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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
JPET 289:1641–1647, 1999
Vol. 289, No. 3
Printed in U.S.A.
Effects of Self-Administered Cocaine on Plasma
Adrenocorticotropic Hormone and Cortisol in Male
Rhesus Monkeys1
JILLIAN H. BROADBEAR, GAIL WINGER, THEODORE J. CICERO, and JAMES H. WOODS
Departments of Psychology (J.H.B., J.H.W.) and Pharmacology (G.W., J.H.W.), University of Michigan Medical School, Ann Arbor, Michigan;
and Department of Psychiatry (T.J.C.), Washington University, St. Louis, Missouri
Accepted for publication January 14, 1999
This paper is available online at http://www.jpet.org
Since the original observation that cocaine administration
resulted in activation of the hypothalamic-pituitary-adrenal
(HPA) axis via a corticotropin-releasing hormone (CRH)-mediated mechanism in the rat (Rivier and Vale, 1987; Moldow
and Fischman, 1987), a number of published studies have
attempted to address the significance of this effect. Activation of the HPA axis by cocaine is not unique to the rat; the
same has been reported in rhesus monkeys (Sarnyai et al.,
1996) as well as in human subjects (Mendelson et al., 1989;
Vescovi et al., 1992; Heesch et al., 1995). In humans, the rise
in plasma adrenocorticotropic hormone (ACTH) subsequent
to i.v. administered cocaine has been shown to mirror the
time course of cocaine’s distribution in the blood (Scholar et
al., 1998), both of which precede the slower and more sustained cortisol response (Wilkins et al., 1992). Scholar and
Received for publication September 9, 1998.
1
This work was supported by United States Public Health Service Grant
DA 09161. Results from this study were originally presented at the annual
meeting of the College of Problems of Drug Dependence in June, 1997. Animals
used in these studies were maintained in accordance with the University of
Michigan Committee on Animal Care and Guidelines of the Committee on the
Care and Use of Laboratory Animal Resources, National Health Council (Department of Health, Education and Welfare, ISBN 0 –309-05377–3, revised
1996).
0.01, 0.03, 0.1, and 0.3 mg/kg/injection cocaine were then
evaluated using a fixed-ratio 30, time-out 10-min schedule of
reinforcement in seven male monkeys. Blood was sampled
before, during, and after self-administration sessions. Self-administration of cocaine produced dose-dependent increases in
cortisol and ACTH. One dose of cocaine (0.03 mg/kg/injection),
although reliably self-administered, did not produce a significant increase in HPA axis activity. These results indicate that
although cocaine dose-dependently increases HPA axis activity, the HPA effect is more likely a consequence of overall
cocaine intake than it is an indicator of cocaine doses that are
sufficient to maintain self-administration behavior.
coworkers’ results also indicate that in experienced cocaine
users, the administration of cocaine rapidly triggers the release of CRH, which in turn stimulates the rise in plasma
ACTH.
Manipulations that use surgical or pharmacological means
to decrease HPA activity in rats also produce a notable increase in both the dose and time needed for the acquisition of
cocaine self-administration (Goeders and Guerin, 1994).
These manipulations also decrease ongoing self-administration behavior (Goeders and Guerin, 1996a) as well as reduce
the likelihood of a resumption in drug-maintained responding after a period of abstinence or saline extinction (Piazza et
al., 1994; Piazza and le Moal, 1998). In related studies, rats
that were designated as “high responders” after being prescreened for their locomotor and corticosterone responses to
either a novel environment or an i.p. amphetamine injection
also showed an increased propensity to self-administer amphetamine (Piazza et al., 1989, 1991) or cocaine (Goeders and
Guerin, 1996) at smaller doses. Collectively, the results of
these studies have led to speculation that individuals whose
HPA axis is highly responsive to a stressor may possess a
physiological profile that renders them more vulnerable to
drug abuse (Piazza and le Moal, 1996; Goeders, 1997).
ABBREVIATIONS: CRH, corticotropin-releasing hormone; HPA, hypothalamic-pituitary-adrenal; ACTH, adrenocorticotropic hormone; FR, fixedratio; TO, time-out; AUC, area under curve.
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ABSTRACT
This study was designed to examine the effects of self-administered cocaine on hypothalamic-pituitary-adrenal (HPA) axis
activity in rhesus monkeys. Initially, basal release of cortisol and
adrenocorticotropic hormone (ACTH) was measured in singly
housed male and female monkeys (n 5 9) over a 24-h period
using plasma samples obtained from indwelling venous catheters. Basal cortisol and ACTH levels in both male and female
rhesus monkeys demonstrated a circadian pattern of release, with
peak levels for cortisol (19.60 6 2.16 mg/dl) and ACTH (19.63 6
2.56 pg/ml) measured at 6:00 AM. The nadir for ACTH (6.27
6 0.62 pg/ml) occurred at 6:00 PM, preceding the cortisol nadir
(5.55 6 1.21 mg/dl) at 9:00 PM. The reinforcing effects of saline,
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Broadbear et al.
Materials and Methods
Subjects
Seven adult male rhesus monkeys (Macaca mulatta), weighing
between 9.0 and 14 kg, and three adult females, weighing between
5.0 and 7.4 kg, were used in this study. These monkeys were individually housed in stainless steel cages measuring 83.3 3 76.2 3
91.4 cm deep (Bryan Research Equipment Corporation, Bryan, TX)
located in a laboratory that contained a total of 24 monkeys. The
monkeys were fed 8 to 14 Purina Monkey Chow biscuits twice daily
to maintain adult body weight and water was available ad libitum.
The laboratory was illuminated from 7:00 AM to 10:30 PM. Each
monkey had an indwelling venous catheter in a femoral, internal, or
external jugular vein. Catheters were inserted during aseptic surgery under ketamine (10 mg/kg) and xylazine (2 mg/kg) anesthesia.
After placement in the vein, the catheter was guided s.c. to the
mid-scapular region where it exited the monkey. The external portion of the catheter was protected inside the cage by a flexible
stainless steel arm, with one end of the arm attached to the doublelayer polyester jacket (Lomir, New York, NY) worn by the monkey
and the other bolted to the rear of the cage.
Circadian Rhythm Study. Six male and three female monkeys
were subjects for this study. All monkeys had been acclimated to the
jacket and flexible arm apparatus over a period of months or years.
Five monkeys had a history of cocaine self-administration, two monkeys had received cocaine passively on one or more occasions, and
two monkeys were cocaine-naive. Ketamine, used for sedation, was
the only psychoactive drug noted in the histories of the latter two
monkeys. For those monkeys conditioned to cocaine self-administration, testing was suspended in this phase of the study. Blood (1.4 ml)
was sampled at 3-h intervals over a 24-h period from the rear of the
cage via the venous catheter. Each monkey was exposed to this
sampling procedure once only. Sample collection and handling is
described below.
Cocaine Self-Administration Study. Seven adult male monkeys (five of whom were in the circadian study) were subjects for this
study. Four of the seven monkeys had 1 or more years experience
with the self-administration of different doses of cocaine under the
fixed-ratio (FR) 30 time-out (TO) 10 min. The remaining three subjects were more recently trained and had 1- to 6-months’ experience
with cocaine self-administration under the FR 30 TO 10 min schedule. Each monkey had blood samples taken between one and twelve
times (four on average) at each dose of cocaine or saline.
Apparatus
Each cage had a 15- 3 20-cm panel fixed to the right wall of the
cage. Each panel had three stimulus lights, two red and one central
green light, placed above two response levers. The red stimulus light
over the right lever signaled drug availability. Drug delivery was
contingent on the monkey emitting the required response (30 lever
presses). The green center light was illuminated for the duration of
the drug infusion, 1 ml over 5 s. During each 10-min time-out, all
stimulus lights were extinguished and responding had no programmed consequences.
The experiment was controlled by IBM/PS2 computers located in
an adjacent room. The computers were programmed using Med Associates software (Georgia, VT).
Procedure
Circadian Rhythm Study. Blood sampling for the study of basal
release of ACTH and cortisol took place on two separate occasions.
Five monkeys were tested on the first occasion and four on the
second. Blood (1.4 ml) was sampled at 3-h intervals, beginning at
9:00 AM and ending with the 9:00 AM sample the following day.
Self-administration testing for the monkeys in this study was suspended for the duration of the basal sampling period, although the
other monkeys in the room were tested as usual. The blood sample
handling procedure is described below.
Self-Administration Study. Drug self-administration sessions
were scheduled twice daily for 130 min starting at approximately
10:00 AM and 4:00 PM. There was a maximum of 13 infusions
available in each session. The effect of cocaine self-administration on
ACTH and cortisol was measured primarily before, during, and after
the morning session, although on a few occasions the HPA response
to cocaine was measured during the evening session for comparison.
All seven monkeys were tested with saline, 0.01, 0.03, 0.1, and 0.3
mg/kg/injection cocaine on an FR 30 TO 10 min schedule of reinforcement. The criteria required for a stable baseline of self-administration behavior were response rates of greater than one response per
second for 0.03 mg/kg/injection cocaine, and delivery of the maximum number of injections available during the session (13 injec-
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Although it is generally accepted that passive cocaine administration stimulates activity of the HPA axis, there are
very little published data demonstrating the effects of selfadministered cocaine on HPA activity. The only exception
was in a study done by Goeders and Guerin (1996b) where
single samples of blood were obtained from rats before and
after self-administration of different doses of cocaine. Mean
plasma corticosterone levels after cocaine self-administration
were reported to be significantly elevated above levels measured before cocaine exposure for all of the doses of cocaine
that were tested. However, there was no indication as to
whether this increase was dose-dependent in terms of either
the dose of cocaine that was available, or the number of
infusions that were taken.
Complex logistics are involved in studying the relationship
between cocaine administration and the corresponding HPA
response. Environmental factors such as handling of the
animals, needle poke in the case of both i.p. cocaine administration and peripheral blood sampling, and relocation to a
testing enclosure may each produce substantial HPA activation quite apart from any effect produced by the cocaine
(Elvidge et al., 1976; Blank et al., 1983; Reinhardt et al.,
1990; Capitanio et al., 1996). These kinds of manipulations
may actually blunt the response to cocaine as a prior increase
in baseline ACTH and glucocorticoids may reduce HPA reactivity to subsequent stimulation via negative feedback
(Keller-Wood and Dallman, 1984; Dallman et al., 1994), as
well as obscure differences between cocaine and saline controls. This is not to say that all extra-hypothalamic CRH
release is inhibited in the same way; however the apparent
sensitivity of the HPA system to extraneous stimuli highlights the need for use of familiar procedures that minimize
disturbance to the subject.
In the present study, we initially examined the basal release of ACTH and cortisol and its circadian rhythmicity in
male and female monkeys, some of whom were experienced
with cocaine self-administration and some of whom had no
such experience. Using these data as a reference, we evaluated the HPA response to self-administered cocaine in the
morning and afternoon in male rhesus monkeys with extensive histories of cocaine self-administration. To minimize
both disturbance to the monkeys as well as experimenterinduced increases in ACTH and cortisol, testing took place in
their home cages and blood was sampled from behind each
cage via the same indwelling venous catheter as was used for
drug infusions.
Vol. 289
1999
Self-Administered Cocaine: HPA Response in Rhesus Monkeys
Results
Circadian Rhythm. Fig. 1 shows the plasma levels of
ACTH and cortisol measured in blood samples taken at 3-h
intervals over a 24-h period. Basal plasma cortisol and ACTH
levels in both male and female rhesus monkeys demonstrated a circadian pattern of release during the sampling
period (Fig. 1A). Both cortisol and ACTH levels differed
across the 24-h sampling period (ACTH: df 5 8, F 5 3.75, p ,
.001; cortisol: df 5 8, F 5 4.87, p , .0001). The details from
post hoc pairwise comparisons are listed in the legend to Fig.
1. Peak levels for plasma cortisol (19.60 6 2.16 mg/dl) and
ACTH (19.63 6 2.56 pg/ml) occurred at 6:00 AM. The nadir
for plasma ACTH (6.27 6 0.62 pg/ml) occurred at 6:00 PM,
preceding the cortisol nadir (5.55 6 1.21 mg/dl), which occurred at 9:00 PM. Although the female monkeys in this
study appeared to have higher cortisol and ACTH peaks than
male rhesus monkeys (Fig. 1, B and C), this difference was
not statistically significant. A comparison between monkeys
with a cocaine self-administration history (n 5 5; all male)
versus those with no such history (n 5 4; 1 male, 3 female)
showed a near-significant difference in basal cortisol levels,
with the monkeys lacking self-administration history tending to have higher levels (df 5 1, F 5 5.00, p , .06), but there
Data Analysis
Circadian Rhythm Study. The plasma cortisol and ACTH levels
over the 24-h sampling period were averaged for each sampling time
according to gender and then analyzed for gender differences. In the
absence of a sex difference, the data for male and female monkeys
were averaged and analyzed as described below.
Self-Administration Study. Rate of responding during each session was defined as the number of responses emitted while the red
stimulus light was on divided by the number of seconds that the light
was illuminated (responses/s). The total dose of cocaine (mg/kg) for
each monkey was the number of infusions taken during the session
multiplied by the dose per infusion (mg/kg/injection). Plasma cortisol
(mg/dl) and ACTH (pg/ml) levels are shown in raw form as well as
after normalization to area under curve (AUC) data. AUC values
provide an estimate of the cortisol or ACTH release relative to basal
levels during the self-administration session. AUC values were calculated according to the trapezoidal rule (e.g., Tallarida and Murray,
1987). The presession plasma level before each experiment was used
as the reference for the calculation of the AUC for cortisol
(mg z min/dl) or ACTH (pg z min/ml). The AUC was calculated from
the six samples taken before, during, and 15 min after the session.
Statistics
All data are presented as mean 6 S.E.M. One or two-way ANOVA
and post hoc pairwise comparisons using the Tukey HSD test of
significance (p , .05) were carried out using Statistica (v.5.0; Statsoft, Tulsa, OK). When experiments were replicated within subjects,
the mean response for each subject was used in calculating treatment effects across subjects.
Fig. 1. Basal levels of plasma cortisol (mg/dl) and ACTH (pg/ml) exhibiting circadian cyclicity. A, plasma was sampled from unrestrained monkeys (six males, three females) at 3-h intervals from the rear of the cage
via indwelling venous catheter. Comparison of basal release of cortisol
(mg/dl; B) and ACTH (pg/ml; C) in male and female subjects; there were
no significant gender differences. a, cortisol lower than at 09:00 and 00:00
(p , .05), and 00:00 h (p , .005). b, cortisol higher than at 18:00, 09:00,
and 00:00 (p , .005). c, ACTH lower than at 18:00 (p , .005) and 00:00
PM (p , .05). d, ACTH higher than at 18:00 and 09:00 (p , .01).
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tions). In addition, when saline was available for self-administration,
(2.5 to 50% of all sessions) response rates were required to be less
than 20% of the rates for 0.03 mg/kg/injection cocaine, with total
saline injections numbering fewer than thirteen.
Blood was sampled no more than two or three times per week. A
sample of venous blood was drawn via the catheter 5 to 30 min before
the morning session, and then again after the 1st, 4th, 8th, and 13th
infusions (or at approximately 5, 30, 70, and 130 min after the
session began if the monkey’s response rate slowed during the session). Blood samples continued to be drawn at 15 min postsession,
and at hourly intervals for the next 3 h, making a total of nine blood
draws. When sampling took place during the evening session, blood
continued to be drawn at the same intervals as during the morning
session, making a total of 13 blood draws for the day. Each blood
sample (1.1–1.4 ml) was placed in a 2 ml Vacutainer (Becton Dickinson & Co., Franklin Lakes, NJ) containing 0.04 ml of 7.5% EDTA
and immediately placed on ice. After each blood sample, 1.5 to 3 ml
of 30 U/ml heparin saline solution was infused into the catheter and,
when sampling was done during sessions in which cocaine was
available, a volume of the cocaine solution equal to the catheter
volume was injected (0.6 –1.5 ml). Samples were centrifuged at 5,000
RPM and 4°C for 5 min and then the plasma (0.7 ml) was pipetted
into 2-ml Cryovials (Corning Costar Corp., Cambridge, MA) and
stored at 280°C until assay. Samples were sent on dry ice to Washington University (St. Louis, MO) where ACTH and cortisol levels
were measured using radioimmunoassay kits (cortisol: Diagnostic
Products Corporation, Los Angeles, CA; ACTH: Nichols Institute
Diagnostics, San Juan Capistrano, CA). In 90% of cases, single
determinations were made for both cortisol and ACTH levels from
each blood sample. Ten percent of samples were assayed in duplicate
to determine inter- and intra-assay variability. Each cortisol and
ACTH kit was used to measure approximately 100 samples. For the
cortisol assay, the range of detection was 0.2 to greater than 50 mg/dl.
Interassay variability was 4 to 6.5%, and intra-assay variability was
3 to 5%. For the ACTH assay, the range of detection was 0.5 to 1500
pg/ml. Interassay variability was 7%, and intra-assay variability was
3%.
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Broadbear et al.
Fig. 2. Comparison of response rate (responses/s) versus total cocaine
intake (mg/kg) when saline or cocaine (mg/kg/injection) was available for
self-administration (n 5 7). Cocaine (or saline) availability was signaled
by a red stimulus light that remained illuminated until the requisite
number of lever presses had been emitted (FR 30, TO 10 min). Drug or
saline delivery was signaled by a green stimulus light. Each session
lasted 130 min and a maximum of 13 infusions was possible. The response rates for 0.01 mg/kg/injection cocaine and saline were not significantly different. Cocaine intake for each dose differed across all doses
tested (p , .05). a, response rate is lower than for 0.03, 0.1, and 0.3
mg/kg/injection cocaine (saline: p , .001; 0.01 mg/kg/injection cocaine:
p , .01).
Fig. 3. Mean plasma cortisol levels (mg/dl, A) and ACTH levels (pg/ml, B)
determined from blood sampled before, during, and after saline or cocaine
(mg/kg/injection) self-administration (n 5 7). Procedural details as for
Fig. 2. a, greater than for saline, p , .05. b, greater than for saline and
0.01 mg/kg/injection cocaine, p , .05. c, greater than for saline, 0.01, and
0.03 mg/kg/injection cocaine, p , .05. d, greater than for saline and 0.03
mg/kg/injection cocaine, p , .05.
pling time (df 5 4, F 5 22.23, p , .001) and dose 3 sampling
time (interaction: df 5 16, F 5 2.40, p , .005) both had
significant effects on plasma ACTH. Post hoc pairwise comparisons evaluating the effect of both dose and sampling time
for cortisol and ACTH are summarized in the legend to
Fig. 3.
The cortisol and ACTH response to 0.3 mg/kg/injection
cocaine when it was self-administered during the morning or
afternoon sessions is compared in Fig. 4. Several monkeys
showed a diminished HPA response to 0.3 mg/kg/injection
cocaine self-administration during the afternoon session, despite the fact that response rates and cocaine intake did not
differ between morning and afternoon sessions (data not
shown). The greater sensitivity of the HPA axis to cocaine
during the morning session corresponds with higher basal
levels of cortisol and ACTH, whereas during the evening
session, basal HPA activity is approaching its nadir (see
Fig. 1).
The AUC data for plasma ACTH and cortisol release is
shown in Fig. 5. These values represent the cumulative release of ACTH and cortisol above presession levels during the
cocaine (or saline) self-administration sessions. Betweensubjects ANOVA, measuring the effect of cocaine dose on
cortisol or ACTH AUC, did not reveal any statistical difference among the monkeys in their HPA response to cocaine or
saline self-administration. Subsequent 1-way ANOVA revealed a significant effect of cocaine dose on both cortisol
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was no difference in basal ACTH levels between the two
groups (data not shown). Six of the nine monkeys showed an
additional cortisol peak at 12:00 PM, whereas eight of the
nine monkeys showed an increase in ACTH at this time.
Cocaine Self-Administration. The response rate and
cocaine intake from the cocaine self-administration study are
shown in Fig. 2. The response rate for the session was lowest
when saline was available for self-administration (0.3 6 0.1
responses/s) and increased as a function of the available dose
of cocaine (0.01– 0.1 mg/kg/injection). The ascending arm of
the dose-response curve was generated, with the peak rate of
responding (3.5 6 0.5 responses/s) maintained by 0.1 mg/kg/
injection cocaine. There was a slight, nonsignificant rate
decrease at 0.3 mg/kg/injection cocaine (2.6 6 0.4 responses/
s), the largest dose that was tested. Total drug intake (mg/kg)
was positively related to the dose of cocaine that was available for self administration. One-way ANOVA was used to
examine the effects of cocaine dose on both rate of responding
and total drug intake (rate: df 5 4, F 5 20.52, p , .001;
intake: df 5 4, F 5 5177, p , .001), indicating that increasing
the dose of cocaine led to significantly increased rates of
responding and cocaine intake. The results of subsequent
pairwise comparisons are shown in the legend to Fig. 2.
Cocaine self-administration produced dose-dependent increases in plasma cortisol and ACTH levels (Fig. 3, top and
bottom, and Table 1). Presession, as well as peak withinsession plasma ACTH and cortisol levels, are presented for
each dose of cocaine (Table 1). The peak plasma level of
cortisol generally occurred later in the session than the
ACTH peak (Table 1). Plasma levels of ACTH and cortisol
decreased during the 3 h after the morning self-administration session, taking between 1 and 3 h to return to presession
levels. Plasma cortisol levels obtained from samples 2 to 6
taken during the self-administration session were examined
for effects of dose and sampling time using 2-way ANOVA.
Dose (df 5 4, F 5 5.07, p , .005), sampling time (df 5 4, F 5
10.48, p , .001) and dose 3 sampling time (interaction: df 5
16, F 5 2.79, p , .001) all had significant effects on plasma
cortisol. Plasma ACTH levels were similarly examined. Sam-
Vol. 289
1999
Self-Administered Cocaine: HPA Response in Rhesus Monkeys
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TABLE 1
Characteristics of plasma ACTH and cortisol levels after cocaine self-administration
Cocaine
Time of ACTH Peak
mg/kg/injection
0 (presession)
0 (saline)
0.01
0.03
0.1
0.3
ACTH (6S.E.M.)
Time of Cortisol Peak
mg/dl
pg/ml
8th
13th
8th
8th
8th
infusion
infusion
infusion
infusion
infusion
6.56 2 10.32
11.82 6 2.2
19.76 6 3.82
20.95 6 2.59
22.12 6 2.99
29.16 6 2.85
Cortisol
(6S.E.M.)
, pre-session
13th infusion
15 min postsession
13th infusion
13th infusion
9.43 2 11.89
11.20 6 1.00
14.48 6 1.73
18.00 6 1.57
20.19 6 0.97
(df 5 4, F 5 12.82, p , .001) and ACTH AUC (df 5 4, F 5
2.84, p , .05). The results of post hoc pairwise comparisons
are described in the legend to Fig. 5.
Discussion
The results of the circadian study presented here demonstrate a diurnal rhythmicity in the release of ACTH and
cortisol in both male and female rhesus monkeys. This basal
release constituted a stable baseline from which the HPA
axis response to self-administered cocaine could be measured. Males and females were no different with respect to
the timing of the peak, nadir, or magnitude of the plasma
ACTH and cortisol levels. Four of the nine monkeys tested
had no self-administration history. These four tended to have
higher cortisol levels; however, ACTH levels for both groups
were the same. This difference may reflect either drug-taking
history or the novelty of the experimental procedure, as three
of these monkeys had undergone their first catheter placement surgeries within 2 weeks of the circadian study. Comparison of the male and female data is complicated by the fact
that all of the female monkeys in our study also belonged to
the group that lacked self-administration history.
Our circadian data showed a second, smaller peak at 12:00
PM for the majority of subjects. Additional peaks in ACTH
and cortisol have been reported in humans (Slag et al., 1981;
Goldman et al., 1985) and were attributed to meal ingestion,
particularly high protein lunches. The unexpected rise in
ACTH and cortisol seen in our data is unlikely to be due to
food ingestion as the monkeys were fed at 8:30 AM and 2:30
PM daily. The only other activity likely to have disrupted
basal release of cortisol and ACTH was the 2-h 10-min selfadministration session scheduled daily from 10:00 AM until
12:10 PM. Although the monkeys in this study had their
self-administration sessions suspended during the sampling
period, the remaining monkeys in the room were tested as
usual. A recent study by Caggiula and coworkers (1998)
reported that rats showed a conditioned elevation of plasma
corticosterone in response to environmental cues associated
with nicotine delivery. The fact that a self-administration
session did take place during the sampling time makes the
possibility of a conditioned HPA axis response the most likely
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Fig. 4. Effect of self-administered
cocaine (0.3 mg/kg/injection) on
plasma cortisol (mg/dl) and ACTH
(pg/ml) during morning or afternoon self-administration sessions
in five subjects. The HPA response
to cocaine was more robust in
some monkeys during the “AM
SESSION”, when basal cortisol
and ACTH levels were at a peak,
than during the “PM SESSION”
when basal HPA activity was approaching its nadir (see Fig. 1).
Rates of responding as well as cocaine intake during the morning
and afternoon sessions were comparable for each monkey. Other
details as for Fig. 2.
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Broadbear et al.
explanation. The fact that four of the nine monkeys had no
self-administration history suggests that this increase may
have resulted from a more general social effect.
A few earlier studies have shown evidence for circadian
release of plasma ACTH (Kalin, 1986) and cortisol (Quabbe
et al., 1982) in male rhesus monkeys, and cortisol in female
rhesus monkeys (Leshner et al., 1978). In these earlier studies, all subjects but one were chronically chair-restrained. It
is interesting to note that in the one paper where a caged,
freely moving monkey was compared with the chronically
chair-restrained monkeys (Quabbe et al., 1982), the freely
moving monkey had cortisol levels that were similar to his
restrained counterparts, as well as to our monkeys. Although
we did not investigate whether hormonal fluctuations in the
female monkeys affected cortisol and ACTH release, Leshner
and coworkers (1978) sampled throughout the menstrual
cycle and found no consistent variations in cortisol levels.
Our study was not designed to measure the secretory pulses
that accompany the circadian fluctuations, as this has already been studied by Sarnyai and coworkers (1995), who
examined the ultradian release of both cortisol and ACTH at
2-min intervals and concluded that the pulse frequency, interpulse interval, and pulse amplitude in male rhesus monkeys was very similar to what has been measured in humans.
Cocaine served as a reinforcer in this study. Both rate of
responding and total cocaine intake increased as a function of
cocaine dose (Fig. 2, Table 1), similar to what has been
described previously (e.g., Winger, 1993). As the cocaine dose
available for self-administration was increased, there was a
dose-dependent increase in ACTH and cortisol release, although only at the highest doses of cocaine (0.1 and 0.3
mg/kg/injection) were these increases in ACTH and cortisol
statistically greater than were measured for saline. When
blood was sampled during the afternoon self-administration
session, a diminished HPA response to cocaine was noted in
some monkeys, perhaps indicating that diurnal fluctuations
in the release of ACTH and cortisol were associated with
alterations in the sensitivity of the HPA axis to cocaine
administration. It is important to note that under these experimental conditions, a dose of cocaine (0.03 mg/kg/injection) that was sufficient to maintain behavior above saline
levels did not produce a significant elevation in HPA activity
above levels produced by saline self-administration. In fact,
under these schedule conditions there was no difference in
the rates of responding maintained by 0.03, 0.1, and 0.3
mg/kg/injection cocaine, although the intake of cocaine differed markedly, as did the ACTH and cortisol response. This
is evidence for a dissociation between doses of cocaine that
clearly maintained responding versus doses that clearly elevated HPA activity. So although HPA activation by cocaine
appeared dose-dependent, a dose of cocaine that maintains
self-administration behavior does not necessarily produce
significant HPA activation. This point is discussed further
below.
It is difficult to ascertain from other published work in this
field whether a dose of cocaine will produce the same HPA
response when it is injected by the investigator or self-administered by the subject. When cocaine was injected i.v. into
rats, it produced a dose-dependent increase in plasma ACTH
(Rivier and Vale, 1987) and corticosterone (Moldow and Fischman, 1987). The one paper that directly addressed cocaine
self-administration and activation of the HPA axis in the rat
did not provide an estimate of cocaine intake (Goeders and
Guerin, 1996b). This prevents a comparison of the results of
these two studies. The only work of this kind in rhesus
monkeys examined the plasma ACTH and cortisol response
to a single infusion of 0.4 and 0.8 mg/kg cocaine in males
(Sarnyai et al., 1996) and females (Sarnyai et al., 1995).
Although female monkeys showed no change in HPA function
in response to cocaine, increases in ACTH and cortisol levels
in male monkeys were proportional to the cocaine-induced
level of behavioral activation. It is noteworthy that the preinfusion cortisol and ACTH levels in most of the monkeys in
the study by Sarnyai et al. (1996) are far greater (cortisol is
2-fold higher and ACTH is 4-fold higher) than in the monkeys
in the present study, perhaps reflecting procedural differences between the studies. A consequence of these high baseline values may have been a blunting of cocaine’s effect on
HPA activity. Sarnyai gave 0.4 and 0.8 mg/kg i.v. in a single
infusion, whereas in the present study, monkeys self-administered cocaine incrementally with the total dose (0.13, 0.39,
1.3, and 3.9 mg/kg) being injected over the course of a 2-h
session. Sarnyai found that the subgroup of monkeys that
were responsive to cocaine had increases in cortisol and
ACTH release after the 0.8 mg/kg but not after the 0.4 mg/kg
dose. In the present study, the dose of cocaine that resulted in
a cumulative intake of 0.39 mg/kg (0.03 mg/kg/injection) did
not lead to a significant increase in ACTH and cortisol release, despite the fact that this dose of cocaine maintained
high rates of responding. The earliest indication in the session that cocaine was increasing HPA axis activity beyond
saline levels was after the 4th infusion of 0.3 mg/kg/injection
(total dose 5 1.2 mg/kg over 30 min), and after the 8th
infusion of 0.1 mg/kg/injection (total dose 5 0.8 mg/kg over 70
min). Thus it is possible that the dose of i.v. cocaine that
marks the threshold for activation of the HPA axis lies between 0.4 and 0.8 mg/kg. If this were the case, it could be
anticipated that doses of cocaine that, either singly or cumulatively, do not reach this range, would not activate the HPA
axis. This casts some doubt on any suggestion that glucocorticoid release may be integral to cocaine’s reinforcing effects.
The results presented here are in agreement with previous
reports that cocaine administration is correlated with in-
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 5, 2017
Fig. 5. Cumulative release (AUC) of plasma cortisol (ug z min/dl) versus
ACTH (pg z min/ml) above basal (presession) levels during saline or
cocaine (mg/kg/injection) self-administration (n 5 6). One monkey was
not included as there was no within-session sampling done. Details as for
Fig. 2. a, greater than the cortisol AUC generated by saline self-administration (p , .005). b, greater than the cortisol AUC for saline, 0.01, and
0.03 mg/kg/injection cocaine (p , .005). c, greater than the ACTH AUC
for saline (p , .05).
Vol. 289
1999
Self-Administered Cocaine: HPA Response in Rhesus Monkeys
creased HPA activity. However, in contrast to previous studies, the data presented here were collected from awake, minimally disturbed monkeys, behaving in their home cages, and
with control over cocaine delivery. Under these conditions,
male and female monkeys exhibited similar, normal diurnal
variation in basal ACTH and cortisol release. In male monkeys with an extensive cocaine self-administration history,
plasma ACTH and cortisol levels increased as a function of
cocaine intake, indicating that self-administered cocaine
dose-dependently increased HPA activity. Nevertheless,
there was evidence that small, but nevertheless reinforcing,
doses of cocaine failed to produce significant activation of the
HPA axis. Thus, the procedure used in this study for examining cocaine’s effect on HPA function demonstrated a low,
stable cortisol and ACTH baseline upon which a clear effect
of cocaine was measured.
Acknowledgments
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Send reprint requests to: Jillian Broadbear, University of Michigan, Department of Pharmacology, 1301 MSRB 3, Ann Arbor, MI 48109-0632. E-mail:
[email protected]
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We thank Myrtle Barrett, Deborah Huntzinger, Amy Foster, and
Brenda Winger for their expert technical assistance.
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