John R. Mantsch et al- Corticosterone Facilitates the Acquisition of Cocaine Self- Administration in Rats: Opposite Effects of the Type II Glucocorticoid Receptor Agonist Dexamethasone

8/3/2019 John R. Mantsch et al- Corticosterone Facilitates the Acquisition of Cocaine Self- Administration in Rats: Opposite Eff

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Corticosterone Facilitates the Acquisition of Cocaine Self-Administration in Rats: Opposite Effects of the Type II

Glucocorticoid Receptor Agonist Dexamethasone

1

JOHN R. MANTSCH, DAVID SAPHIER and NICK E. GOEDERS

Departments of Pharmacology and Therapeutics (J.R.M., D.S., N.E.G.) and Psychiatry (N.E.G.), Louisiana State University Medical Center,Shreveport, Louisiana

Accepted for publication May 18, 1998 This paper is available online at http://www.jpet.org

ABSTRACT

The effect of corticosterone on the acquisition of cocaine-seeking behavior was investigated in rats using ascendingdose-response curves for intravenous cocaine self-administra-tion. Rats pretreated daily with corticosterone (2.0 mg/kg i.p.)acquired cocaine self-administration at a lower dose comparedwith vehicle-treated controls. In contrast, daily corticosteronepretreatment did not alter food-maintained responding. Co-caine self-administration was not affected by the type I (miner-alocorticoid) receptor agonist, aldosterone (100 g/kg). How-ever, rats treated with the type II (glucocorticoid) receptoragonist, dexamethasone (10 or 100 g/kg) did not acquireself-administration at any dose tested. The 100 g/kg dose ofdexamethasone attenuated food-reinforced behavior and de-creased body weight, but these effects were not observed withthe 10 g/kg dose. Dexamethasone dose-dependently attenu-

ated the plasma corticosterone response to self-administeredinfusions or intraperitoneal injections of cocaine, indicating thatthe ability of dexamethasone to block cocaine-induced corti-costerone secretion may have contributed to its effects onself-administration. Administration of aldosterone (100 g/kg)together with 10 g/kg dexamethasone restored self-adminis-tration to the level of vehicle-treated rats, suggesting that typeI receptor occupation by corticosterone may be required for theacquisition of this behavior. These results indicate that stress-induced corticosterone secretion may provide a substratethrough which stressors interact with cocaine reinforcement.Additionally, the finding that dexamethasone blocks the acqui-sition of cocaine self-administration may be relevant to thedevelopment of novel approaches to the treatment of cocaineaddiction.

The characterization of factors that contribute to the onsetof compulsive drug-seeking behavior is crucial to the formu-lation of effective treatment strategies for drug abuse. It isestimated that out of the total population of individuals whoinitially try cocaine, only 10% to 15% will eventually becomeaddicted (Gawin, 1991). Others are able to use cocaine casu-ally over extended periods of time without ever progressingto compulsive use (Siegel, 1984). Although there are no reli-able predictors of individual vulnerability to cocaine addic-tion in humans (Gawin, 1991), it is likely that environmental variables are critical determinants. Exposure to stressfulenvironmental stimuli has been reported to enhance individ-ual sensitivity to the behavioral (Antelman et al., 1980; Ma-cLennan and Maier, 1983) and neurochemical (Sorg and Ka-livas, 1991) effects of psychostimulants in rats. Theseobservations have been extended to include the effects of

stressors on the reinforcing properties of psychostimulants.It has been demonstrated that isolation housing (Schenk et

al., 1987), repeated tailpinch (Piazza et al., 1990), socialstress (Miczek and Mutschler, 1996), daily exposure to un-controllable electric footshock (Goeders and Guerin, 1994),

and the stress of witnessing another rat being subjected toshock (Ramsey and Van Ree, 1993) all facilitate the acquisi-tion of intravenous cocaine or amphetamine self-administra-tion in rats. In consideration of these findings, it can be

hypothesized that the interaction between stressors and co-caine occurs as a result of the activation of one or morecommon pharmacological effector systems.

The HPA axis is commonly activated by cocaine and stres-sors. Acute cocaine administration stimulates the release of-endorphin, ACTH and corticosterone in rats (Moldow andFischman, 1987). Similar to the stressor-induced secretion of ACTH and corticosterone (Rivier and Plotsky, 1986), thisresponse appears to be dependent on CRF (Rivier and Vale,1987). Cocaine also stimulates the release of cortisol in hu-

Received for publication March 3, 1998.1 This work was supported by United States Public Health Service Grants

DA06013 and DA0583601 from the National Institute on Drug Abuse.

ABBREVIATIONS: HPA, hypothalamo-pituitary-adrenal; CRF, corticotropin releasing factor; ACTH, adrenocorticotropic hormone; LR, low

responder; HR, high responder; EFS, electric footshock; MR, mineralocorticoid receptor; GR, glucocorticoid receptor; VEH, vehicle; CORT,

corticosterone; ALDO, aldosterone; DEX, dexamethasone; ANOVA, analysis of variance; DA, dopamine.

0022-3565/98/2871-0072$03.00/0THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 287, No. 1Copyright 1998 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A.JPET 287:7280, 1998

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mans (Baumann et al., 1995), apparently through effects onthe CRF-driven pulsatile secretion of ACTH (Teoh et al.,1994). Individual variability in sensitivity to many of thebehavioral and neurochemical effects of psychostimulantsappears to be directly related to differences in corticosteronebefore and at the time of drug exposure (see Piazza and LeMoal, 1996, for review). Rats classified as HR based on theirlocomotor responses to a novel environment display a higher

locomotor response to an amphetamine challenge and aremore predisposed to develop amphetamine self-administra-tion when compared with LR rats (Piazza et al., 1989). Thesedifferences between HR and LR rats are eliminated by theadministration of corticosterone (Piazza et al., 1991). It hasalso been demonstrated that ADX rats will not develop co-caine self-administration over a range of doses (Goeders andGuerin, 1996a; Deroche et al., 1997), while drugs that blockthe synthesis of corticosterone, such as metyrapone (Goedersand Guerin, 1996a) and ketoconazole (Goeders and Guerin,1997), attenuate cocaine self-administration once it has beenestablished. Thus, it is apparent that the stimulation of cor-ticosterone secretion by cocaine is important, if not neces-

sary, for its establishment as a positive reinforcer.It is also likely that corticosterone provides a substratethrough which exposure to stressors can influence individualpredisposition to self-administer cocaine. A highly significantpositive correlation has been reported between the facilita-tion of cocaine self-administration by uncontrollable electricfootshock and the effects of footshock on plasma corticoste-rone (Goeders and Guerin, 1996b). In these experiments,plasma corticosterone was always elevated above a criticalthreshold in self-administering rats, suggesting that the ef-fects of stressors on cocaine sensitivity may have been attrib-utable to their effects on corticosterone secretion. In thepresent experiment, the ability of CORT administration tomimic the effects of uncontrollable stress on the acquisitionof cocaine-seeking behavior was investigated using an as-cending dose response curve for intravenous cocaine self-administration in rats. The potential roles of type I MR andtype II GR in the effects of corticosterone on self-administra-tion were assessed using the MR agonist, ALDO and the GRagonist DEX.

Materials and Methods

Subjects. Ninety adult, male Wistar rats (Harlan Sprague Daw-ley, Indianapolis, IN) 80 to 100 days old at the start of the experi-ments were used. Fifty rats were used to investigate the effects ofdaily drug pretreatments on ascending dose-response curves for in-travenous cocaine self-administration. The remaining 40 rats wereused to determine the effects of these pretreatments on the plasmacorticosterone response to intraperitoneal injections of cocaine. Allrats were housed individually in cages equipped with a laminar flowunit and air filter in a temperature- and humidity-controlled, AAA-LAC-accredited animal care facility on a reversed 12-hr light-darkcycle (lights on at 6:00 p.m.). Rats were maintained at 85% to 90% oftheir free-feeding body weights by presentations of food pellets (P. J.Noyes, Lancaster, NH; 45 mg) during the behavioral sessions whenapplicable and/or by supplemental feeding (Purina Rat Chow) andhad access to water ad libitum. All procedures were carried out inaccordance with the NIH Principles of Laboratory Animal Care(NIH publication No. 8523).

Venous catheterization and drug delivery. For the cocaineself-administration experiments, each rat was implanted with a

chronic indwelling jugular catheter under sodium pentobarbital an-

esthesia (50 mg/kg i.p.) with methylatropine nitrate pretreatment(10 mg/kg i.p.) using previously reported procedures (Koob and Goe-ders, 1989; Goeders and Guerin, 1996b). A silicon catheter (0.20 mmo.d. 0.037 mm i.d.) was inserted into the right posterior facial veinand pushed down into the jugular vein until it terminated outsidethe right atrium. The catheter was sutured to tissue surrounding the

vein and continued subcutaneously to the back where it exited justposterior to the scapulae via a Marlex mesh/dental acrylic/22-guageguide cannula (Plastic One, Roanoke, VA) assembly. This assembly

was anchored to tissue under the skin for attachment of a stainlesssteel spring leash (Plastics One, Inc.) which was connected to a 20 mlsyringe in a motor-driven pump (Razel, Stamford, CT) via a leak-proof fluid swivel suspended above the chamber to allow the deliveryof drug solutions. The swivel and leash assembly was counterbal-anced to permit relatively unrestrained movement of the animal.The animals were injected with sterile penicillin G procaine suspen-sion (75,000 units i.m.) immediately before surgery, and they wereallowed a minimum of 5 days to recover after surgery. The swivel andleash assembly was always connected during the experimental ses-sions. At the end of each session the leash was disconnected, thecatheter was filled with Urokinase (250,000 i.u.) to eliminate bloodclots, and a dummy cannula was inserted into the guide before ratswere returned to their home cages. Catheter patency was tested

regularly by obtaining blood from the catheter. If blood could not beobtained, methohexital sodium (1.5 mg) was infused through thecatheter. In this case, a functional catheter was indicated by imme-diate, light anesthesia.

Experimental apparati. Modified plastic and stainless steel op-erant conditioning chambers contained in sound-attenuating cubi-cles (Med-Associates, Lafayette, IN) were used for the self-adminis-tration experiments. The operant chambers were equipped with tworetractable response levers with stimulus lights located above eachlever. One lever was mounted on the front wall of the chamber nextto a food pellet dispenser. The other lever was mounted in the centerof the back wall. The cubicles were also equipped with an exhaust fanthat supplied ventilation and white noise to mask extraneous sound.Programming and data collection were performed using Med-PCsoftware and an IBM-compatible personal computer and interface

system (Med-Associates).Measurement of locomotor responses to novelty and co-

caine. Rats were initially screened for their locomotor responses toa novel environment and to an acute intraperitoneal injection ofcocaine. It has been reported that the behavioral responses to noveltyof individual rats can predict their propensity to self-administeramphetamine (Piazza et al., 1989). To control for this potentialsource of variability, rats were assigned to the drug treatmentgroups so that the mean locomotor responses to novelty and cocainedid not significantly differ between groups. Locomotor testing wasconducted in 48 cm long 25 cm wide Plexiglas chambers containedwithin a photocell apparatus (Coulbourn, Allentown, PA) consistingof two photocell beams evenly spaced across the length of eachchamber. The number of individual breaks of the front and backbeams, consecutive beam breaks (crossovers), and total locomotorcounts were recorded over 60-min sessions. On the first day of loco-motor testing (novelty), animals were placed into the chambers andactivity was measured immediately for 60 min. On day 2, the loco-motor response to an injection of saline (0.9% NaCl, 1 ml/kg i.p.) wasrecorded after a 60-min acclimation period. On day3, the locomotorresponse to an acute injection of cocaine HCl (15 mg/kg i.p., NationalInstitute on Drug Abuse) was recorded after acclimation.

Food-reinforced responding. Rats were initially trained to re-spond under a fixed-ratio 1 (FR1) schedule of food reinforcementduring daily sessions. At the start of these sessions, the food (front)lever was extended and the corresponding stimulus light was illu-minated. Each response on the food lever resulted in the presenta-tion of a single food pellet (45 mg) into the dispenser. This wasimmediately followed by a 25-sec timeout period during which the

lever was retracted and the stimulus light extinguished. Sessions

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were terminated after 60 min or when 100 food pellets were deliv-ered. Once stable patterns of food-reinforced responding were ob-served (i.e., 100 food pellets obtained in 10 min or less for 1 week),food sessions were only conducted once weekly to control for potentialnonspecific effects of the drug treatments on operant behavior.

Acquisition of intravenous cocaine self-administration. Theacquisition of intravenous cocaine self-administration was deter-mined using an ascending dose-response curve as previously re-ported (Goeders and Guerin, 1994). Rats were allowed to self-admin-

ister cocaine or vehicle (heparinized 0.9% NaCl bacteriostatic saline)under an FR1 schedule of reinforcement during daily 1-hr sessions.During these sessions, only the drug (back) lever was extended andthe corresponding stimulus light illuminated. Each depression of thelever resulted in an intravenous infusion (200 l over 5.6 sec) ofcocaine or vehicle solution followed by a 20-sec timeout period duringwhich the lever was retracted and the stimulus light extinguished.During the initial 2 weeks of the study, a base line for responding onthe drug lever was established with only vehicle available for self-administration. This was followed by the initiation of the daily drugtreatment regimen (see below). Drugs were administered daily for 2weeks before the determination of the dose-response curve. Duringthis 2-week period, no behavioral experiments were performed.These treatments persisted daily throughout the course of the ex-

periment. Rats were then tested for the acquisition of intravenouscocaine self-administration using an ascending cocaine dose-re-sponse curve. During dose-response testing, food sessions were con-ducted on Mondays and self-administration sessions were conductedon Tuesday through Friday. Control rates of responding were estab-lished with only vehicle available for self-administration during thefirst week. Rats were then tested with a very low dose of cocaine(0.03125 mg/kg/inf) that is not normally self-administered by rats inour laboratory. This dose was doubled weekly so that each rat wastested with 0.0, 0.03125, 0.0625, 0.125, 0.25, 0.5 and 1.0 mg/kg/infcocaine. Subsequent to dose-response determination in each rat,cocaine self-administration was extinguished by replacing the co-caine solution with vehicle for 4 consecutive sessions.

Drug treatments. Rats were divided into 6 treatment groups. Alltreatments were administered daily, starting 2 weeks before dose-

response testing and continuing through the remainder of the exper-iment. Rats received daily i.p. injections of VEH (bacteriostatic sa-line 0.9% NaCl, n 10), CORT (2.0 mg/kg, suspended in saline, n 7; Sigma, St. Louis), ALDO (100 g/kg dissolved in saline, n 7;Sigma), DEX (10 or 100 g/kg dissolved in saline, n 6 for each;Sigma) or a combination of DEX and ALDO (10 g/kg DEX and 100g/kg ALDO, n 6). During dose-response testing, the presessiontreatment time for each of the drugs was 15 min except for DEX,which was administered 60 min before the sessions.

Plasma corticosterone responses to self-administered infu-

sions of cocaine. The plasma corticosterone response to singleself-administered infusions of cocaine was determined in some ratsas follows. Rats were placed in the self-administration chambers asdescribed above. After the self-administration of single infusions of

vehicle, 0.0625, 0.25 or 1.0 mg/kg/inf cocaine, the session was termi-nated and blood for plasma corticosterone determination was ob-tained 15 min postinfusion from the catheter (when possible) or fromthe tail vein under light methohexital sodium (5.0 mg/kg i.v.) anes-thesia (Goeders and Guerin, 1996b). Blood (500 l) was collectedinto preheparinized tubes and placed on ice. Blood was centrifuged toallow separation of plasma, which was collected and frozen at 20Cuntil needed. Plasma corticosterone was measured using the Immu-nochem Double Antibody Corticosterone assay kit (ICN Biomedi-cal, Irvine, CA).

Plasma corticosterone responses to intraperitoneal injec-

tions of cocaine. The effects of drug treatments on the plasmacorticosterone response to i.p. injections of cocaine was measured inan additional 40 rats. As above, these rats received daily i.p. injec-tions of VEH, CORT, ALDO or one of the two doses of DEX ( n

8/group). For these experiments, blood for plasma corticosterone

determination was obtained from the tail vein of conscious rats after2 weeks of habituation to the blood sampling procedure as describedpreviously (Simar et al., 1997). Rats were wrapped in a hand towel,and 1 to 2 mm was cut from the tip of the tail. Corticosterone wasmeasured as described above. All blood sampling was performedbetween 9:00 a.m. and noon. On the first day of drug treatments(acute) the corticosterone response to an i.p. injection of 20 mg/kgcocaine was determined 20 min postinjection. This was followed by 2weeks of drug treatments, during which no sampling was performed.

A dose-response curve for the plasma corticosterone response to i.p.injections of cocaine after chronic drug treatments was then deter-mined. Rats were tested for their corticosterone responses to 0.0, 5.0,10.0 and 20.0 mg/kg cocaine (i.p., 20 min postinjection). The sequenceof cocaine dosing was randomized and blood samples were obtainedno more than twice weekly for 3 weeks. The plasma corticosteroneresponse to 20 mg/kg cocaine was also tested after a 3-day treatmentwashout to determine the persistence of the effects of the drugtreatments on the corticosterone response to cocaine. All drugs wereadministered 45 min before cocaine injections except for DEX, whichwas administered 90 min before cocaine. These pretreatment timeswere chosen so that they would correspond with points in the middleof the 60-min self-administration sessions from the previous exper-iments. At the end of the experiment, these rats were killed by

decapitation and thymus and adrenals were dissected so that theirweights could be determined.Statistical analysis. Data collected during the self-administra-

tion experiments included the mean number of infusions self-admin-istered per session for each dose of cocaine and the mean rates offood-reinforced responding during the weekly food sessions. Self-administration sessions were conducted Tuesday through Friday,and the means were determined from data from the final 3 sessions(i.e., Wednesday through Friday) for each dose. The acquisition ofcocaine self-administration was defined as the lowest dose at whichthe mean number infusions/session was significantly greater thanthe base-line measurements (P .05). The significance of the differ-ences between drug and vehicle treatment conditions and betweendoses of cocaine within treatment groups was determined usingrepeated measures analysis of variance (ANOVA). Post-hoc analyses

were performed using the Fishers Protected Least Significant Dif-ference test (Fishers PLSD). The significance of differences in themean corticosterone responses (ng/ml) to cocaine were determined asdescribed above. One-way ANOVA was used to determine any sig-nificance of differences in body, thymus and adrenal weights be-tween groups.

Results

The 6 treatment groups did not significantly differ in theirmean body weights or locomotor responses to novelty or acuteinjections of cocaine (15 mg/kg i.p.) at the start of the exper-iment (data not shown).

Effects on food-reinforced responding. Table 1 shows

the base-line rates of food-reinforced responding (responses/min S.E.M.) and the effects of the various treatments onfood reinforcement at timepoints corresponding to the dosesof cocaine that were available for self-administration eachweek. A significant effect of the 100 g/kg dose of DEX onfood-reinforced responding was observed over time [Timeeffect, F(7,173) 5.861, P .0001; Time Treatment inter-action, F(7,2) 4.103, P .0001]. The rate of responding wassignificantly decreased from base line at the timepoints cor-responding to weeks during which 0.25 and 1.0 mg/kg/infcocaine were available for self-administration (P .05 foreach). At the 1.0 mg/kg/inf timepoint, the response rate in100 g/kg DEX-treated rats was also significantly less than

in VEH controls (P .05). This effect on food-reinforcement

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was not apparent in rats treated with the 10 g/kg dose ofDEX. No other significant differences in food-reinforced re-sponding within or between treatment groups were observed.

Effects on the acquisition of intravenous cocaine

self-administration. The effect of daily pretreatment withCORT (2.0 mg/kg i.p.) on the ascending dose-response curvefor iv cocaine self-administration is illustrated in figure 1.The acquisition of cocaine self-administration by both VEH-and CORT-treated rats was indicated by a significant effectof dose [Dose effect, F(6,109) 6.41, P .0001]. CORT-treated rats acquired cocaine self-administration at a lowerdose (0.0625 mg/kg/inf; P .05 vs. base line) than VEH-treated controls (0.125 mg/kg/inf; P .0001). A significanttreatment effect of CORT was also observed [Treatment ef-fect, F(1,109) 5.699, P .05]. The mean number of infu-sions/session at the 0.0625 mg/kg/inf dose of cocaine inCORT-treated rats was significantly greater than in VEH-treated rats (P .05). The effects of daily pretreatments with ALDO (100 g/kg i.p.) or DEX (10 or 100 g/kg i.p.) are

shown in figure 2A. In ALDO-treated rats, a significant effectof dose was observed [Dose effect, F(6,114) 3.495, P .001]. Similar to the VEH controls, rats from the ALDO group

acquired cocaine self-administration at the 0.125 mg/kg/in-fusion dose (P .05). No significant differences betweenALDO- and VEH-treated rats were observed. Although therewas no significant effect of treatment in rats treated dailywith the 10 or 100 g/kg doses of DEX compared with VEH,a significant interaction between dose and treatment wasobserved [Treatment Dose, F(2,6) 2.350, P .05]. Incontrast to VEH-treated rats, significant acquisition of co-caine self-administration did not occur at any dose of cocainetested in rats treated with either dose of DEX. A small butstatistically non-significant trend toward acquisition was ob-served in the 10 g/kg DEX group at the 0.5 mg/kg/inf dose ofcocaine. Figure 2B shows the effects of coadministration of100 g/kg ALDO on the 10 g/kg DEX-induced suppressionof cocaine self-administration. No significant differences inself-administration were observed at any dose between ratstreated with the DEX/ALDO combination and those treatedwith 10 g/kg dose of DEX alone. However, a significant

effect of dose was observed [Dose effect, F(1,83)

3.498, P

.01]. In contrast to rats treated with 10 g/kg DEX alone, ratstreated with the DEX/ALDO combination did acquire self-administration at the 0.125 mg/kg/infusion dose as definedby a significantly greater number of infusions/session at thisdose compared with base line (P .05). Significant differ-ences from base line were also observed at the 0.25 and 0.5mg/kg/infusion doses of cocaine in this group.

Extinction of cocaine-reinforced responding. InVEH-treated rats, replacement of the cocaine solution withsaline for 4 consecutive days after the determination of thedose-response curves produced a pattern of extinction char-acterized by a high level of responding on day 1 (51.63 6.57

responses per session) followed by a progressive decline inresponding from days 2 to 4. On day 4, the mean number ofinfusions per session (15.13 3.16) approached that ob-served under base-line conditions. Similar extinction pat-terns were observed in the CORT and ALDO treatmentgroups (data not shown). During extinction, there was asignificant effect of day [F(3,139) 34.18, P .0001] and aninteraction between extinction day and drug treatment[Day Treatment, F(3,4) 3.20, P .01]. On day 1, themean numbers of responses in the 10 and 100 g DEX groups(24.75 11.35 and 18.4 6.2 respectively) were significantlyless than the number of responses in VEH-treated rats (P .05 for each). No significant differences in responding were

observed between groups on extinction days 2 through 4.

TABLE 1

Rates of food-reinforced responding (responses/min S.E.M.) in drug treatment groups during food sessions corresponding to the weeks duringwhich the various doses of cocaine were available for self-administrationRats were trained to respondunderan FR1scheduleof food reinforcementand were testedweekly. Significant differences between groupsand withingroups were determinedusing repeated-measures ANOVA with Fishers PLSD post-hoc testing.

TreatmentResponse rate

Base line 0.0 0.03125 0.0625 0.125 0.25 0.5 1.0

responses/min

VEH 16.71 1.38 16.18 1.65 17.10 1.82 16.02 1.75 17.18 1.69 17.20 1.26 16.80 1.55 15.50 1.04CORT 17.76 1.15 17.55 1.59 17.53 1.22 18.27 1.31 18.62 1.28 19.35 1.09 18.18 1.17 18.90 1.66

ALDO 16.08 0.63 15.41 0.95 15.38 1.09 16.60 0.86 16.05 0.98 16.01 0.89 17.41 1.98 15.73 1.98DEX (10 g/kg) 19.02 1.23 18.94 1.38 15.35 2.39 17.13 1.40 15.53 1.84 17.96 2.39 16.02 1.73 14.01 1.60DEX (100 g/kg) 18.91 1.02 19.42 2.37 16.52 1.68 14.67 3.27 13.49 3.25 10.64 3.59a 11.52 3.04 8.36 3.15a,b

DEX ALDO 15.50 1.37 15.03 1.05 14.81 0.93 15.56 1.01 13.86 1.93 12.87 2.28 14.20 2.50 13.09 1.16

a P .05 vs. VEH control.b P .05 vs. base line.

Fig. 1. Ascending dose-response curves for intravenous cocaine self-ad-ministration in rats pretreated daily with CORT (2.0 mg/kg; n 7) or

VEH (n 10). Data points represent the mean number of infusions persession ( S.E.M.) for each dose of cocaine. The significance of thedifferences between treatments or doses was determined using repeatedmeasures analysis of variance followed by post-hoc testing using theFishers Least Significant Difference test. The acquisition of cocaineself-administration was defined by the lowest dose of cocaine in eachtreatment group at which the mean number of infusions/session wassignificantly greater than base line responding. P .05 vs. base line.

P .05 CORT vs. VEH.



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Corticosterone responses to self-administered infu-

sions of cocaine. The effects of daily pretreatments withVEH, DEX (10 or 100 g/kg) or the combination of DEX (10g/kg) and ALDO (100 g/kg) on the plasma corticosterone

response to single self-administered iv infusions of cocaineare presented in figure 3. Despite a trend toward increases inplasma corticosterone with increasing doses of cocaine inVEH-treated rats, no significant effect of dose was observed.However, there was a highly significant effect of treatment[F(3,67) 61.790, P .0001]. DEX dose-dependently sup-pressed the plasma corticosterone responses to infusions ofsaline and to the 0.0625, 0.25, and 1.0 mg/kg/infusion doses ofcocaine. Significant decreases compared with VEH-treatedcontrols were observed in both the 10 g/kg (P .05 for all)and 100 g/kg (P .01 for all) treatment groups. In the 100g/kg DEX group, plasma corticosterone was almost unmea-surable (i.e., 5 ng/ml) after the infusion of each dose of

cocaine. Coadministration of ALDO (100 g/kg) with 10

g/kg DEX failed to reverse the inhibitory effects of DEX onthe plasma corticosterone response to cocaine.

Corticosterone responses to intraperitoneal injec-

tions of cocaine. The effects of daily pretreatments with VEH, CORT, ALDO, and DEX (10 and 100 g/kg) on theplasma corticosterone responses to i.p. injections of cocaineare illustrated in figures 4 and 5. Figure 4 shows the effectsof chronic treatment with these drugs on the plasma cortico-sterone response to a randomized sequence of i.p. injectionswith various doses of cocaine (0, 5, 10, and 20 mg/kg). Sig-nificant effects of cocaine dose (Dose effect, F(3,146) 2.916,P .05) and drug treatment (Treatment effect, F(4,146)

80.280, P

.0001) were observed. In VEH-treated rats, co-caine produced a dose-dependent increase in plasma cortico-sterone with significant increases compared with the 0 mg/kgdose after the administration of 10 (P .01) and 20 (P .001)

Fig. 2. Ascending dose-response curves for intravenous cocaine self-ad-ministration in rats pretreated daily with ALDO (100 g/kg; n 7), DEX(10 or 100 g/kg; n 6 for each dose) or VEH (n 10; fig. 2A) or in rats

treated daily with VEH, DEX (10 g/kg) alone or DEX in combinationwith ALDO (100 g/kg; n 6; fig. 2B). Data points represent the meannumber of infusions per session ( S.E.M.) for each dose of cocaine. Thesignificance of the differences between treatments or doses was deter-mined using repeated measures analysis of variance followed by post-hoctesting using the Fishers Least Significant Difference test. The acquisi-tion of cocaine self-administration was defined by the lowest dose ofcocaine in each treatment group at which the mean number of infusions/session was significantly greater than base line responding. P .05 vs.base line. P .001 vs. base line.

Fig. 3. Effects of daily pretreatment with VEH, DEX (10 or 100 g/kg),or a combination of DEX (10 g/kg) and ALDO (100 g/kg) on the plasmacorticosterone responses to single self-administered i.v. infusions of co-caine. Data points represent mean plasma corticosterone concentrations(ng/ml S.E.M.). Corticosterone was measured 15 min after the self-administration of single infusions of cocaine or saline. The significance ofthe differences between treatments or doses was determined using re-peated measures analysis of variance followed by post-hoc testing usingthe Fishers Least Significant Difference test. P .05 vs. VEH-treatedrats. P .01 vs. VEH-treated rats.

Fig. 4. Effects of daily pretreatment with CORT (2.0 mg/kg), ALDO (100g/kg), DEX (10 or 100 g/kg) or VEH on the plasma corticosteroneresponses to i.p. injections of cocaine (n 8/dose). Data represent themean plasma corticosterone response (ng/ml S.E.M.) 20 min afterinjection with cocaine or saline after at least 14 days of daily drugtreatments. Drug pretreatments were administered 45 min before co-caine injections, except for DEX, which was administered 90 min beforecocaine injections. The significance of the differences between treatmentsor doses was determined using repeated measures analysis of variancefollowed by post-hoc testing using the Fishers Least Significant Differ-ence test. P .01 DEX vs. VEH. P .01 vs. 0 mg/kg (base line). P

.05 vs. VEH



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mg/kg cocaine. Plasma corticosterone after injection with 20mg/kg cocaine was also significant when compared with the 5mg/kg dose of cocaine. As expected, CORT pretreatment re-sulted in increases in plasma corticosterone which were sig-nificantly greater than those seen in VEH-treated rats afteradministration of 0 (P .0001) and 5 (P .05) mg/kg cocaine. At the 0 mg/kg cocaine dose, administration of CORT (2.0mg/kg i.p.) produced almost a 200% increase in the plasmaconcentration of the hormone compared with VEH-treatedcontrols. These findings indicate that i.p. injections withCORT resulted in significant elevations in plasma corticoste-rone concentrations 45 min after administration, a timepointwhich corresponds to the middle of the self-administrationsessions in the previous experiments. The differences be-tween CORT- and VEH-treated rats were attenuated withthe administration of 10 and 20 mg/kg cocaine. No dose-related effects of cocaine were observed in CORT-treatedrats, indicating that the elevated corticosterone may haveprevented further cocaine-induced increases of the hormonevia feedback mechanisms. Daily ALDO pretreatment did notaffect the corticosterone response to i.p. injections of cocainecompared with VEH treatment. Daily pretreatment with

DEX (10 and 100 g/kg) dose-dependently suppressed theplasma corticosterone responses to i.p. injections of cocaine ina manner similar to that observed with self-administered ivinfusions of cocaine. After injections of saline (0 mg/kg co-caine), plasma corticosterone was significantly decreased inthe 10 (P .001) and 100 (P .01) g/kg DEX groupscompared with VEH-treated controls. Likewise, the plasmacorticosterone responses to 5, 10 and 20 mg/kg cocaine weresignificantly decreased in both DEX treatment groups com-pared with VEH treatment (P .0001 for all). Under allconditions, corticosterone in the 100 g/kg DEX-treated ratswas virtually undetectable (10 ng/ml), while the meanplasma corticosterone concentration in the 10 g/kg DEX

group remained at 50 ng/ml.

The corticosterone responses to i.p. injections of 20 mg/kgcocaine after acute and chronic treatment with VEH, CORT, ALDO, and DEX (both doses) and after a 3-day treatmentwashout period are depicted in figure 5. Significant differ-ences between treatment groups [F(4,97) 60.658, P .0001] and between 20 mg/kg cocaine dosing conditions[F(2,97) 5.171, P .05] were observed, as was a significantinteraction between treatment and dosing conditions [F(4,2)

3.356, P .01]. No significant differences in the plasmacorticosterone response to 20 mg/kg cocaine (i.p.) were ob-served after acute or chronic treatment with VEH, CORT, orALDO, or after a 3-day washout of these daily treatments. Inrats treated with 100 g/kg DEX, the plasma corticosteroneresponse to 20 mg/kg cocaine after a single treatment withDEX was significantly greater than the response afterchronic (at least 2 weeks) DEX administration (P .01). Theplasma corticosterone response to 20 mg/kg cocaine was notrestored after the termination of treatment for 3 consecutivedays. Under all dosing conditions, the corticosterone re-sponse to cocaine in 100 g/kg DEX-treated rats was signif-icantly less than in VEH-treated rats (P .001). No differ-

ences between acute and chronic treatment with the 10 g/kgdose of DEX were observed in the plasma corticosteroneresponses to 20 mg/kg cocaine. In both cases, the corticoste-rone responses were significantly less than those observed inVEH-treated controls (P .001). However, the plasma corti-costerone response to cocaine in this group was almost com-pletely restored to concentrations observed in VEH-treatedrats after a 3-day washout period during which DEX treat-ment was discontinued. The response after DEX washoutwas significantly greater than that observed after eitheracute or chronic treatment with 10 g/kg DEX (P .0001 forboth). However, the corticosterone response to cocaine wasstill significantly less than that displayed in VEH-treatedrats after the same washout period (P .05).

Effects on body, thymus and adrenal weights. Theeffects of the various treatments on mean body, thymus andadrenal weights and on the ratios of adrenal and thymus tobody weight at the end of the experiment are represented intable 2. Significant effects of treatments were observed onbody weight [F(4,39) 17.006, P .0001], thymus weights[F(4,39) 114.486, P .0001], adrenal weight [F(4,39) 18.848, P .0001], the ratio of thymus/body weights [F(4,35) 109.951, P .0001] and the ratio of adrenal/body weight[F(4,39) 13.516, P .0001]. Significant decreases in thy-mus weight (P .05) and thymus/body weight (P .01) wereobserved in CORT-treated rats compared with VEH-treatedcontrols. An inverse proportion exists between the activation

of type II receptors in the thymus and thymus weight, mak-ing this variable a useful measure of peripheral type II re-ceptor occupation (Akana et al., 1985). CORT treatment didnot significantly affect total body or adrenal weights. Signif-icant dose-related effects of DEX on all of the above measureswere observed. Daily administration of 100, but not 10, g/kgDEX resulted in a significant decrease in body weight at theend of the experiment compared with VEH-treated controls(P .0001). Significant reductions in thymus weight andthymus/body weight were also observed in rats treated with10 and 100 g/kg DEX (P .0001 for all comparisons). In the100 g/kg group, the thymus was indiscernable (thymusweights of 0 were used for statistical analysis). Significant

decreases in adrenal weights and adrenal/body weight ratios

Fig. 5. Plasma corticosterone responses to cocaine after acute or chronicpretreatment with CORT, ALDO, DEX, or VEH, or after a 3-day drugtreatment washout period. Data represent the mean plasma corticoste-rone concentrations (ng/ml S.E.M.) 20 min after i.p. injections withcocaine (20 mg/kg). Drug pretreatments were administered 45 min beforecocaine injections, except for DEX, which was administered 90 min beforecocaine injections. The effects of acute pretreatment were measured onday 1 of the dosing regimen. The effects of chronic pretreatment weremeasured after 15 days of drug administration. The effects of treatmentwashout were determined by discontinuing drug treatment for 3 days

before the cocaine injection. The significance of the differences betweentreatments or doses was determined using repeated measures analysis ofvariance followed by post-hoc testing using the Fishers Least SignificantDifference test. P .01 vs. acute treatment. P .05 vs. VEH. P .0001 vs. chronic and acute treatment



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compared with VEH-treated rats (P .0001 for both) wereobserved in rats treated with 100, but not 10, g/kg DEX.This difference probably reflects atrophy of the adrenals as aresult of negative feedback of DEX on ACTH secretion.

Discussion

The results of these experiments demonstrate that daily

pretreatment with CORT (2.0 mg/kg i.p.) facilitates the ac-quisition of cocaine-seeking behavior in rats, as observed bya leftward and upward shift in the ascending dose-responsecurve for intravenous cocaine self-administration. CORT-treated rats acquired self-administration at a lower dose ofcocaine than did VEH-treated controls (0.0625 vs. 0.125 mg/kg/infusion). In contrast, no significant differences in food-maintained responding were observed between these treat-ment groups. The present results are consistent withfindings that corticosterone is necessary for the establish-ment and maintenance of cocaine self-administration in rats(Goeders and Guerin, 1996a; 1996b; Deroche et al., 1997) andwith reports that CORT-treated rats are more sensitive tothe reinforcing (Piazza et al., 1991) and locomotor activating(Marinelli et al., 1997; Cador et al., 1993) effects of psycho-stimulants.

Previous studies from this laboratory have demonstratedthat daily preexposure to uncontrollable EFS facilitates theacquisition of cocaine self-administration in rats (Goedersand Guerin, 1994). In these experiments, a significant posi-tive correlation was observed between the effects of EFS onplasma corticosterone and on self-administration (Goedersand Guerin, 1996a), suggesting that the facilitation of self-administration by EFS may have been mediated by cortico-sterone. In the present experiment, the CORT dosing regi-men was designed to mimic the schedule of EFS exposureused in these previous studies. CORT treatment increased

plasma corticosterone concentrations by almost 200% (e.g.,300 ng/ml). Although these concentrations are higher thanthose observed after EFS in the previous experiments (e.g.,200 ng/ml; Goeders and Guerin, 1996a), they are still withinthe EFS stressor-induced range under certain conditions (un-published observations). The finding that corticosterone andEFS produce similar effects on cocaine self-administrationprovides further evidence that corticosterone may be a sub-strate through which environmental variables interact withthe reinforcing effects of cocaine.

Corticosterone produces many of its effects by binding totwo types of cytosolic receptors (Joels and De Kloet, 1994).The type I (mineralocorticoid) receptor has a higher affinity

for corticosterone and is usually occupied at basal concentra-

tions of the hormone. In contrast, the type II (glucocorticoid)receptor has a lower affinity for corticosterone and is morelikely to be occupied when corticosterone concentrations areelevated (e.g. during stress or after cocaine administration).To determine the roles of type I and type II receptors in theeffects of corticosterone on cocaine self-administration, ratswere treated daily with the type I receptor agonist, ALDO, orthe type II receptor agonist, DEX, and ascending dose-re-

sponse curves for cocaine self-administration were deter-mined.

Daily administration of either ALDO or DEX failed toproduce CORT-like effects on the acquisition of cocaine self-administration. Interestingly, however, DEX-treated rats didnot acquire self-administration at any dose. This effect wasassociated with significant attenuations of food-maintainedresponding and weight loss in rats treated with 100 g/kg butnot 10 g/kg DEX. In rats treated with 10 g/kg DEX, nosignificant differences from base line were observed in self-administration despite a trend toward acquisition at thehigher doses of cocaine. Compared with the other treatmentgroups, DEX-treated rats also displayed a significantly at-

tenuated extinction response pattern when the cocaine wasreplaced with saline.

The finding that DEX-treated rats did not acquire cocaineself-administration was unexpected. However, these results areconsistent with reports that DEX pretreatment blocks the loco-motor stimulating effects of cocaine and amphetamine in mice(Capasso et al., 1996). We hypothesized that the effects of DEXmay have been a result of feedback inhibition of the HPAresponse to cocaine, since the dose-response curves for cocaineself-administration in the DEX-treated groups resembled thoseobserved in ADX rats (Goeders and Guerin, 1996a; Deroche etal., 1997). In addition to mediating many of the physiologicaleffects of glucocorticoids, type II receptors are also important for

negative feedback on the HPA axis in response to elevatedcorticosterone (Dallman et al., 1994). Thus, administration ofDEX has been reported to attenuate the plasma corticosteroneresponses to stressors (Donald, 1966) and cocaine (Simar et al.,1997). In the present study, treatment with DEX produceddose-dependent decreases in the plasma corticosterone re-sponses to either i.p. or single self-administered iv infusions ofcocaine. In fact, in both DEX-treated groups, plasma corticoste-rone was also significantly decreased after saline administra-tion, suggesting that basal concentrations of the hormone werereduced. Cocaine-induced increases in corticosterone were re-stored after DEX treatment was discontinued for 3 days in the10 g/kg but not the 100 g/kg DEX group. Thus, daily pre-

treatment with 10 g/kg DEX blocked cocaine self-administra-

TABLE 2

Mean body, thymus, and adrenal weights and the mean ratios of thymus and adrenal to total body weights ( S.E.M.) in rats treated daily with vehicle (VEH), corticosterone (CORT), aldosterone (ALDO) and dexamethasone (DEX)Significant differences between groups were assessed using ANOVA with Fishers PLSD post-hoc testing.

Treatment Body Weight Thymus Weight Adrenal weight Thymus/body weight Adrenal/body weight

g mg combined mg

VEH 347.63 3.93 236.00 4.99 67.38 5.02 0.68 0.02 0.19 0.01CORT 352.63 3.05 204.13 12.40a 74.75 4.89 0.58 0.03a 0.21 0.02

ALDO 357.63

3.39 223.63

11.18 78.50

4.24 0.63

0.03 0.22

0.01DEX (10 g/kg) 338.50 4.23 143.88 10.35b 60.00 2.38 0.43 0.04b 0.18 0.01DEX (100 g/kg) 308.38 7.62b 0.00c 35.25 2.31b N/Ac 0.11 0.01b

a P .0001 vs. VEH control.b P .01 vs. VEH control.c Thymus was indiscernible in these rats.



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tion without producing long-term suppression of the HPA axis.In both the 10 and 100 g/kg DEX groups, significant decreasesin the plasma corticosterone response to cocaine were observedafter a single DEX pretreatment. For the 100 g/kg dose ofDEX, the corticosterone response to cocaine was further dimin-ished after chronic DEX treatment compared with its acuteadministration, suggesting a cumulative effect of the DEXtreatment.

Based on the decreases in thymus weight observed in theDEX-treated rats, it is probable that DEX was occupying typeII receptors peripherally. Peripheral type II receptors, mostlikely in the anterior pituitary, are believed to be importantfor the feedback inhibitory effects of DEX on the HPA axis(De Kloet et al., 1974). However, in the present study, theextent to which type II receptors within the brain were occu-pied is unknown. DEX penetrates the brain relatively poorly(Rees, 1974) and may even be actively transported out thecentral nervous system (De Kloet, 1997). Western blot anal-ysis of brain tissue from the DEX-treated rats indicated thatno significant down-regulation of type II receptors occurredin a number brain regions (unpublished observation). Thus,

it is possible that the present findings reflect the unusualpharmacodynamic profile of DEX itself, rather than the ef-fects of central type II receptor occupation.

Under basal corticosterone concentrations, type I receptorsare predominantly occupied, while type II receptors remainlargely unbound (Joels and De Kloet, 1994). In the presentstudy, plasma corticosterone was 60 ng/ml or less in ratstreated with 10 g/kg DEX and was virtually undetectable inrats treated with 100 g/kg DEX under all conditions. Ineither case, it is likely that plasma concentrations of cortico-sterone were low enough that type I receptors were not fullyoccupied. Thus, DEX treatment may have resulted in a phys-iologically abnormal state in which type II receptors were

bound but type I receptor occupation was submaximal. Al-though it had no effects on cocaine self-administration byitself, coadministration of the type I receptor agonist ALDO(100 g/kg) with DEX (10 g/kg) restored self-administrationto levels observed in VEH-treated rats. This DEX/ALDOcombination, at the doses used, did not produce CORT-likeeffects on self-administration (e.g., facilitation of acquisitionvs. VEH-treated rats). The restoration of self-administrationby ALDO was not accompanied by a reversal of the DEX-induced suppression of the corticosterone response to co-caine. Thus, type I receptor occupation by basal corticoste-rone concentrations may be necessary for the acquisition ofcocaine self-administration. These findings are consistent

with reports that the occupation of type I receptors is re-quired for the locomotor stimulating effects of cocaine(Marinelli et al., 1997).

It has been demonstrated that exposure to stress or treat-ment with CORT, but not DEX, facilitates ethanol self-ad-ministration in rats (Fahlke et al., 1995). In these experi-ments, the effects of CORT were not blocked by antagonistsat type I (RU 28318) or type II (RU 38486) receptors, indi-cating that CORT may have been acting independently ofthese receptors. A non-MR/GR effect of CORT could explainthe ability of DEX to prevent the acquisition of cocaine self-administration despite its occupation of type II receptors. Insuch a scenario, the type II receptor-mediated feedback inhi-

bition of the HPA axis by DEX could block any non-GR effects

of corticosterone related to reinforcement by preventing therelease of the hormone in response to cocaine.

An important role for the mesocorticolimbic dopaminergic(DA) system in drug reinforcement has been clearly estab-lished (Koob, 1992). It has been demonstrated that the facil-itation of the acquisition of cocaine self-administration bysocial stress is associated with an enhancement of DA trans-mission within this system (Tidey and Miczek, 1997). It has

also been reported that corticosterone in the range of stress-induced concentrations can stimulate the release of DA in thenucleus accumbens (Piazzaet al., 1996). Thus, corticosterone,and its effects on mesocorticolimbic DA transmission, may bean interface through which stress and cocaine reinforce-ment interact.

In summary, the results from these experiments demon-strate that daily pretreatment with corticosterone facilitatesthe acquisition of intravenous cocaine self-administration inrats. These findings suggest that corticosterone may providea substrate through which environmental factors interactwith the reinforcing effects of cocaine and other drugs ofabuse. Differences in plasma corticosterone before or at the

time of cocaine exposure may be critical determinants ofwhether or not individuals will progress to compulsive druguse and may provide a target for clinical intervention onceself-administration has been established. Finally, the find-ings that daily treatment with dexamethasone blocks theacquisition of cocaine self-administration may be relevant tothe development of novel pharmacotherapeutic approachesto the treatment of cocaine addiction.

Acknowledgments

The authors gratefully acknowledge G. F. Guerin, G. E. Farrar,and E. Padgett for their expert technical assistance and Drs. A. J.Dunn and J. D. Steketee for their invaluable advice.

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Send reprint requests to: Nick E. Goeders, Ph.D., Department of Pharma-cology & Therapeutics, LSU Medical Center, P.O. Box 33932, 1501 KingsHighway, Shreveport, LA 71130-3932. E-mail: [email protected]


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John R. Mantsch et al- Corticosterone Facilitates the Acquisition of Cocaine Self- Administration in Rats: Opposite Effects of the Type II Glucocorticoid Receptor Agonist Dexamethasone