys could use only one hand, Remi(C) 4 – –
rather than pressing multiple levers, to select Remi(R) 3 2 2
2084 Coc(C) 2 2 1
between the drug options. The procedure
Coc(R) 1 – –
required that monkeys hold down the left
Remi(C) 4 – –
lever (e.g., with the left hand) of the three- Remi(R) 3 1 2
lever panel while completing a response 3506 Coc(C) 1 1 2
requirement on another lever (e.g., with the Coc(R) 2 – –
Remi(C) 3 – –
right hand). At the start of a session, a white
Remi(R) 4 2 1
stimuluslightabovetheleftleverflashed(0.5s
on/off)untiltheleftleverwaspressed.Once
the lever was pressed, the white stimulus light premorphine demand only, monkeys were
above the left lever stopped flashing (turning exposed to a condition in which the center
solid white) and the stimulus light above the lever was the operative cocaine lever and
operative lever turned to the color correlated another condition in which the right lever
with the drug associated with that lever. As was the operative cocaine lever. Cocaine was
longastheleftleverwashelddown,responses correlated with a red stimulus light in both
on the operative lever counted toward com- cases; a red light above the operative lever
pletion of the response requirement. If the signaled that completion of the response
monkey stopped holding the left lever, the requirement would result in a cocaine infu-
lightabovetheoperativedrugleverwasturned sion. Demand also was assessed with remifen-
off and the white light above the left lever tanil available for responding on either the
flashed until the left lever was again pressed. center or right lever across conditions. Remi-
Releasingtheleftleversuspendedtheongoing fentanil was correlated with a blue stimulus
schedules, but did not reset the number of light. Each drug was tested on each of the two
responses already made toward the ratio leverstoensurethatnoleverbiasesexistedfor
requirement. the center or right lever as the result of the
Premorphine demand. The premorphine de- left-lever holding procedure. No biases were
mand functions (demand functions obtained observed, so these conditions were collapsed
priortodailymorphineinjections)forcocaine across lever-type in order to generate a single
and remifentanil were reported in a previous cocaine and remifentanil demand curve con-
study conducted by Wade-Galuska et al. sisting of eight sessions at FR 10 and FR 100,
(2007). The same general procedure was used and four sessions at the other ratios. The
to generate all demand functions reported in averageconsumptionateachratiowasusedin
this experiment, including those obtained by the creation of the premorphine demand
Wade-Galuskaetal.Theresponserequirement curve. Once morphine injections began and
was increased after every two consecutive throughout the remainder of the experiment,
sessions according to an ascending sequence cocaine was associated with the center lever
ofratios:10,32,100,320,562,and1000.After and remifentanil was associated with the right
this entire sequence of ratios was tested, two lever. Table 1 shows the order in which drugs
consecutive sessions at FR 10 followed by two were tested when generating demand func-
consecutivesessionsatFR100wereconducted tions before,during, andafterdailymorphine
foreachdrugforreplicationpurposes.During exposure. The order was counterbalanced
CHOICE AND DEMAND FOR REMIFENTANIL AND COCAINE 79
across monkeys and across exposures within conducted twice daily, once in the morning
each monkey. andonceintheafternoon).Duringtheperiod
Premorphinechoice. Following thecompletion of daily morphine administration, choice and
ofdatacollectionfortheexperimentreported demand data were analyzed separately for
by Wade-Galuska et al. (2007) and immediate- sessionsoccurringatthe3-hrand20.5-hrtime
ly prior to the start of daily morphine points.
injections, 30 mg/kg/inf cocaine and 0.3 mg/ Choice sessions continued while daily mor-
kg/inf remifentanil (or 0.03 mg/kg/inf remi- phine injections were administered. Although
fentanilforMonkey3506)weremadeavailable notexplicitlyquantified,afterabout2weeksof
concurrently. Cocaine was available following morphine injections, one or more signs of
the completion of an FR 10 schedule on the mild withdrawal, including increased vocaliza-
center lever and remifentanil was available tion, salivation, and irritability, were observed
followingthecompletionofthesameresponse prior to injections. These symptoms typically
requirement on the right lever. Under these were alleviated upon the administration of
circumstances, holding the left lever down morphine,indicatingamilddegreeofphysical
turned on both the red stimulus light above dependence on morphine. Monkeys also
the center lever and the blue light above the experienced some weight loss over the course
right lever allowing monkeys to respond for of morphine administration. We concluded
either drug. The FR 10 response requirement that this was likely due to morphine-induced
on one lever did not reset if a response(s) decreases in food consumption rather than
occurred on the other lever during the withdrawal-induced decreases in appetite be-
completion of a ratio. The response require- cause food consumption generally increased
ment for both drugs was reset only at the start as the time since the most recent morphine
of a new ratio following an infusion and injection increased (up to the time of the
subsequent 45-s timeout. subsequent injection).
Choice sessions consisted of at least one After at least 2 weeks and when choice was
leverreversal(twowereconductedforMonkey stable in sessions conducted at each time
2084), during which remifentanil was earned point, demand functions were again obtained
from completing a ratio on the center lever for cocaine and remifentanil while daily
and cocaine from completing a ratio on the morphine injections continued. Each ratio
right lever. The stimulus light colorassociated was in effect for two consecutive sessions as
with each drug remained the same as it had previously described, so that at least one
been before. In all cases, preference tracked session was conducted 3 hr after morphine
the reversal and choice was nearly identical to and one session was conducted 20.5 hr after
thatobservedpriortothereversal.Areturnto morphine at each response requirement. At
standard lever conditions (cocaine available least one response requirement (usually 10,
on the right lever and remifentanil on the 32, or 100) was then replicated. For the
center) followed. Again, preference tracked monkey (3506) that was tested with a small
this change. Behavior was judged stable dose of remifentanil (0.03 mg/kg/inf) in
(during the lever reversal and the return to choice sessions, the dose was increased to
standard lever conditions) when at least six 0.3 mg/kg/inf because the smaller dose did
sessions were conductedand whennoincreas- not maintain behavior in the context of a
ing or decreasing trends in choice were demand procedure.
observed. Only data from the last six sessions Postmorphine choice. Following daily mor-
ofthereturntostandardleverconditionswere phine administration, Monkey 3956 became
used in the calculation of premorphine ill for reasons unrelated to the study, and was
choice. euthanized. The remaining monkeys were
Daily morphine administration. Once choice returned to the procedure that allowed them
between cocaine and remifentanil was stable, to choose between cocaine and remifentanil.
dailyinjectionsof3.2mg/kgmorphinebegan. The remifentanil dose was decreased to
Each injection was administered i.v. approxi- 0.03 mg/kg/inf for Monkey 3506 in order to
mately 3hr prior totheafternoonsession and compare preference before and after daily
20.5 hr prior to the session that occurred the morphine administration. Also, Monkey 3953
following morning (recall that sessions were experienced a catheter failure at the end of
80 T. WADE-GALUSKA et al.
Table2
The average number of drug infusions earned over the last six stable choice sessions of each
condition, including sessions prior to daily morphine (Pre), sessions occurring 3 and 20.5 hr
followingeachmorphineinjectionduringdailymorphine,andsessionsconducted4to5weeks
followingdailymorphine(Post).Standarddeviationisshowninparentheses.
Pre 3hr 20.5hr Post
Monkey Coc Remi Coc Remi Coc Remi Coc Remi
3956 20(7) 83(3) 22(7) 20(8) 4(2) 86(6) – –
3953 19(7) 86(3) 10(4) 82(7) 10(3) 96(3) 31*(5) 80*(3)
2084 34(3) 48(5) 44(15) 15(4) 14(4) 101(6) 48(9) 54(11)
3506 88(2) 4(3) 70(9) 7(8) 36(10) 22(7) 68(7) 4(3)
*Databasedonchoicesessionsinwhichleverswerereversed.Seetextforadditionaldetails.
daily morphine administration and had a 1- Theparameteraprovidesanindexofelasticity
weekhiatus and catheterimplantationsurgery ofdemand:Asaincreases,consumptiondrops
prior to returning to the choice procedure. off more quickly with increases in price.
Once she resumed choice at the end of this Conversely, smaller values of a reflect more
hiatus, she responded exclusively for remifen- inelastic functions in which consumption
tanil. It is believed that this was because her decreases more slowly with increases in price.
most recent history was with remifentanil as HurshandSilberbergarguedthataprovidesa
theonlydrugavailable.Becauseofthis,alever measure of the reinforcing effectiveness of a
reversal was conducted and stable choice (see commodity. For instance, if opioid withdrawal
Table 2), in which remifentanil was chosen at increasesthereinforcingeffectivenessofaself-
premorphine levels (as well as during daily administered drug, the a parameter should
morphineadministration)wasagainobserved. decrease.
Approximately 4 to 5 weeks later, demand The graphing and statistical software Prism
was reassessed for each drug (see Table 1 for (GraphPad Software, Inc., San Diego, CA) was
theorderthatdrugsweretested)accordingto used in the graphing and statistical analysis of
the demand procedure previously described. demand functions. We fitted the exponential
All sessions lasted 2 hr and were conducted demandfunctiontotheindividualsubjectand
twicedailyatthesametimeseachday(oncein group data for each drug and time point: pre,
the morning and once in the afternoon), 3 hr, 20.5 hr, and post. In cases in which
7 days per week. monkeys did not earn an injection, a value of
0.1 was assigned because the log of zero is
Data Analysis undefined. We focused on two parameters of
Demand curves. The exponential demand the exponential demand equation: a and Q0.
equation(Hursh&Silberberg,2008)wasfitted As described, a represents elasticity of de-
to the average number of drug deliveries mand. We also analyzed the Q0 parameter as
earned at each response requirement. In this anindexoftheinitiallevelofdemandbecause
equation: it is possible that demand curves could shift
vertically without affecting demand elasticity.
logQ~logðQ Þzk(cid:1)e{aP{1(cid:2), For each drug, the values of these parameters,
0
alongwithgoodness of fit (R2), were obtained
Q represents the number of drug deliveries at both for the group and individually at each
eachresponserequirement,orprice(P).Q is point of the study.
0
an estimate of consumption at zero-price and Response rate. Rates of responding were
mathematicallyrepresentsthey-intercept.The calculated for all sessions. However, the left
parameter k is a scaling parameter represent- lever-holding procedure used in the present
ing the range of the dependent variable in experiment required that monkeys hold down
logarithmic units. We set k at a constant value the left lever in order to gain access to the
of 3 for all analyses because it was the smallest schedule(s)ineffect.Therefore,thetimeused
whole number whose antilog (1000) was in the calculation of response rate was
greater than all observed dependent values. incremented only when the left lever was
CHOICE AND DEMAND FOR REMIFENTANIL AND COCAINE 81
beinghelddown.Thistimewasnotincremen- edjustslightlyfasterforremifentanil)whereas
ted during infusions or during the time spent the cocaine-preferring monkey (3506) re-
in timeout following an infusion, when left- sponded more rapidly for cocaine than for
lever holding had no programmed conse- remifentanil (right panels, Figure 1). Re-
quences. Response rates were calculated as sponse rates maintained by cocaine increased
the number of responses divided by the 3 hr following morphine administration for
adjusted session time. This procedure for Monkeys 3956, 2084, and 3506, although rates
calculating rates did not reflect the number eventually returned to premorphine levels for
of infusions earned during the demand Monkey 2084 by the time stable behavior was
procedure, although rates were congruent observed. Rates of remifentanil-maintained
with choice in the choice procedure. responding decreased, with the exception of
Monkey 3506 whose rates generally did not
change relative to premorphine rates. This
RESULTS
likely was due to a floor effect that resulted
Choice from the low dose of remifentanil self-admin-
Table 2 shows the average number of istered by this monkey during the assessment
remifentanil and cocaine infusions earned of choice.
during stable choice sessions conducted be- Figure 2 shows choice of remifentanil and
fore (pre), during, and following (post) daily response rates for remifentanil and cocaine in
morphine administration. Prior to the start of the sessions that occurred 20.5 hr following
daily morphine injections, 3 of the 4 monkeys each morphine injection. Choice of remifen-
showed a preference for remifentanil, al- tanil (relative to cocaine) increased for all
though Monkey 2084 chose remifentanil monkeys with the exception of Monkey 3953,
much less relative to the other monkeys whose preference for remifentanil remained
(approximately 60% versus 80%; see Figure 1, unchanged relative to premorphine. Whereas
unconnected data points above first sessions) Monkey3506didnotdevelopapreferencefor
exhibiting this preference. In an attempt to remifentanil as the result of daily morphine
evaluatethestudyparametersinamonkeythat exposure, he did consume more remifentanil
initially preferred cocaine, the remifentanil than in the premorphine condition (during
doseforMonkey3506 wassmaller:0.03g/kg/ which he chose cocaine almost exclusively).
inf. Under these conditions, this monkey Responseratesforremifentanilincreasedover
showed a near- exclusive preference for the course of morphine administration for
cocaine. Monkeys 3956, 2084, and 3506. Concurrently,
During the period of daily morphine injec- rates of responding for cocaine decreased for
tions, choice of remifentanil varied across Monkeys 3956 and 2084. Monkey 3953’s rates
monkeys in the sessions conducted 3 hr did not change appreciably for either drug.
following injections (left panels, Figure 1). Following evaluation of demand (results
Monkeys 3956 and 2084 both showed about a below),dailymorphineinjectionswerediscon-
50% decrease in their choice of remifentanil tinuedandtheremainingmonkeyswereagain
and a corresponding increase in their choice allowed to choose between cocaine and
ofcocaine.However,thischangeinchoicewas remifentanil. The number of injections of
abruptforMonkey2084andmoregradualfor each drug in stable postmorphine choice
3956. Monkey 3953 showed an initial decrease sessions is shown in Table 2. For the most
in choice of remifentanil from 80% to 60% part the pattern of choice returned to pre-
over the first 2 days of morphine administra- morphine levels. The number of overall
tion. Thereafter, choice of remifentanil recov- injections increased slightly for Monkey 2084,
ered to premorphine levels. Choice of a whereas the number of cocaine injections was
smaller dose of remifentanil remained at elevated relative to previous conditions for
premorphine levels (near-zero) for Monkey Monkey 3953 and remained low relative to
3506. premorphine conditions for Monkey 3506.
Premorphine response rates reflected pref-
Demand
erence: The remifentanil-preferring monkeys
responded more rapidly for remifentanil For each monkey and time point, the mean
compared to cocaine (Monkey 2084 respond- numbers of infusions earned at each response
82 T. WADE-GALUSKA et al.
Fig. 1. Choicebetweenadoseofremifentanilandadoseofcocaine3hrafterdailyadministrationof3.2mg/kg/inj
morphinein4rhesusmonkeys.Percentchoiceofremifentanilisshownontheleftordinateandratesofresponding
maintainedbythedosesofremifentanilandcocaineareshownontherightordinate.Theinitialdatapointandthe
horizontaldashedlinerepresentpremorphinechoice;theerrorbarsarestandarddeviations.Dailysessionsareshownon
theabscissa.Notethatthedoseofremifentanilis0.03mg/kg/injforMonkey3506(bottom)and0.3mg/kg/injforthe
othermonkeys.
requirement are shown in Tables 3 (cocaine) demand equation was fitted to the individual
and 4 (remifentanil). Shown in parentheses subject infusion data for each drug and time
are the average response rates (responses/s). point.Withrespecttococainedemand,theQ
0
Figure 3 shows the group mean number of parameter—representing an estimate of con-
cocaine (top panel) and remifentanil(bottom sumption at zero-price—was higher for each
panel) infusions earned as a function of the monkeyinthe20.5-hrandpostmorphinetime
response requirement on a log–log scale at periods relative to the premorphine period.
each time point. The Q parameter also was higher in the 3-hr
0
For each drug, the exponential demand period relative to the premorphine period for
equation(Hursh&Silberberg,2008)thenwas 3 of 4 monkeys. With respect to the a
fitted separately to the data from each time parameter, for each monkey the postmor-
point.Obtaineda,Q ,andgoodness-of-fit(R2) phine demand curve was more inelastic than
0
values are shown in the Group section of the premorphine demand curve, as indicated
Table 5. Also shown in Table 5 are the same by lower a values. In 3 of 4 monkeys, demand
parameters obtained when the exponential curvesobtained atthe 20.5-hr time pointsalso
CHOICE AND DEMAND FOR REMIFENTANIL AND COCAINE 83
Fig. 2. Choicebetweenadoseofremifentanilandadoseofcocaine20.5hrafterdailyadministrationof3.2mg/kg/
injmorphinein4rhesusmonkeys.Percentchoiceofremifentanilisshownontheleftordinateandratesofresponding
maintainedbythedosesofremifentanilandcocaineareshownontherightordinate.Theinitialdatapointandthe
horizontaldashedlinerepresentpremorphinechoice;theerrorbarsarestandarddeviations.Dailysessionsareshownon
theabscissa.Notethatthedoseofremifentanilis0.03mg/kg/injforMonkey3506(bottom)and0.3mg/kg/injforthe
othermonkeys.
were more inelastic relative to the premor- 3-hr time period was more elastic (higher a
phine curves. Demand elasticity 3-hr postmor- values) for each monkey. Three of four
phine resembled that obtained premorphine. monkeys exhibited less elastic demand func-
Examination of the individual subject data tions 20.5 hr after a morphine injection
in Table 5 also shows that with respect to relativetothatobtainedpremorphine.Finally,
remifentanil demand, the Q parameter was 2of3monkeyscontinuedtoexhibitlesselastic
0
lowerforeachmonkeyatthe3-hrtimeperiod demand functions during the postmorphine
relative to the premorphine period. In addi- determination relative to the premorphine
tion, 3 of 4 monkeys exhibited enhanced Q determination.
0
parameters 20.5 hr after a morphine injection Figure 4showsthegroupdemandcurvesfor
relative to the premorphine demand curve. cocaine and remifentanil at each time period.
TheQ parameterobtainedpostmorphinewas These demand curves are the same curves as
0
slightlylowerthanthatobtainedpremorphine presented in Figure 3, but here they are
for each monkey. grouped by time period for the purposes of
Relative to the premorphine demand curve, additional comparisons. In the premorphine
theremifentanildemandcurveobtainedatthe baseline, cocaine demand was more elastic
84 T. WADE-GALUSKA et al.
Table3
The average number of infusions and response rate (responses/s; shown in parentheses)
associatedwithdemandforcocainepriortodailymorphine(Pre),3and20.5hrfollowingeach
morphineinjectionduringdailymorphine,and4to5weeksfollowingdailymorphine(Post).
Monkey FR Pre 3hr 20.5hr Post
3956 10 74(3.2) 92(5.6) 81(1.3) –
32 41(3.0) 69(5.6) 90(5.4) –
100 22(2.8) 20(5.4) 49(5.8) –
320 2(1.6) 1(5.6) 9(6.2) –
562 0(1.2) 0(3.6) 0(3.1) –
1000 0(0.9) 0(4.0) 0(5.2) –
3953 10 80(1.8) 96(1.4) 99(1.3) 115(2.0)
32 46(2.3) 67(1.7) 78(1.4) 99(2.3)
100 34(2.5) 27(1.1) 29(1.8) 38(2.4)
320 16(1.8) 2(0.3) 10(2.2) 11(2.3)
562 5(1.4) 0(0.1) 2(2.6) 7(2.6)
1000 0(0.7) 0(0.1) 0(1.2) 1(1.0)
2084 10 87(1.5) 47(1.9) 111(1.7) 112(2.4)
32 79(1.8) 33(2.3) 109(4.2) 91(3.9)
100 48(2.8) 24(1.6) 93(5.2) 70(4.6)
320 14(2.3) 23(2.2) 54(4.6) 23(4.3)
562 2(1.3) 2(1.0) 32(4.2) 17(4.6)
1000 0(0.6) 8(1.6) 16(4.6) 2(5.6)
3506 10 62(2.2) 57(1.5) 60(1.0) 88(1.1)
32 44(2.4) 44(2.6) 71(1.6) 67(1.5)
100 27(2.1) 43(1.7) 37(2.4) 38(2.1)
320 12(2.4) 0(1.5) 23(2.8) 22(2.8)
562 7(2.4) 0(0.9) 11(3.2) 6(2.5)
1000 1(2.1) 0(1.0) 4(2.8) 1(1.6)
Table4
The average number of infusions and response rate (responses/s; shown in parentheses)
associatedwithdemandforremifentanilpriortodailymorphine(Pre),3and20.5hrfollowing
each morphine injection during daily morphine, and 4 to 5 weeks following daily
morphine(Post).
Monkey FR Pre 3hr 20.5hr Post
3956 10 85(3.8) 17(3.3) 91(4.2) –
32 51(3.7) 2(2.8) 72(5.0) –
100 17(3.5) 0(4.0) 38(6.0) –
320 4(3.3) 0(2.4) 5(5.9) –
562 2(2.9) 0(4.4) 0(4.1) –
1000 0(2.4) 0(4.6) 0(2.1) –
3953 10 92(0.7) 30(0.2) 68(0.6) 92(0.8)
32 72(1.2) 28(0.4) 64(1.1) 59(0.7)
100 43(1.5) 5(0.3) 36(1.4) 33(0.9)
320 17(1.9) 0(0.2) 17(3.1) 13(1.5)
562 8(2.2) 0(0.0) 3(2.6) 7(2.2)
1000 3(1.6) 0(0.0) 1(3.1) 3(2.6)
2084 10 76(0.7) 65(0.2) 95(0.7) 84(0.5)
32 67(1.3) 46(0.4) 89(1.5) 74(0.9)
100 46(1.9) 31(0.7) 72(2.5) 53(1.5)
320 20(2.7) 9(0.8) 44(4.0) 31(2.8)
562 7(3.2) 8(1.0) 30(3.9) 23(3.2)
1000 2(2.7) 0(0.4) 4(2.5) 13(3.7)
3506 10 73(1.4) 30(0.8) 99(2.2) 66(1.9)
32 58(1.5) 17(0.8) 87(2.3) 57(2.1)
100 31(2.4) 4(1.4) 65(2.7) 42(2.0)
320 14(2.7) 4(0.5) 35(3.0) 23(2.4)
562 6(2.7) 0(0.0) 21(3.1) 13(2.3)
1000 2(2.7) 0(3.3) 7(3.7) 5(2.8)