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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics
JPET 288:550 –560, 1999
Vol. 288, No. 2
Printed in U.S.A.
Effects of Phentermine on Responding Maintained under
Multiple Fixed-Ratio Schedules of Food and Cocaine
Presentation in the Rhesus Monkey1
FRANCIS H. E. WOJNICKI, RICHARD B. ROTHMAN,2 KENNER C. RICE and JOHN R. GLOWA
Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland (J.R.G.); and Laboratory of Medicinal
Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (J.R.G.,
F.H.E.W., K.C.R.)
Accepted for publication July 28, 1998
This paper is available online at http://www.jpet.org
There is current interest in whether pharmacological
treatments can be developed that will decrease cocaine abuse
in humans. One approach to assessing this possibility is to
test potential treatments on behaviors associated with the
abuse potential of cocaine (Woolverton and Kleven, 1991). A
number of reports have shown that cocaine self-administration can be decreased by drug treatment. However, high
doses of any drug can decrease any behavior, questioning
whether these drug-induced decreases in cocaine self-administration are behaviorally specific. Some drugs decrease cocaine self-administration at doses that have less of an effect
Received for publication March 6, 1997.
1
This work was supported, in part, by a National Institute on Drug Abuse
Interagency Agreement no. RA-ND-94 to 24 and by National Institute on Drug
Abuse Grant RO1 DA09820 (J.R.G., Principal Investigator). Portions of the
data were presented at the Society for Neuroscience Meeting, Miami, FL, 1994.
All animal procedures conformed to the Guide for Care and Use of Laboratory
Animals endorsed by the National Institutes of Health.
2
Clinical Psychopharmacology Section, National Institute on Drug Abuse/
National Institutes of Health Addiction Research Center, Baltimore, MD.
After subacute treatment was terminated, rates of cocainemaintained responding generally recovered to levels comparable to those seen during untreated control sessions. Phentermine (0.3–3 mg/kg) did not generally increase responding
associated with a very low (1 mg/kg/injection) unit dose of
cocaine, suggesting that the decrease in cocaine-maintained
responding at higher unit doses was not the result of a leftward
shift in the cocaine unit dose-effect function. Phentermine
(0.1–3 mg/kg) decreased responding maintained by 1-[2-[bis(4fluorophenyl) methoxy]ethyl]-4-[3-phenylpropyl] piperazine
(GBR 12909) (30 mg/kg/injection) at doses similar to those that
decreased food-maintained responding. These results show
that phentermine is effective in decreasing cocaine self-administration and suggest that it may be an effective medication for
cocaine abuse.
on comparable rates of food-maintained responding. For example, buprenorphine (Mello et al., 1989), SKF 38393 (Katz
and Witkin, 1992), GBR 12909 (Glowa et al., 1995a), and
CFT (Glowa and Wojnicki, 1996) decrease responding maintained by cocaine at doses that have little or no effect on
food-maintained responding. The difference in effect of these
drugs on food- and cocaine-maintained responding suggests
that self-administration was not decreased due to a nonspecific effect of drug treatment, as a nonspecific effect would be
expected to decrease both behaviors. However, several additional interpretations of these decreases in cocaine selfadministration remain.
If drug treatments selectively affect the potency of cocaine,
they could decrease responding maintained by peak unit
doses of cocaine without affecting food-maintained performances. Dopamine (DA) antagonists clearly shift the unit
dose-effect function for cocaine to the right (Bergman et al.,
1990; Glowa and Wojnicki, 1996), suggesting that they decrease the potency of cocaine. Some (Caine and Koob, 1995),
ABBREVIATIONS: GBR 12909, 1-[2-[bis(4-fluorophenyl) methoxy]ethyl]-4-[3-phenylpropyl] piperazine; CFT, 2-b-carboxymethoxy-3-b-(4-fluorophenyl)tropane; DA, dopamine; FR, fixed-ratio; mult, multiple; TO, time-out; LH, limited hold; resp/sec, responses per second.
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ABSTRACT
Drugs that decrease drug-maintained responding at doses that
do not decrease other behaviors in animals may be suitable
candidates for development as medications to treat drug abuse
in humans. The present study examined whether this effect
could be obtained with phentermine, a drug that has been
reported to decrease cocaine intake in humans. Rhesus monkeys were trained under multiple fixed-ratio 30-response
schedules of food and i.v. cocaine delivery. Phentermine was
always given as a slow, i.v. infusion. Acute treatment with
phentermine (0.3–10 mg/kg) decreased cocaine-maintained responding at doses that did not decrease, or decreased less,
food-maintained responding for each of three unit doses of
cocaine (10 –100 mg/kg/injection). Subacute treatment with
phentermine (3 or 5.6 mg/kg, daily) also decreased cocainemaintained responding more than food-maintained responding.
1999
Behavioral Effects of Phentermine
Materials and Methods
Subjects. Eleven adult male rhesus monkeys (Macaca mulatta;
nos. 31, 44, 72, 675, 872, 522, 573, 561, 941, 769, and 450), weighing
6.8 to 9.0 kg were studied. Each monkey was maintained at approx-
imately 90% of its free-feeding weight. All monkeys had been previously trained to sit in a restraint chair (Primate Products, Redwood
City, CA) during experimental sessions and had previous experience
with FR schedules of food, cocaine (1–100 mg/kg/injection), and in
some cases (monkey nos. 675, 872, 573, 561, 941, and 769), GBR
12909 delivery. All animals had previous experience with GBR
12909 pretreatment, and some animals had previous experience with
GBR 12935 (no. 561), d-amphetamine and CFT (nos. 72, 31, and 44),
or single/combined doses of phentermine and fenfluramine (nos. 675,
872, 522, and 573) pretreatment.
Apparatus. Monkeys responded in one of four enclosed operant
chambers that were approximately 60 cm wide 3 100 cm high 3 90
cm deep. Each chamber was equipped with a ventilating fan, house
light, and an aluminum panel facing the monkey. The panel was
equipped with two response levers (BRS/LVE, Beltsville, MD), four
pairs of lights, and a water spout. Response levers were modified by
removing the standard “paddle” and replacing it with a solid aluminum (1 3 3 3 1⁄4 inches) paddle, which pivoted on a pair of pins. A
downward force of about 20g (0.196 N) on either lever produced an
audible click of a feedback relay and a response. Food (1-g banana
pellets; P.J. Noyes Co., Lancaster, NH) was delivered by a solenoidactivated food pellet dispenser (BRS/LVE) to the receptacle immediately in front of the monkey 10 cm above the waist plate. An indwelling i.v. jugular catheter and vascular-access port (Access
Technologies, Skokie, IL) was implanted in each monkey (Glowa et
al., 1995a,b). A sterile infusion line connected the vascular-access
port to a syringe driver. Events were programmed by a computer
system (MED-PC) and monitored on cumulative recorders.
Procedure. Animals were trained to exit the cage and to sit in a
restraint chair using a pole and collar technique. They were then
weighed, placed in the chamber, and the area over the port was
scrubbed with betadine and alcohol. The port was accessed with a
syringe fitted with a huber-point needle. Before the start of each
session (after presession drug administration), the port and catheter
were first flushed with saline and then filled with the drug reinforcer
(cocaine or GBR 12909).
Animals were previously trained under two variants of a mult FR
30-response (FR30) food, FR30 cocaine schedule of reinforcement
(Glowa et al., 1995a; 1997). Under each variant, 30 responses in the
presence of red stimulus lights produced a food delivery; 30 responses in the presence of blue stimulus lights produced a drug
(cocaine or GBR 12909) delivery. Each reinforcer delivery was followed by a 3-sec time-out (TO), during which all stimuli were turned
off and responding had no programmed consequences. Each FR30
was constrained by a 60-sec LH, such that if 30 responses were not
emitted within 60 sec, the availability of a reinforcer was terminated,
a 3-sec TO was produced, and both the FR requirement and the LH
time were reset. Food or drug availability was limited to discrete
components within a session. Each component limited the availability of reinforcers to a maximum of 10. Components terminated when
10 reinforcers, 10 LHs, or any combination of the two to total 10
occurred. Food and drug components strictly alternated and were
separated by a TO. In the variant used to assess the acute and
subacute effects of phentermine, the session began with a 15-min
TO, followed by a food component, a 5-min TO, and then a cocaine
component; two food pellets were delivered as each reinforcer in the
food component. In the variant used to assess the effects of phentermine on responding that produced a low unit dose of cocaine or GBR
12909, the session began with a food component, followed by a
10-min TO, a drug component, and then a 10-min TO; one food pellet
was delivered as each reinforcer in the food component. One session,
consisting of four cycles of either sequence, was conducted daily.
Total session times depended upon rates of responding, but control
sessions typically required a minimum of 90 min. Sessions were
conducted daily, 5 to 7 days a week. Phentermine was always given
before the session, by slow infusion (see drugs).
Acute Assessment. This experiment assessed the effects of a
range of acute doses (0.3–10 mg/kg) of phentermine on responding
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but not all (Glowa et al., 1995a; Glowa and Wojnicki, 1996)
functional DA agonists can shift the unit dose-effect function
for cocaine to the left. Further studies will be necessary to
determine whether DA agonists decrease self-administration
by affecting the potency of cocaine.
Drug treatment may decrease the reinforcing effects of
cocaine. A number of procedures have been used to provide a
metric of the reinforcing effects of drugs including progressive-ratio performances, choice situations, and the acquisition or extinction of responding (Katz, 1990). Lesions of specific brain structures (e.g., Caine and Koob, 1994), certain
drugs (e.g., Roberts and Richardson, 1992), or access to alternative reinforcers (e.g., Nader and Woolverton, 1991) can
decrease these measures of the reinforcing effects of cocaine.
However, few studies have determined whether drugs decrease these measures for other events to an extent comparable to that seen for cocaine.
Drug treatment may also decrease responding that is less
resistant to change (Nevin, 1974) more than responding
maintained under other conditions. For example, Egli et al.
(1992) showed that the same dose of a drug decreases responding maintained by relatively low densities of food presentation more than responding maintained by higher densities of food presentation. Other studies have reported that
doses of several drugs decrease responding maintained by
low unit doses of cocaine more than responding maintained
by high unit doses (Caine and Koob, 1995; Glowa et al.,
1995a; Mello and Negus, 1996). These results suggest that
responding maintained by events with greater reinforcing
efficacies are more resistant to change. If food is a more
effective reinforcer, drug treatment could decrease cocaine
self-administration without affecting food-maintained responding.
Because few studies have studied a sufficient range of
conditions to address these interpretations, the current experiments were designed to assess the effects of drug treatment on responding maintained by food and several different
unit doses of cocaine. Phentermine was chosen because preliminary data suggested it could decrease cocaine-maintained responding at doses that had less of an effect on
food-maintained responding (Glowa et al., 1997). Phentermine is an indirect DA agonist thought to exert its effects
primarily by increasing the release of DA (Rothman et al.,
1996). It has been given in combination with fenfluramine
(fen-phen) to decrease food intake in obese humans (Weintraub et al., 1984). Similarities between excessive food and
drug intake led Hitzig (1993) to propose the use of this drug
combination as a medication for drug abuse, although there
have been recent concerns regarding its safety (Mark et al.,
1997). A case study suggested phentermine was effective in
decreasing cocaine intake in humans (Rothman et al., 1994).
Thus, an additional purpose of the present studies was to
determine if a drug that was effective in decreasing cocaine
intake in humans could decrease cocaine-maintained responding in laboratory animals at doses that did not affect
food-maintained responding.
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Wojnicki et al.
component varied less than 20%. Control data were typically taken
from all sessions on Thursdays over the period when animals were
dosed on Tuesdays and Fridays. Control data were expressed either
as the mean (6S.D.) absolute response rate (resp/sec) or reinforcer
deliveries, or as a mean 6 coefficient of variation [(SD/mean) 3 100]
for percent of control data. Changes in within-session performance
were characterized by the number of reinforcer deliveries to occur in
each component.
Drugs.
GBR12909•2HCl
(1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl] piperazine) was synthesized by the Laboratory of Medicinal Chemistry/National Institute of Diabetes and
Digestive and Kidney Diseases/National Institutes of Health. Cocaine was provided by the National Institute on Drug Abuse (Rockville, MD). Both drugs were dissolved in sterile water, diluted with
saline, and delivered (0.75 ml/10 kg, i.v.) at a rate of 0.27 ml/sec. Unit
doses were manipulated by changing the concentration (10 mg/kg/
injection 5 133 mg/liter). Phentermine (Sigma, St. Louis, MO) was
dissolved in saline and delivered as a slow (;2 ml/min) i.v. infusion
beginning 30 min before a session, for approximately 15 min (i.e., the
infusion terminated about 15 min before the session began). All dose
calculations were based on the salt.
Results
Acute Assessment. Control rates of responding and numbers of reinforcer deliveries for both food and cocaine when
different unit doses (10, 30, and 100 mg/kg/injection) of cocaine-maintained responding are shown in Table 1. When the
unit dose was 10 mg/kg/injection, rates of responding in both
the food component and the cocaine component were relatively high and similar to each other. At 10 mg/kg/injection,
all 40 food deliveries and almost all the cocaine deliveries
were obtained. When the unit dose was 30 mg/kg/injection,
the average rate of responding in the food component was
similar to food-maintained rates when the unit dose was 10
mg/kg/injection, but rates of responding in the cocaine component were decreased. At 30 mg/kg/injection, almost all food
deliveries were obtained, but the number of cocaine deliveries was decreased about 25%. When the unit dose was 100
mg/kg/injection, the average rate of responding in the food
TABLE 1
Mean individual and group control rates of responding (resp/sec; RR)
and numbers of reinforcer deliveries (Del) under each component of a
mult FR30 food (Fd), FR30 cocaine (Coc) schedule, taken from 4 –9
intervening control sessions when effects of phentermine were assessed
(6S.D.)
Three unit doses (10, 30, or 100 mg/kg) of cocaine were studied.
Monkey no.
Fd RR
Coc RR
675
872
522
573
Group
7.56 6 0.37
5.74 6 0.57
2.46 6 0.23
4.08 6 0.33
4.95 6 0.38
675
872
522
573
Group
9.05 6 0.52
5.26 6 0.92
2.86 6 0.33
2.96 6 0.42
5.03 6 0.54
872
522
573
Group
3.62 6 0.98
2.88 6 0.47
2.57 6 0.41
3.02 6 0.62
Fd Del
Coc Del
10 mg/kg/injection
7.28 6 0.74
2.46 6 0.55
2.66 6 1.05
3.03 6 0.62
3.86 6 0.74
40.0 6 0
40.0 6 0
40.0 6 0
40.0 6 0
40.0 6 0
40.0 6 0
38.6 6 0.7
37.4 6 3.0
37.2 6 4.7
38.3 6 2.3
40.0 6 0
40.0 6 0
40.0 6 0
37.7 6 1.9
39.4 6 0.5
27.2 6 3.8
35.0 6 8.0
27.7 6 4.1
33.2 6 2.6
30.8 6 4.6
40.0 6 0
40.0 6 0
40.0 6 0
40.0 6 0
19.3 6 10.7
18.5 6 0.6
13.3 6 6.5
17.1 6 5.9
30 mg/kg/injection
2.95 6 1.74
3.33 6 1.12
1.83 6 0.45
2.25 6 0.61
2.50 6 0.98
100 mg/kg/injection
0.60 6 0.36
0.67 6 0.35
0.29 6 0.15
0.52 6 0.28
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maintained by food and different unit doses of cocaine. Acute assessments typically occurred on Tuesdays or Fridays, and control data
were obtained from the four to nine intervening sessions on
Thursdays. Doses of phentermine were usually tested at least twice.
Responding of monkey nos. 872, 522, 675, and 573 was maintained at
10 mg/kg/injection cocaine until stable, and then the effects of phentermine were assessed. The unit dose was then increased to 30
mg/kg/injection cocaine, responding was allowed to stabilize, and the
effects of phentermine were determined again. Doses higher than
those necessary to almost completely decrease cocaine-maintained
responding were not given to individual animals. The unit dose was
then decreased to 10 mg/kg/injection cocaine, and the effects of subacute phentermine were determined (see below). After the subacute
assessment, the unit dose was increased to 100 mg/kg/injection cocaine, responding was allowed to stabilize, and the effects of phentermine were determined. Monkey no.675 was not studied at 100
mg/kg/injection cocaine.
Subacute Assessment. This experiment assessed the effects of
repeated daily doses of phentermine on food- and cocaine-maintained
responding. Responding of monkey nos. 872, 522, 675, and 573 was
maintained at 10 mg/kg/injection cocaine until stable. Control rates
of responding were taken from three sessions immediately preceding
the assessment of the effects of an acute dose of 5.6 mg/kg phentermine. The subacute effects of 5.6 mg/kg phentermine were then
assessed for the following six to eight consecutive sessions in a
manner identical to that described for acute dosing. The subacute
effects of 3 mg/kg phentermine were then assessed during the following four to eight sessions. The subacute effects of saline were then
assessed during the next four sessions. Finally, the acute effects of
5.6 mg/kg phentermine were re-determined in the next session.
Low Unit-Dose Assessment. Two experiments assessed the effects of phentermine when responding produced a low unit dose of
cocaine. In the first experiment, responding of monkey nos. 31, 44,
and 72 was maintained under a mult schedule with a unit dose of 10
mg/kg/injection cocaine until stable, then the unit dose was decreased
to 1 mg/kg/injection. When rates of responding in the cocaine component had decreased compared with those during the 10 mg/kg/injection unit dose of cocaine, 3 mg/kg phentermine was given before the
next session. On subsequent Tuesdays and Fridays (except for the
last dose of 1 mg/kg), the effects of 1.7 mg/kg, 1 mg/kg, 0.3 mg/kg, and
then 1 mg/kg phentermine were assessed. For the second experiment, responding of monkey nos. 31, 44, 522, and 72 was maintained
under a mult schedule with a unit dose of 10 mg/kg/injection cocaine
until stable. Then the unit dose was decreased to 1 mg/kg/injection,
and an FR30 cocaine (1 mg/kg/injection), TO 20-min schedule was
placed into effect (i.e., food-maintained responding was not studied,
and a 20-min TO was used to keep session lengths comparable to
those of the first experiment). When rates of responding had decreased compared with those in the cocaine component during the
preceding baseline (10 mg/kg/injection unit dose of cocaine) conditions, 1 mg/kg phentermine was given before the next session. After
two intervening sessions without infusions, the effects of 1 mg/kg
were reassessed.
Assessment on GBR 12909-Maintained Responding. This experiment assessed the effects of phentermine on responding maintained by food and GBR 12909. Responding of four monkeys (nos.
561, 941, 769, and 450) was maintained under a mult FR30 food,
FR30 GBR 12909 (30 mg/kg/injection) schedule until stable. The
effects of a range of acute doses of phentermine were then studied.
Acute assessments typically occurred on Tuesdays or Fridays, and
control data were obtained from sessions on five intervening Thursdays. Doses of phentermine were tested at least twice.
Data Analysis. For each experiment, session rates of responding
were calculated for each type of component (food or drug) and averaged over consecutive control sessions to provide an average rate of
responding per component type, per monkey. Stability during baseline conditions was defined as no trend in rate of responding and at
least three consecutive sessions when mean rates in the cocaine
Vol. 288
1999
553
liveries over the session, with two exceptions. With 1 mg/kg
phentermine cocaine deliveries decreased over the session.
With 5.6 mg/kg phentermine (the highest dose studied) cocaine deliveries only occurred in the first component of the
session. When 30 mg/kg/injection cocaine-maintained responding, the number of cocaine deliveries decreased over
successive components of the session. Phentermine had little
effect on this trend except that, with 3 mg/kg, the trend was
not apparent, and with the highest dose studied (10 mg/kg),
cocaine deliveries occurred only in the first component of the
session. When 100 mg/kg/injection cocaine-maintained responding, there was a general decrease in the number of drug
deliveries over the session, although the number of deliveries
in the third component was often greater than that in the
second component.
Figure 2 displays representative cumulative response
records for control performances at three different unit doses
of cocaine and the effects of selected doses of phentermine.
These records are arranged sequentially as the first through
fourth (left to right) pairs of food (left) and cocaine (right)
components to occur during a session. They show that, for
each unit dose of cocaine, food maintained high rates of
responding that were largely unchanged over the session.
They also show that, with 10 mg/kg/injection, uniform rates of
cocaine-maintained responding occurred over the session,
and with the two higher unit doses of cocaine, rates of cocaine-maintained responding declined over the session.
These records illustrate that low doses of phentermine had
little effect on the rates and patterns of responding maintained by either event and higher doses of phentermine decreased responding maintained by 10 and 30 mg/kg/injection
cocaine. The record of baseline performance with 100 mg/kg/
injection shows that high rates of responding initially occurred in each cocaine component, but after a few cocaine
deliveries responding decreased.
Subacute Assessment. Fig. 3 shows that the effects of
both acute and subacute phentermine differed across monkeys. For monkey nos. 872 and 522, the initial acute dose of
Fig. 1. Acute effects of phentermine on rates of responding maintained under a mult FR 30 food (E), FR 30 cocaine (M) schedule with different unit
doses (10 –100 mg/kg/injection, left-right) of cocaine. Abscissa; dose of phentermine (mg/kg). Ordinate; effect, expressed as the mean (6S.E.M.) percent
of individual control rates of responding (n 5 3– 4, see below); control variability (filled symbols) is expressed as the average of individual coefficients
of variation. Monkey no. 675 was not studied at 100 mg/kg/injection (n 5 3), and at this unit dose only one animal (no. 872) was given 10 mg/kg. Doses
higher than 3 mg/kg phentermine were never given to no. 573 during acute studies.
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component was decreased compared with those at lower unit
doses. This was due both to a decrease with monkey no. 872
and because the three monkeys with the lowest rates of
responding were studied in this condition. At this unit dose,
all food deliveries were obtained. At 100 mg/kg/injection,
rates of cocaine-maintained responding were decreased compared with those maintained by lower unit doses in the same
monkeys, and the number of cocaine deliveries was decreased
about 50% (see Fig. 3).
Figure 1 shows the mean effects of phentermine on responding maintained by food and three different unit doses of
cocaine (10, 30, and 100 mg/kg/injection). In general, phentermine had little effect on food-maintained responding, although there was one exception: for monkey no. 573, rates of
food-maintained responding were decreased by 1 mg/kg (at
10 mg/kg/injection) and 3 mg/kg (at all three unit doses)
phentermine. Low doses (0.3– 0.56 mg/kg) of phentermine
increased rates of responding maintained by 10 and 30 mg/
kg/injection cocaine. Doses of phentermine greater than 1
mg/kg generally decreased cocaine-maintained responding in
a dose-dependent manner. With the exception of monkey
no.573, doses of phentermine greater than 0.56 mg/kg always
decreased cocaine-maintained responding to a greater extent
than food-maintained responding. Table 2 shows that phentermine dose-dependently decreased the number of cocaine
deliveries at doses that generally had little or no effect on the
number of food deliveries. The decrease in the number of food
deliveries with 1.7 and 3 mg/kg of phentermine at 30 mg/kg/
injection cocaine was due solely to monkey no. 573.
The total number of food deliveries was equally distributed
over all four components of the session for all unit doses of
cocaine and treatment doses of phentermine (data not
shown). Table 2 shows that the distribution of cocaine deliveries over the session varied with the unit dose of cocaine.
When the unit dose was 10 mg/kg/injection, almost all available cocaine deliveries were obtained in each of the four
cocaine components during control sessions. Phentermine
generally had little effect on the distribution of cocaine de-
Behavioral Effects of Phentermine
554
Wojnicki et al.
Vol. 288
TABLE 2
The mean total number (6S.D.) of food and cocaine deliveries per session (max. 5 40), and the mean number of cocaine deliveries in each of the
four cocaine components of a session (max. 5 10), when responding was maintained under a mult FR30 food FR30 cocaine (10, 30, or 100 mg/kg/
injection) for control sessions and when various doses of phentermine were given before the session
Unit dose
Total food
deliveries
Total cocaine
deliveries
Component
no. 1
Component
no. 2
Component
no. 3
Component
no. 4
9.7
10.0
10.0
7.5
2.0
0.0
9.8
10.0
8.0
6.0
3.5
0.0
9.5
8.3
10.0
4.9
3.1
0.0
7.9
8.6
9.5
7.6
6.0
3.4
3.8
0.0
7.0
6.8
9.5
5.6
4.0
2.9
1.5
0.0
6.1
6.0
4.8
5.6
2.5
3.3
1.0
0.0
4.8
3.5
2.0
0.5
1.3
0.0
3.4
4.0
2.7
1.0
1.0
2.0
2.4
3.5
1.3
0.0
0.0
0.0
10 mg/kg/injection (n 5 4)
Dose phentermine
Control
0.3 mg/kg
0.56 mg/kg
1 mg/kg
3 mg/kg
5.6 mg/kg
40 6 0
40 6 0
40 6 0
36.3 6 7.4
36 6 10.6
40 6 0
38.3 6 2.3
38.6 6 2.8
38.7 6 2.1
27.0 6 7.8
14.2 6 11.4
0.3 6 1.6
9.4
9.8
10.0
8.5
3.9
0.8
30 mg/kg/injection (n 5 4)
39.4 6 0.5
35.1 6 11.1
40 6 0
38.6 6 3.9
29.5 6 14.9
31.6 6 15.9
40 6 0
40 6 0
30.8 6 4.6
29.6 6 7.3
33.0 6 2.4
28.0 6 8.1
19.5 6 0.7
12.4 6 10.4
14.3 6 11.7
1.0 6 1.4
9.7
9.1
10.0
9.1
7.0
2.9
4.5
1.0
100 mg/kg/injection (n 5 3)
Dose phentermine
Control
0.3 mg/kg
1 mg/kg
3 mg/kg
5.6 mg/kg
10 mg/kg
40 6 0
40 6 0
40 6 0
33.5 6 9.2
40 6 0
40
17.0 6 5.9
19.0 6 1.4
10.3 6 1.5
2.5 6 0.7
6.0 6 8.5
7.0
phentermine decreased cocaine-maintained responding completely with little or no effect on food-maintained responding.
For monkey no. 675, the initial acute dose of phentermine
decreased cocaine-maintained responding completely and decreased food-maintained rates of responding about 25%. Subacute 5.6 mg/kg phentermine consistently decreased cocainemaintained responding but had different effects on foodmaintained responding in each of these animals. This
subacute dose had no effect in monkey no. 522, and decreased
rates of responding in monkeys no. 675 and 872. Lowering
the subacute dose of phentermine to 3 mg/kg sustained the
decrease in rates of cocaine-maintained responding previously observed with 5.6 mg/kg in these three monkeys. With
subacute 3 mg/kg phentermine, rates of food-maintained responding were either unaffected (no. 522), similar to those
seen with 5.6 mg/kg phentermine (no. 872), or increased
compared with 5.6 mg/kg phentermine (no. 675). When subacute saline was given before the session instead of phentermine, rates of cocaine-maintained responding increased compared with those seen with subacute phentermine. When the
effects of an acute dose of 5.6 mg/kg phentermine were redetermined after the subacute saline series, they were similar
to those seen with the same acute dose given before the
subacute series.
For monkey no. 573, both acute and subacute doses of 5.6
mg/kg phentermine (Fig. 3, lower right) decreased food and
cocaine-maintained responding completely. When the subacute dose was lowered to 3 mg/kg phentermine, rates of
food-maintained responding increased compared with those
seen with 5.6 mg/kg phentermine, while rates of cocainemaintained responding remained at near-zero levels. Subsequently, when saline was given before the session, rates of
6.5
7.5
4.3
1.0
1.7
5.0
cocaine-maintained responding increased. When the acute
effects of 5.6 mg/kg phentermine were redetermined, both
food and cocaine-maintained responding were almost completely decreased.
For each animal (except monkey no. 573), acute 5.6 mg/kg
phentermine had little effect on the number of food deliveries; excluding the second and third session for monkey no.
675, the number of food deliveries with subacute 5.6 mg/kg
phentermine averaged 38.3 per session. During the subacute
3 mg/kg phentermine, the number of food deliveries per session averaged 39.8 (including monkey no. 573). During the
subacute saline, the number of food deliveries was always 40.
Low Unit-Dose Assessment. Fig. 4 (top) shows that before decreasing the unit dose of cocaine, 10 mg/kg/injection
sustained high mean rates of food (2.92 resp/sec) and cocaine
(3.05 resp/sec) maintained responding. This figure also shows
that, when the unit dose of cocaine was decreased to 1 mg/
kg/injection, rates of responding in the cocaine component
decreased over the first three sessions to about 1.23 resp/sec,
and rates of responding during the food component also decreased to about 2.66 resp/sec. When 3 mg/kg was given
before the next session, phentermine had little effect on rates
of responding in the food component but decreased rates of
responding in the cocaine component. Rates of responding in
both components continued to decline on days when phentermine was not given. On subsequent occasions, lower doses of
phentermine increased rates of food-maintained responding,
although these increases never exceeded the rate of foodmaintained responding previously observed at 10 mg/kg/injection. Phentermine only decreased responding in the cocaine component. Phentermine had no effect on the number
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Dose phentermine
Control
0.3 mg/kg
0.56 mg/kg
1 mg/kg
1.7 mg/kg
3 mg/kg
5.6 mg/kg
10 mg/kg
1999
Behavioral Effects of Phentermine
555
of food deliveries and decreased the number of cocaine deliveries (data not shown).
When cocaine-maintained responding was re-established
(or initially, for no. 522) with 10 mg/kg/injection, mean rates
of both cocaine- (2.02 resp/sec) and food- (1.92 resp/sec),
maintained responding were lower than those seen in the
first experiment. This was partially due to the low food rates
for no. 522, and partially to a decrease in rates for no. 31 (see
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Fig. 2. Representative cumulative response
records showing performances maintained under the mult FR 30 food, FR 30 cocaine schedule at three different unit doses of cocaine and
for the effects of phentermine on food- and
cocaine-maintained (10 and 30 mg/kg/injection
only) responding. Sessions consisted of four
cycles (left-to-right) of an FR30 food component (left record of each row) and an FR30
cocaine (right record) component; responding
during between-component TOs has been excised to conserve space. The recorder ran continuously during a session. Horizontal portions of the record indicate when responding
did not occur. The pen stepped up with each
response and reset after completion of a component. Short vertical deflections on the
record indicate reinforcer deliveries. Abscissa;
time. Ordinate; cumulative responses.
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Wojnicki et al.
Vol. 288
legend for Fig. 4). When both the food component was eliminated and the unit dose was decreased to 1 mg/kg/injection,
rates of responding in the cocaine component decreased over
the subsequent six sessions. When 1 mg/kg phentermine was
given before the eighth session, mean rates of responding
decreased compared with the preceding session. This effect
occurred for all animals except no. 31. Mean rates of responding on the session following 1 mg/kg phentermine were increased compared with the session preceding phentermine in
all animals. However, mean rates of responding during the
next (tenth) session with 1 mg/kg/injection were increased
more than those of the ninth session, an effect primarily due
to increased rates in two monkeys (no. 522 and no. 72). When
1 mg/kg phentermine was given on the eleventh session of
exposure to a unit dose of 1 mg/kg/injection, mean rates of
responding were decreased compared with all preceding
days.
Assessment on GBR 12909-Maintained Responding.
Under the mult FR 30 food, FR 30 GBR 12909 schedule,
food-maintained high rates of responding (see Fig. 5) and all
food deliveries were obtained for three of the four monkeys.
One monkey (no. 450) never responded in the fourth food
component, resulting in 30 food deliveries per session and
lower rates of responding in the food component. GBR 12909
maintained high rates of responding (see the legend of Fig. 5)
and under baseline conditions almost all GBR 12909 deliveries were obtained (range 5 39.6 6 0.9 –37.6 6 1.7).
Figure 5 shows that phentermine had different effects on
responding maintained by food and GBR 12909 in each monkey. For one monkey (no. 561), phentermine had no effect on
food-maintained responding. For another (no. 941), phentermine decreased GBR 12909-maintained responding at doses
lower than the doses that decreased food-maintained responding. For a third monkey (no. 450), phentermine decreased food-maintained responding at lower doses than
those that decreased GBR 12909-maintained responding. For
the fourth monkey (no. 769), phentermine decreased both
food- and GBR 12909-maintained responding over a similar
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Fig. 3. Effects of subacute doses of
phentermine on responding maintained under a mult FR 30 food (E), FR
30 cocaine (M, 10 mg/kg/injection)
schedule in four monkeys. For each
monkey, predrug control rates of responding (cross-hatched symbols) are
compared with the effects of acute administration of 5.6 mg/kg phentermine
(filled symbols), subacute administration of 5.6 and then 3 mg/kg phentermine, subacute saline (open symbols),
and then the reassessment of acute
administration of 5.6 mg/kg phentermine (filled symbols) in sequential order. Abscissa; consecutive sessions of
the experiment. Ordinate; absolute
rates of responding (resp/sec).
1999
Behavioral Effects of Phentermine
557
range of doses. In general, the effects of phentermine on
reinforcer deliveries were similar to those seen on rates of
responding (data not shown).
Discussion
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Fig. 4. (top) Mean (6S.E.M.) absolute rates of responding (resp/sec)
maintained by food (44, 2.13 6 0.37; 31, 3.39 6 0.41; 72, 2.26 6 0.38) and
cocaine (44, 2.07 6 0.16; 31, 5.17 6 0.16, 72, 1.90 6 0.83) under a mult
FR30 food (F), FR 30 cocaine (f, 10 mg/kg/injection) schedule, and the
effects of phentermine (doses studied on sessions 4, 6, 9, 11, and 13 are
indicated) on food- (E) and cocaine- (M) maintained responding when the
unit dose was decreased to 1 mg/kg/injection (n 5 3). (bottom) Mean
(6S.E.M.) absolute rates of responding maintained by food (44, 2.14 6
0.22; 31, 3.17 6 0.06; 72, 2.33 6 0.24; 522, 1.34 6 0.22) and cocaine (44,
1.40 6 0.61; 31, 3.11 6 0.36, 72, 1.32 6 0.12; 522, 2.25 6 0.89) under a
mult FR30 food (F), FR 30 cocaine (f, 10 mg/kg/injection) schedule, and
the effects of changing the schedule to FR 30 cocaine (M, 1 mg/kg/injection), TO 20-min, and assessing the effects of 1 mg/kg phentermine on
sessions 8 and 11 (n 5 4). Abscissa; consecutive sessions of the experiment. Ordinate; mean absolute rate of responding.
Phentermine decreased cocaine-maintained responding in
the current study. Earlier reports showed that methamphetamine decreased methamphetamine-maintained responding
(Pickens et al., 1968), and d-amphetamine or phenmetrazine
decreased cocaine-maintained responding (Wilson and
Schuster, 1973). Together, these studies suggested that drug
self-administration could be decreased by drugs that have
pharmacological effects similar to those of the reinforcer.
However, the behavioral specificity of those results was not
established in the previous studies. The current study shows
that phentermine could decrease cocaine-maintained responding at doses that do not decrease food-maintained responding in the same animal during the same session. These
findings are similar to those of recent studies showing that
GBR 12909 (Glowa et al., 1995a, b), CFT (Glowa and
Wojnicki, 1996), and cocaine (Glowa and Fantegrossi, 1997)
decrease cocaine-maintained responding at doses that have
less of an effect on food-maintained responding. These results
are important because they clearly show that cocaine-maintained responding can be affected by doses of drugs less than
those that have nonspecific effects. They also add to a growing literature showing that drugs can affect responding
maintained by drug and food differently. However, the current study also raises several issues with respect to interpreting those differences.
The current study does not support the possibility that cocaine-maintained responding is decreased because phentermine affects the potency of cocaine. There is no evidence of a
rightward shift in the unit dose-effect function for cocaine, as
responding maintained by unit doses from 10 to 100 mg/kg/
injection is affected by phentermine in a similar manner. Phentermine does not generally increase low rates of responding
associated with a low unit dose (1 mg/kg/injection) of cocaine,
consistent with earlier reports showing that GBR 12909 (Glowa
et al., 1995a) and CFT (Glowa and Wojnicki, 1996) do not
increase responding associated with a low unit dose of cocaine
in the monkey. These data suggest that phentermine does not
shift the unit dose-effect function for cocaine to the left. In
contrast, because the D3 agonist 7-OH-DPAT increases
responding associated with low unit doses of cocaine in the rat
(Caine and Koob, 1995), some drugs may produce a leftward
shift. The differences between these effects raise questions as to
whether drug-induced increases in responding associated with
low doses of cocaine are species-specific, occur with only certain
types of DA agonists, or are unrelated to the reinforcing effects
of cocaine.
A distinctive feature of many drugs that selectively decrease cocaine-maintained responding is that they support
self-administration under other conditions. The possibility
has been raised that treatment of drug self-administration
with an agent that has pharmacological effects similar to
those of the self-administered drug may result in a satiationlike effect (Wilson and Schuster, 1973). A related possibility
is that response-independent drug treatment substitutes for
response-dependent drug delivery. Substitution is a functional relationship between reinforcers that is inferred when
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a change in the cost (responses/unit dose) for one reinforcer
results in a change in the consumption of another reinforcer
(Hursh, 1993). Decreases in drug-maintained responding
have been well documented in studies where concurrent access to alternative reinforcers has been arranged (Carroll et
al., 1989; Nader and Woolverton, 1991). Response-independent delivery of a potentially reinforcing event may have
effects on responding similar to those of alternative reinforcement. Rachlin and Baum (1972) maintained responding under concurrent variable-interval schedules of food delivery,
varying several reinforcement parameters. As expected,
when the relative magnitude or frequency of food delivery
was increased in one component, responding in the alternate
component decreased. A similar effect was observed in the
alternate component when response-independent food was
delivered in the other component. Response-independent delivery of phentermine may represent a situation in which the
minimal cost (i.e., free) of drug delivery decreases consumption of a more expensive alternative commodity (i.e., cocaine).
This interpretation is consistent with the results of Wurster
et al. (1977), in which treatment with methadone decreased
choice for heroin while increasing choice for food. However,
as few studies have directly addressed whether more direct
measures of the reinforcing effects of drugs are decreased by
drug treatment, these conclusions remain speculative.
Previous studies have noted that GBR 12909 (Glowa et al.,
1995a), 7-OH-DPAT (Caine and Koob, 1995), and cocaine
(Glowa and Fantegrossi, 1997) decrease responding maintained by lower unit doses of cocaine more than responding
maintained by higher unit doses of cocaine. Other studies
have shown that drugs decrease responding maintained by
lower densities of food delivery more than responding maintained by higher densities of food delivery (Egli et al., 1992).
These differences in the effects of drug on responding maintained by the same event may occur because responding
maintained under conditions that engender more effective
reinforcement is more resistant to change than responding
maintained under conditions engendering less effective reinforcement (Nevin, 1974). It has been argued that higher unit
doses of cocaine are more effective reinforcers based on the
results of choice (Johanson and Schuster, 1975), progressiveratio (Roberts and Richardson, 1992), and response acquisition (Schenk et al., 1991) procedures. In the current research,
however, phentermine decreased responding maintained by
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Fig. 5. The effects of phentermine on
responding maintained by food (E;
561, 4.22 6 0.19; 941, 9.17 6 0.97; 769,
3.80 6 0.45; 450, 1.12 6 0.03) and GBR
12909 (M, 30 mg/kg/injection; 561,
2.12 6 0.50; 941, 5.83 6 2.65; 769,
2.60 6 0.45;50, 4.55 6 0.90) under a
mult FR 30 food, FR 30 GBR 12909
schedule in four different monkeys.
Abscissa; dose of phentermine (mg/kg).
Ordinate; effect, expressed as the
mean of individual effects (control
variability is shown as 6 coefficient of
variation).
1999
559
gent data pertaining to their ability to modify the neurobehavioral effects of cocaine.
The sustained difference in effect of phentermine on foodand cocaine-maintained responding under most of the subacute treatment conditions provided additional data showing
that phentermine could affect those two behaviors differently. One monkey (no. 573) in these studies illustrated that
individual differences in drug effects occur with phentermine. For this monkey, relatively low acute doses (1 mg/kg) of
phentermine decreased food-maintained responding when
the unit dose was 10 mg/kg/injection, and higher doses (3
mg/kg) decreased responding maintained by both events to a
comparable extent. However, acute doses of 1 and 1.7 mg/kg
phentermine decreased responding maintained by 30 mg/kg/
injection cocaine, and the subacute dose of 3 mg/kg phentermine decreased responding maintained by 10 mg/kg/injection
cocaine to a greater extent than food-maintained responding
in this monkey. Thus, while this monkey appeared to be more
sensitive to the rate-decreasing effects of phentermine in
general, in each experiment at least one dose of phentermine
decreased responding maintained by cocaine to a greater
extent than food-maintained responding. Thus, phentermine
produced selective effects in every monkey.
In summary, the current findings are important for several
reasons. They link recent observations that phentermine can
decrease cocaine intake in humans to decreases in cocainemaintained responding in animals. This observation could
help validate the use of self-administration studies to identify effective pharmacotherapies for drug abuse (Mello and
Negus, 1996). Because phentermine may exert effects
through mechanisms distinct from those of DA reuptake
inhibitors, the range of drugs observed to produce selective
decreases on cocaine self-administration was extended by
this study. The apparent efficacy of phentermine in selectively decreasing responding maintained by relatively high
unit doses of cocaine may be particularly interesting with
respect to its potential as a treatment for cocaine abuse in
humans and for interpreting drug-induced decreases in drugmaintained responding. Further research is needed to identify factors that contribute to individual differences in the
effects of drugs on responding maintained by cocaine and the
extent to which drug treatment modifies the reinforcing effects of cocaine.
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