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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics
JPET 323:599–605, 2007
Vol. 323, No. 2
123042/3263400
Printed in U.S.A.
Drug and Reinforcement History as Determinants of the
Response-Maintaining Effects of Quinpirole in the Rat
Gregory T. Collins and James H. Woods
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan
Received March 19, 2007; accepted August 2, 2007
Growing evidence suggests that D2 and D3 receptors may
play important roles in the mediation of the reinforcing properties of drugs of abuse such as cocaine (e.g., Heidbreder et
al., 2005; Newman et al., 2005). Not only are D2 and D3
receptors expressed at high levels within the nucleus accumbens (Lévesque et al., 1992; Gurevich and Joyce, 1999; Stanwood et al., 2000) but also in both monkey and human, D2/D3
receptor levels have been found to be inversely correlated
with the positive reinforcing effects of psychostimulants. In
human subjects asked to rate the subjective effects of methylphenidate, those with lower striatal D2/D3 receptor levels
reported a more pleasant effect compared with those with
higher striatal D2/D3 receptor levels (Volkow et al., 1999). In
addition, monkeys with lower striatal levels of D2/D3 receptors more readily self-administered cocaine compared with
monkeys with higher striatal D2/D3 levels, suggesting that
the reinforcing effects of cocaine differed between the two
groups (Morgan et al., 2002). Furthermore, a history of coThis research was supported by U.S. Public Health Service National Institute on Drug Abuse Grants DA20669 and DA019322.
Article, publication date, and citation information can be found at
http://jpet.aspetjournals.org.
doi:10.1124/jpet.107.123042.
response-contingent cocaine or were administered noncontingent cocaine; all rats were subsequently allowed to respond for
quinpirole. Only rats that previously responded for cocaine
showed quinpirole-maintained responding; all other conditions
failed to establish quinpirole-maintained responding. Although
the high levels of quinpirole-maintained responding observed
when quinpirole was substituted for cocaine are suggestive of
positive reinforcing effects, these response-maintaining effects
were highly dependent upon both drug and reinforcement history, suggesting that quinpirole may only function as a reinforcer under very specific conditions. The behavioral effects of
quinpirole under these situations represent a novel constellation of actions relative to other drug reinforcers, and they suggest that the direct effects of self-administered quinpirole may
be important in establishing the response-maintaining effects.
caine exposure has been shown to result in long-lasting decreases in striatal D2/D3 receptor levels (Volkow et al., 1993;
Nader et al., 2006), presumably resulting in a strengthening
of the reinforcing and enteroceptive effects of cocaine.
Further evidence for the involvement of D2 and D3 receptors in the reinforcing effects of drugs has been provided
through the study of D2/D3 agonists and antagonists in a
variety of operant procedures in animals. In drug discrimination experiments, D2/D3 agonists often generalize to cocaine-trained cues (Barrett and Appel, 1989; Terry et al.,
1994; Barrett et al., 2001), suggesting that the D2 and/or D3
receptors may, at least in part, mediate the enteroceptive
effects of cocaine. In addition, in reinstatement procedures,
D2/D3 agonists have been shown to induce nonreinforced,
drug-appropriate, responding (Khroyan et al., 2000; De Vries
et al., 2002). Antagonists at D2/D3 receptors have been
shown to inhibit the capacity of drug-paired cues (Gilbert et
al., 2005), stress (Xi et al., 2004), and drug “primes” (Andreoli
et al., 2003) to reinstate responding that was previously
reinforced by a variety of drugs. Furthermore, and of direct
relevance to the present study, a variety of D2/D3 agonists
have been shown to be self-administered in rats (Caine and
ABBREVIATIONS: LED, light-emitting diode; inj, injection; FR, fixed ratio; TO, time-out; ANOVA, analysis of variance; GBR 12909, 1-{2-[bis-(4fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate).
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ABSTRACT
The present study examined the effect of drug and reinforcement history on quinpirole-maintained responding in rats. Quinpirole (0.01, 0.032, or 0.1 mg/kg per injection) was assessed as
a reinforcer in experimentally naive rats, as well as in rats
trained to self-administer cocaine, remifentanil, ketamine, or
food under a fixed ratio 1 schedule of reinforcement. Quinpirole
failed to maintain responding in experimentally naive rats, or in
ketamine- or food-trained rats. However, robust responding
was maintained in rats with a history of cocaine reinforcement,
and modest levels of responding were observed in rats with a
history of responding for remifentanil. In a second set of studies, the effects of protracted drug histories on quinpirole-maintained responding in food-trained rats were assessed. Rats
were maintained with food reinforcement, and different groups
of rats were then allowed to respond for saline, quinpirole, and
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Collins and Woods
Materials and Methods
Subjects. Male Sprague-Dawley rats (350 –375 g) were obtained
from Harlan (Indianapolis, IN), and they were maintained in a
temperature- and humidity-controlled environment, on a 12-h dark/
light cycle with lights on at 7:00 AM. Rats were allowed free access
to food before the start of experiments, and they were maintained
with ⬃20 g of food per day for the duration of the experiments. All
studies were performed in accordance with the Guide for the Care
and Use of Laboratory Animals, as adopted and promulgated by the
National Institutes of Health, and all experimental procedures were
approved by the University of Michigan Committee on the Use and
Care of Animals.
Surgery. Rats were surgically prepared with chronic indwelling
jugular catheters in both the right and left jugular veins under
ketamine/xylazine (100:10 mg/kg i.m.) anesthesia. Catheters were
tunneled under the skin and attached to stainless steel tubing,
exiting the back through a metal tether button that was sutured to
the muscle between the scapula. Rats were allowed 5 to 7 days to
recover from surgery before the start of any experiments. Catheters
were flushed with 0.2 ml of heparinized saline (100 U/ml) before the
start of self-administration sessions as well as after the completion of
the session to ensure patency.
Apparatus. All experimental sessions were conducted in operant
conditioning chambers [30.5 ⫻ 24 ⫻ 21 cm (width ⫻ depth ⫻ height);
MED Associates, St. Albans, VT] placed inside sound-attenuating
cubicles. Each chamber was equipped with a single nosepoke device
(ENV-114BM; MED Associates) positioned 6 cm above the stainless
steel grid floor, and it was illuminated with a yellow stimulus light.
Each chamber was also equipped a green LED stimulus light, located
above the nosepoke, and a white house light. An air-driven pneumatic syringe pump (IITC, Woodland Hills, CA) allowed for drug
delivery through Tygon tubing connected to a fluid swivel (Instech
Laboratories Inc., Plymouth Meeting, PA) and spring tether, which
was held in place by a counterbalanced arm. For food self-administration sessions, chambers were also equipped with a liquid food
dipper with a 50-␮l dipper cup (model E14-05; Coulbourn Instruments, Allentown, PA).
Acquisition of Operant Responding and Determination of
Dose-Response Curves. Nosepoke responses were followed by either 0.56 mg/kg/inj cocaine, 0.0032 mg/kg/inj remifentanil, 1.0 mg/
kg/inj ketamine, 0.032 mg/kg/inj quinpirole, saline, or 10-s access to
50 ␮l of liquid food (100% Ensure) during daily, 90-min sessions
under a fixed ratio (FR) 1 schedule of reinforcement. Illumination of
the yellow nosepoke light signaled drug, food, or saline availability,
and subsequent nosepokes resulted in an injection (100 ␮l/kg/0.5 s),
or 10-s access to liquid food during which time a green LED above the
nosepoke was illuminated. Delivery of liquid food was also paired
with the illumination of a light above the dipper to signal food
availability. A 5-s time-out (TO) followed drug delivery and food
presentation during which time the house light was illuminated and
responses were recorded but had no consequence.
Upon acquisition of stable responding, defined as three consecutive sessions with less than 20% difference and no increasing or
decreasing trend in responding, the dose was randomly changed to
allow for the determination of dose-response curves. Rats were allowed to respond for the new dose until stability criteria were met.
Each dose was available for at least five sessions before substitution
of the next, randomly assigned dose. Dose-response curves for each
reinforcer were obtained in separate groups of rats (n ⫽ 6/dose). Each
rat responded for at least three doses of either cocaine (saline, 0.01,
0.032, 0.1, 0.32, 0.56, and 1.0 mg/kg/inj), remifentanil (saline, 0.0001,
0.00032, 0.001, 0.0032, and 0.01 mg/kg/inj), or ketamine (saline,
0.032, 0.1, 0.32, 1.0, and 3.2 mg/kg/inj).
Effect of Reinforcement History on the Response-Maintaining Effects of Quinpirole. To assess the influence of reinforcement
history on the capacity of quinpirole to maintain responding, rats
acquired responding for either drug (0.56 mg/kg/inj cocaine, 0.0032
mg/kg/inj remifentanil, and 1.0 mg/kg/inj ketamine) or nondrug (50
␮l of 100% Ensure) reinforcers under an FR1TO5 schedule of reinforcement as described above. Upon acquisition of stable responding,
quinpirole (0.01, 0.032, or 0.1 mg/kg/inj) or saline was substituted for
a period of 7 days. Rats that were allowed to respond for liquid food
acquired stable responding within the first seven sessions, but they
were given 14 days of training before substitution of quinpirole to
control for the number of sessions required to achieve stable drug
responding. Following substitutions, rats were returned to the initial
reinforcer for a period of 5 days to assess changes in baseline responding.
Effect of Prior Drug Exposure on the Response-Maintaining Effects of Quinpirole. The influence of drug history on the
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Koob, 1993), mice (Caine et al., 2002), and monkeys (Woolverton et al., 1984; Nader and Mach, 1996; Sinnott et al.,
1999) when substituted for cocaine. Taken together, these
findings suggest that D2/D3 agonists may possess enteroceptive and reinforcing properties similar to those of cocaine.
Although the majority of these studies have not examined
the influence of drug and/or reinforcement history on the
capacity of D2/D3 agonists to maintain responding, evidence
in monkeys suggests that the capacity of the D2/D3 agonists
to maintain responding is modified by previous cocaine reinforcement. For example, 7-hydroxy-2-dipropylaminotetralin
and quinpirole were readily self-administered when substituted in monkeys trained to respond for cocaine, but they
failed to maintain responding in experimentally naive monkeys and drug-naive monkeys that were trained to respond
for food (Nader and Mach, 1996; Sinnott et al., 1999). Moreover, 7-hydroxy-2-dipropylaminotetralin did not maintain responding in monkeys before a brief period of cocaine selfadministration, but it did maintain significant levels of
responding after experience with cocaine self-administration
(Nader and Mach, 1996). Although these findings suggest
that the reinforcing properties of D2/D3 agonists may be
influenced by a history of cocaine administration, the influence of different reinforcement and/or drug histories on the
capacity of D2/D3 agonists to maintain responding has not
been systematically addressed.
The aims of the current study was to examine the influence
of both drug and reinforcement history on the capacity of
quinpirole to maintain responding in rats. In the current
study, a history of cocaine reinforcement was sufficient to
establish the response-maintaining effects of quinpirole,
whereas, as reported previously in rhesus monkeys (Nader
and Mach, 1996; Sinnott et al., 1999), quinpirole failed to
maintain responding in experimentally naive and foodtrained rats. Therefore, we explored other drug reinforcement histories with drugs from the opioid (remifentanil) or
dissociative anesthetic (ketamine) classes of drugs that are
known to maintain strong self-administration behavior in
rats. Finally, we determined whether noncontingent cocaine
administration was sufficient to establish the response-maintaining effects of quinpirole, and whether it was necessary
that cocaine reinforcement immediately precede the substitution of quinpirole. Together, these studies suggest that
quinpirole functions to maintain responding under a limited
set of conditions and that the response-maintaining effects of
quinpirole may represent some combination of direct drug
effects, along with a weaker, situational, reinforcing effect in
the rat.
Quinpirole-Maintained Responding in the Rat
Results
Acquisition of Responding and Determination of
Dose-Response Curves. Experimentally naive rats readily
acquired responding for 0.56 mg/kg/inj cocaine, 0.0032 mg/
kg/inj remifentanil, 1.0 mg/kg/inj ketamine, and 10-s access
to 50 ␮l of liquid food (Fig. 1A). Responding maintained by
cocaine, remifentanil, ketamine, or food was generally
greater than for saline within the first three sessions, and
there were no differences in the number of sessions required
to achieve stable responding for cocaine (12.6 ⫾ 0.1 sessions),
remifentanil (13.7 ⫾ 0.1 sessions), or ketamine (11.8 ⫾ 0.1
sessions). Stability was generally observed within the first
seven sessions for liquid food; however, access was provided
for 14 days. Quinpirole (0.032 mg/kg/inj) failed to maintain
Fig. 1. A, acquisition of responding for cocaine (0.56 mg/kg/inj), remifentanil (0.0032 mg/kg/inj), ketamine (1.0 mg/kg/inj), quinpirole (0.032 mg/
kg/inj), food (10-s access to 50 ␮l of 100% Ensure), or saline. Data are
presented as the mean ⫾ S.E.M. (n ⫽ 6) number of reinforced responses
made during the first 10 daily 90-min sessions on an FR1TO5 schedule of
reinforcement. B, dose-response curves for cocaine (saline, 0.01, 0.032,
0.1, 0.32, 0.56, and 1.0 mg/kg/inj), remifentanil (saline, 0.0001, 0.00032,
0.001, 0.0032, and 0.01 mg/kg/inj), and ketamine (saline, 0.032, 0.1, 0.32,
1.0, and 3.2 mg/kg/inj). Data represent the mean ⫾ S.E.M. (n ⫽ 6) number
of responses made during the last three sessions at a particular dose. ⴱⴱ,
p ⬍ 0.01; represents significantly greater levels of responding for individual doses of each drug were determined by one-way ANOVA with post
hoc Dunnett’s tests. Significant differences in responding from saline
during acquisition were determined by two-way ANOVA with repeated
measures and post hoc Bonferroni tests.
responding that was any different from that maintained by
saline at any point during the 10-session acquisition period
(Fig. 1A). As shown in Fig. 1B, cocaine, remifentanil, and
ketamine all maintained dose-dependent responding under
an FR1TO5 schedule of reinforcement, resulting in inverted
U-shaped dose-response curves typical of drug reinforcers.
Effect of Reinforcement History on the ResponseMaintaining Effects of Quinpirole. Responding maintained by quinpirole (0.01, 0.032, or 0.1 mg/kg/inj) or saline
during the 7-day substitution for cocaine (0.56 mg/kg/inj),
remifentanil (0.0032 mg/kg/inj), ketamine (1.0 mg/kg/inj), or
liquid food is shown in Fig. 2, A to D. Differences in quinpirole-maintained responding were observed among the cocaine-, remifentanil-, ketamine-, and food-trained rats. When
substituted for cocaine, quinpirole maintained robust responding at doses 0.032 and 0.1 mg/kg/inj, whereas responding for 0.01 mg/kg/inj quinpirole was no different from responding maintained by saline (Fig. 2A). Responding
maintained by 0.032 and 0.1 mg/kg/inj quinpirole was significantly greater than responding maintained by saline during
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capacity of quinpirole to maintain responding was evaluated in five
separate groups of rats (n ⫽ 6/group). All rats were initially trained
to respond for liquid food under an FR1TO5 schedule of reinforcement. After a 14-day acquisition period, responses that previously
resulted in access to liquid food now resulted in an intravenous
injection of saline (group 1), 0.56 mg/kg/inj cocaine (group 2), or 0.032
mg/kg/inj quinpirole (group 3). Rats in groups 4 and 5 received 45
evenly spaced, noncontingent injections of 0.56 mg/kg/inj cocaine.
For group 4, the delivery of cocaine was paired with the same stimuli
that subsequently accompanied quinpirole delivery (illumination of
the green LED followed by the illumination of the house light for 5 s).
For group 5, the delivery of cocaine was not paired with any additional stimuli. Each of these conditions was maintained for seven
consecutive sessions, and it was followed by five sessions in which
rats were returned to liquid food reinforcement. During the next, test
phase, all rats were allowed to self-administer 0.032 mg/kg/inj quinpirole for a period of 7 days; subsequently, they were returned to
liquid food reinforcement for 5 days to assess changes in baseline
responding.
Drugs. Cocaine hydrochloride [methyl (1R,2R,3S,5S)-3-benzoyloxy-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
hydrochloride] was obtained from the National Institute on Drug Abuse (Bethesda, MD). Remifentanil [methyl 1-(3-methoxy-3-oxopropyl)-4(phenyl-propanoylamino)piperidine-4-carboxylate
hydrochloride],
purchased as Ultiva (GlaxoSmithKline, Uxbridge, Middlesex, UK),
was obtained from the University of Michigan Hospital Pharmacy
(Ann Arbor, MI). Ketamine [2-(2-chlorophenyl)-2-methylaminocyclohexan-1-one] was purchased from Henry Schein (Denver, PA). Quinpirole
[trans-(⫺)-(4aR)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1Hpyrazolo[3,4-g]quinoline hydrochloride] was purchased from SigmaAldrich. (St. Louis, MO). All drugs were dissolved in physiological
saline, and they were administered in a volume of 0.1 ml/kg over a
period of 0.5 s.
Data Analysis. Responses represent the mean ⫾ S.E.M. (n ⫽ 6)
number of responses that resulted in an injection or food delivery,
but they do not include responses made during reinforcement or the
subsequent time-out period. Response stability was defined as three
consecutive sessions with less than 20% difference in responding and
no increasing or decreasing trend in the number of injections earned.
Dose-response curves represent the mean ⫾ S.E.M. (n ⫽ 6) number
of completed ratios during the last three sessions for each dose of
drug or saline. Analysis of dose-response curves was conducted using
a one-way ANOVA with post hoc Dunnett’s tests (GraphPad Prism;
GraphPad Software Inc., San Diego, CA) to determine doses of drug
that maintained significantly greater levels of responding than saline. Significant differences in baseline responding or responding
maintained during substitutions was determined using a two-way
ANOVA with repeated measures and post hoc Bonferroni tests
(SPSS; SPSS Inc., Chicago, IL) to assess differences in responding
between the groups for each session.
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sessions 2 to 7 of the substitution, whereas no significant
differences were observed during the initial day of substitution. In remifentanil-trained rats, significant levels of quinpirole-maintained responding were observed during sessions
2 to 7 when a dose of 0.1 mg/kg/inj quinpirole was substituted. However, responding for doses of 0.01 and 0.032 mg/
kg/inj quinpirole were not significantly different from responding maintained by saline (Fig. 2B). Unlike in rats
trained to respond for cocaine or remifentanil, quinpirole
failed to maintain significant levels of responding at any dose
tested in rats trained to respond for ketamine (Fig. 2C) or
liquid food (Fig. 2D). In fact, as shown in the insets to Fig. 2,
C and D, responding maintained by quinpirole was significantly lower than responding maintained by saline during
the initial day of substitution in both ketamine- (0.032 and
0.1 mg/kg/inj quinpirole) and food (0.01, 0.032, and 0.1 mg/
kg/inj quinpirole)-trained rats.
Rates of responding maintained by quinpirole were not
related to the rate of responding maintained by the baseline
reinforcers. Significant levels of quinpirole-maintained responding were observed in rats that previously responded for
cocaine (⬍50 reinforcers) or remifentanil (⬎100 reinforcers),
whereas quinpirole failed to maintain responding in rats that
previously responded for food (⬎200 reinforcers) or ketamine
(⬍50 reinforcers). Dose-response curves for responding maintained by quinpirole on the last day of substitution for each of
the maintenance reinforcers are shown in Fig. 3.
Effect of Prior Drug Exposure on the ResponseMaintaining Effects of Quinpirole. The effects of prior
contingent saline, quinpirole and cocaine, or noncontingent
cocaine on quinpirole-maintained responding in rats trained
to respond for liquid food are shown in Fig. 4. Although there
were no significant differences in food-maintained responding between any of the groups during the first, second, or
third food components of the experimental paradigm, 0.56
mg/kg/inj cocaine maintained significantly greater levels of
responding than either saline or 0.032 mg/kg/inj quinpirole
Fig. 3. Dose-response curves for the quinpirole (saline, 0.01, 0.032, and
0.1 mg/kg/inj)-maintained responding during the final day of substitution
in rats trained to respond for cocaine (0.56 mg/kg/inj), remifentanil
(0.0032 mg/kg/inj), ketamine (1.0 mg/kg/inj), or food (10-s access to 50 ␮l
of 100% Ensure). Data represent the mean ⫾ S.E.M. (n ⫽ 6) number of
reinforced responses made during the final day of substitution. ⴱⴱ, p ⬍
0.01; significant differences in responding from saline were determined
by one-way ANOVA with post hoc Dunnett’s tests.
throughout the initial 7-day i.v. exposure (Fig. 4). Low levels
of responding were observed when quinpirole (0.032 mg/kg/
inj) was available. When substituted for food, responding
maintained by quinpirole was no different from responding
maintained by saline with the exception of the first day,
when quinpirole-maintained responding was significantly
lower than saline-maintained responding. Rats that received
noncontingent cocaine injections also responded at salinelike levels during the initial exposure period. When all rats
were allowed to respond for 0.032 mg/kg/inj quinpirole, the
previous drug exposure significantly affected behavior. Rats
that had previously responded for either saline or quinpirole
responded for quinpirole at low levels throughout the second
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Fig. 2. Responding maintained during 7-day substitutions of quinpirole (0.01, 0.032, and 0.1 mg/kg/inj) or saline in rats trained to respond for cocaine (0.56 mg/kg/inj)
(A), remifentanil (0.0032 mg/kg/inj) (B), ketamine (1.0
mg/kg/inj) (C), or liquid food (10-s access to 50 ␮l of 100%
Ensure) (D). Responding data during the first 3 days of
substitution in ketamine- and food-trained rats are inset
in C and D, respectively. Data represent the mean ⫾
S.E.M. (n ⫽ 6) number of reinforced responses made during daily 90-min sessions. x, p ⬍ 0.05; represents significant differences in responding maintained by 0.01 mg/kg/
inj quinpirole compared with saline. ⴱ, p ⬍ 0.05; ⴱⴱ, p ⬍
0.01; and ⴱⴱⴱ, p ⬍ 0.001; represent significant differences
in responding between the group that was allowed to
respond for 0.56 mg/kg/inj cocaine compared with the
group that was allowed to respond for saline during the
initial i.v. exposure period. ##, p ⬍ 0.01; represents significant differences in responding between the group that
was allowed to respond for 0.032 mg/kg/inj quinpirole
compared with the group that was allowed to respond for
saline during the initial i.v. exposure period. Significant
differences in responding compared with the saline group
were determined using two-way ANOVA with repeated
measures and post hoc Bonferroni tests.
Quinpirole-Maintained Responding in the Rat
603
i.v. self-administration period (Fig. 4). Conversely, rats that
responded for cocaine during the initial exposure period responded for quinpirole at high rates throughout the second
7-day period (Fig. 4). However, when cocaine was initially
delivered noncontingently, responding for quinpirole was low
and no different from responding observed in rats that initially responded for either saline or quinpirole (Fig. 4). Furthermore, pairing the accompanying stimuli (i.e., illumination of the green stimulus light during infusion and house
light for 5 s thereafter) with the noncontingent administration of cocaine did not increase the capacity of quinpirole to
maintain responding; no differences in quinpirole-maintained responding were observed between the rats that received the accompanying stimuli in addition to the noncontingent cocaine injections, and rats that received
noncontingent cocaine without these stimuli (Fig. 4).
Discussion
The results of this study confirm the findings of previous
studies and extend them in several ways. Similar to reports
in rats (e.g., Caine and Koob, 1993) and monkeys (e.g., Sinnott et al., 1999), quinpirole-maintained dose-dependent responding resulting in an inverted U-shaped dose-response
curve when substituted in rats trained to respond for cocaine.
These studies also support the findings of Nader and colleagues, who demonstrated that although quinpirole maintained responding in animals with a history of cocaine reinforcement, quinpirole failed to maintain responding in
experimentally naive animals, or in those trained to respond
for food (Nader and Mach, 1996; Sinnott et al., 1999). The
current study also assessed the influence of various drug and
reinforcement histories on the capacity of quinpirole to maintain responding. Although quinpirole maintained significant
levels of responding when substituted for cocaine or remifentanil, responding was generally no different from that maintained by saline when quinpirole was substituted for either
ketamine or food. Furthermore, although quinpirole maintained responding in rats with either a remote or proximal
history of cocaine reinforcement, quinpirole failed to maintain responding in rats that were exposed noncontingently to
roughly equivalent doses and patterns of cocaine injection.
These findings suggest that both drug and reinforcement
histories were important determinants in establishing the
response-maintaining effects of quinpirole and that quinpirole was most effective at maintaining responding in rats
with a history of cocaine reinforcement.
Although this study is not the first to describe differences
in the reinforcing properties of drugs following substitution
from different maintenance drugs (e.g., Hoffmeister and
Schlichting, 1972; Young and Woods, 1981; Beardsley et al.,
1990; Wojnicki and Glowa, 1996), they are the first to address
systematically the impact of varying drug and reinforcement
histories on the capacity of a D2/D3 agonist to function as a
reinforcer. Although the two highest doses of quinpirole were
readily self-administered in rats trained to respond for cocaine, only the highest dose of quinpirole maintained significant levels of responding when substituted in remifentaniltrained rats. Differences in drug history (i.e., cocaine and
remifentanil) not only altered the potency of quinpirole to
maintain responding, but other drug histories (i.e., ketamine) failed to establish the response-maintaining effects of
quinpirole altogether. Similar effects of drug history on reinforcing potency have been reported for GBR 12909 in monkeys with a history of responding for high doses of cocaine or
GBR 12909 compared with drug-naive monkeys (Wojnicki
and Glowa, 1996). Although these findings suggest that prior
exposure to some drugs may sensitize animals to the reinforcing effects of drug reinforcers, it is unlikely that sensitization alone accounts for the differences in quinpirole-maintained responding in the current study, because roughly
equivalent amounts of noncontingent cocaine failed to establish the response-maintaining effects of quinpirole, as would
have been expected if cocaine exposure had been sufficient to
sensitize the rats to the reinforcing effects of quinpirole (e.g.,
Robinson and Berridge, 1993; Vezina, 2004).
In addition to shifts in the potency of quinpirole to maintain responding, quinpirole failed to maintain responding
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Fig. 4. Effect of prior drug exposure on the capacity of quinpirole to maintain responding in rats trained to respond for food. Different groups of rats
were either allowed to respond for cocaine (0.56 mg/kg/inj), saline, or quinpirole (0.032 mg/kg/inj), or they received 45 noncontingent injections of
cocaine (0.56 mg/kg/inj) delivered with or without the accompanying stimuli (AS) during the initial i.v. drug exposure period. All rats were allowed
to respond for quinpirole (0.032 mg/kg/inj) during the subsequent i.v. self-administration period. Data represent the mean ⫾ S.E.M. (n ⫽ 6) number
of reinforced responses made during daily 90-min sessions. Responding for the noncontingent cocaine groups during the initial i.v. exposure period
represents the total number of responses made during the 90-min session. ⴱ, p ⬍ 0.05; ⴱⴱ, p ⬍ 0.01; and ⴱⴱⴱ, p ⬍ 0.001; two-way ANOVA with repeated
measures and post hoc Bonferroni tests were used to determine significant differences in responding compared with the group that was allowed to
respond for saline during the initial i.v. exposure period.
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Collins and Woods
transitory. Although quinpirole initially suppressed responding for water, tolerance to this effect seemed to develop
within the first few days, and it was followed by large increases in reward-appropriate responding when water was
subsequently withdrawn (Kurylo and Tanguay, 2003; Kurylo, 2004) or when water was made freely available throughout the experimental session (Cioli et al., 2000; Amato et al.,
2006). Although these data suggest that quinpirole may induce perseverative or “compulsive” responding for water, it
should be noted that these effects were observed when relatively large (ⱖ0.5 mg/kg) doses of quinpirole were administered over a number of days; furthermore, quinpirole has also
been shown to induce hyperdipsia over a similar range of
doses (Fraioli et al., 1997). When taken together, these findings suggest that quinpirole can dose-dependently increase
or decrease operant behavior that has been maintained by
either drug or nondrug reinforcers.
Thus, it is possible that quinpirole-maintained responding
may result from a combination of the direct drug effects on
previously reinforced responding rather than a more general
reinforcing effect of quinpirole. For example, D2/D3 agonists,
given as pretreatments, have been shown to increase previously reinforced responding regardless of whether responding had been extinguished or not. Similar to the findings of
the current study, quinpirole, administered noncontingently,
has been shown to reinstate responding previously reinforced
by cocaine or heroin (Khroyan et al., 2000; De Vries et al.,
2002), but not food (Dias et al., 2004). However, the extent to
which this effect is influenced by the contingent or noncontingent administration of quinpirole remains to be determined. Furthermore, it is likely that the stimuli associated
with reinforcer delivery are also controlling responding;
moreover, quinpirole may be affecting these stimulus functions as well (Wolterink et al., 1993). Thus, quinpirole, and
other D2/D3 agonists, must be studied in animals with a
variety of reinforcement histories, and under a variety of
contingencies and stimulus conditions, to fully understand
their effects on operant responding.
In summary, the results of this study show that although
responding was readily acquired for cocaine, remifentanil,
ketamine, and food, quinpirole failed to initiate or maintain responding at levels any different from those maintained by saline in experimentally naive rats. However,
quinpirole did maintain significant levels of responding in
cocaine- and remifentanil-trained rats, but not in rats that
were trained to respond for ketamine or food, or in rats
that were trained to respond for food and provided a
roughly equivalent history of noncontingent cocaine exposure. Together, these findings suggest that the responsemaintaining effects of quinpirole are highly dependent
upon both drug and reinforcement history, and although
quinpirole is capable of maintaining responding under
some experimental conditions, this may result from a combination of the direct effects of quinpirole on operant responding and a more provisional reinforcing effect serving
to perpetuate operant responding. Further studies are
needed to determine the degree to which the direct drug
effects and the reinforcing properties of quinpirole are
involved in the capacity of quinpirole to maintain responding in animals with a history of cocaine or opioid
reinforcement.
Downloaded from jpet.aspetjournals.org at ASPET Journals on May 3, 2017
when substituted in rats trained to respond for either ketamine or food, suggesting a selectivity to the effect of reinforcer history. Similar effects of drug history have been reported by Young and Woods (1981), who demonstrated that
although phencyclidine, dexoxadrol, and dextrorphan all
maintained responding when substituted for ketamine, each
of these drugs failed to maintain responding when substituted in monkeys maintained on codeine. Similarly, the capacity of MK-801 to maintain responding seems to be dependent upon drug history, because MK-801 maintained
responding when substituted in monkeys trained to respond
for 1-(1-phenylcyclohexyl)piperidine (phencyclidine), but not
cocaine (Beardsley et al., 1990). In both of these studies, the
capacity of substitute reinforcers to maintain responding
was, in large part, attributed to similarities in the discriminative stimulus properties of the substitute and maintenance
drugs. Although it is likely that similarities in the discriminative stimulus effects of quinpirole and cocaine (Barrett and
Appel, 1989; Terry et al., 1994; Barrett et al., 2001) are at
least in part responsible for the capacity of quinpirole to
maintain responding when substituted for cocaine, similar
explanations do not account for the maintenance of responding when quinpirole was substituted for drugs with dissimilar discriminative stimulus effects, such as the ␮-opioid agonist remifentanil (Cook and Beardsley, 2004).
In addition to maintaining responding when substituted
for cocaine, D2/D3 agonists such as quinpirole have also been
shown to possess a variety of direct effects on operant behavior that may influence their capacity to maintain responding
when substituted from different drug- and nondrug-reinforced baselines. For example, in addition to dose-dependently increasing cocaine-appropriate responding in drug
discrimination studies, D2/D3 agonists, such as quinpirole,
have also been shown to increase nonreinforced (cocaineappropriate), responding in animals trained to respond for
cocaine. For example, during sessions when cocaine was unavailable and responding on the injection lever resulted in
saline delivery, D2/D3 agonists dose-dependently increased
injection lever responding in monkeys trained on a two-lever,
cocaine-food choice procedure (Gasior et al., 2004). Similar
increases in cocaine-appropriate responding have been observed following quinpirole pretreatment in reinstatement
procedures (Khroyan et al., 2000; De Vries et al., 2002),
suggesting that quinpirole is capable of inducing cocaineappropriate responding regardless of whether cocaine was
administered as a reinforcer or as a discriminative stimulus.
However, quinpirole has also been shown to reinstate responding previously reinforced by heroin (De Vries et al.,
2002), suggesting a more general effect of quinpirole on previously reinforced responding.
Similar direct effects of quinpirole on operant behavior
have been reported in rats trained to respond for nondrug
reinforcers. For example, when administered at doses
roughly equivalent to those available for injection in the
current study, quinpirole has been shown to suppress foodmaintained responding (Franklin and Tang, 1995; Sanger et
al., 1996), suggesting that, at relatively low doses, quinpirole
possesses response-suppressant effects. Likewise, chronic
treatment with higher doses of quinpirole (ⱖ0.5 mg/kg) has
been shown to suppress responding for water (Cioli et al.,
2000; Kurylo and Tanguay, 2003; Kurylo, 2004; Amato et al.,
2006), although this effect seemed to be time-dependent and
Quinpirole-Maintained Responding in the Rat
Acknowledgments
We acknowledge the excellent editorial assistance of Dr. Gail
Winger and exceptional technical assistance of Michelle Baladi.
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