Content uploaded by Daniel Guzman
Author content
All content in this area was uploaded by Daniel Guzman on May 20, 2020
Content may be subject to copyright.
Heroin attenuates the negative consequences of cocaine in a
runway model of self-administration
Daniel Guzman, Aaron Ettenberg*
Behavioral Pharmacology Laboratory, Department of Psychology (9660), University of California, Santa Barbara, CA 93106, United States
Received 3 May 2004; received in revised form 26 July 2004; accepted 4 August 2004
Available online 29 September 2004
Abstract
It has been presumed that the combination of cocaine (COC)+heroin (HER) is more reinforcing than either of the two drugs alone, thus
leading to their coadministration (bspeedballingQ). An alternative hypothesis is that HER serves to attenuate the undesired negative effects of
COC. To test this notion, male Sprague–Dawley rats (n=31) were trained to run a straight alley for a daily intravenous (IV) injection of COC
(1.0 mg/kg/injection) for 14 trials. Studies in our laboratory have shown that such animals begin to exhibit approach–avoidance behaviors
(bretreatsQ) stemming from concurrent positive and negative associations with the goal box (which, in turn, are the result of COC’s immediate
rewarding and subsequent dysphoric actions). Thus, retreats can be used as a reliable index of COC’s anxiogenic side effects. Following 14
COC-reinforced trials, animals were split into three groups matched on mean retreat frequency. One group (n=11) received IV COC (1.0 mg/
kg/injection) for seven additional trials; the remaining two groups (n=10 each) received an IV injection of COC mixed in a single solution
with either a low dose (0.025 mg/kg/injection) or a high dose (0.1 mg/kg/injection) of HER. It was hypothesized that adding HER would
attenuate the negative consequences of COC administration and thereby produce a reliable decrease in the occurrence of retreats. The
resulting data were consistent with this hypothesis, suggesting that bspeedballingQin human addicts may be motivated by a desire to reduce
the negative impact of COC use.
D2004 Elsevier Inc. All rights reserved.
Keywords: Speedball; Cocaine; Heroin; Drug self-administration; Operant behavior; Runway
1. Introduction
The simultaneous self-administration of opiates and
cocaine is commonly referred to as bspeedballing,Qa
behavior that epidemiological studies have confirmed as
being relatively widespread among drug users (Diaz et al.,
1994; Dolan et al., 1991; Malow et al., 1992; Shutz et al.,
1994; Siegal et al., 1994; Frank and Galea, 1996). Verbal
reports from polydrug users suggest that the combination of
opiates and cocaine produces higher levels of euphoria
compared to those achieved by using either drug alone
(Tutton and Crayton, 1993). In controlled clinical studies,
the administration of intravenous (IV) cocaine and morphine
combinations increased ratings of subjective feelings of
bhighQand blikingQcompared to either morphine or cocaine
alone (Foltin and Fischman, 1992; Walsh et al., 1996).
Similar findings have been reported by animal studies where
low doses of heroin or cocaine, which alone were unable to
sustain IV self-administration in rats, did so when combined
(Rowlett and Woolverton, 1997). These investigators also
reported that heroin shifted the cocaine reward dose–effect
curve to the left, indicating a heroin-modulated increase in
cocaine reinforcement. Cocaine/heroin combinations have
also been shown to produce higher break points than either
drug alone in rats working under progressive ratios
schedules (Ranaldi and Mann, 1998; Duvachelle et al.,
1998), again suggesting that the rewarding impact of the
combination exceeds that of the individual drugs.
An alternative or complimentary explanation for the
high prevalence of opiate and cocaine coadministration
0091-3057/$ - see front matter D2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.pbb.2004.08.009
* Corresponding author. Tel.: +1 805 893 3682; fax: +1 805 893 4303.
E-mail address: ettenberg@psych.ucsb.edu (A. Ettenberg).
Pharmacology, Biochemistry and Behavior 79 (2004) 317 – 324
www.elsevier.com/locate/pharmbiochembeh
might be that the combination ameliorates the aversive
side effects of one or both of the two drugs involved. For
example, Foltin and Fischman (1992) found that human
bspeedballQusers reported less undesired sedation com-
pared to when the opiate was administered alone. In
chronic cocaine users, the addition of an opiate may serve
to reduce the well-documented negative after-effects of
cocaine (Washton and Gold, 1984; Anthon et al., 1989;
Cox et al., 1986; Spotts and Shontz, 1984). In animals,
cocaine has similarly been shown to have negative and
anxiogenic properties (Rogerio and Takahashi, 1992;
Simon et al., 1994; Yang et al., 1992). In our laboratory,
rats trained to run a straight alley once a day for IV
cocaine were observed to develop an ambivalence about
entering the goal box that was behaviorally similar to that
observed in hungry rats approaching a goal box asso-
ciated with food+shock (Ettenberg and Geist, 1991; Geist
and Ettenberg, 1997). These animals approach the goal
box, stop at the entry/threshold, and retreat back toward
the start box in an bapproach–avoidanceQpattern (e.g., see
Miller, 1994), which is thought to represent concurrent
positive (reward) and negative (anxiety) associations with
the goal box where cocaine had been administered on
previous trials. This notion was substantiated by the
observation that approach–avoidance conflict (reflected by
the development of retreats) can be dose-dependently
attenuated by pretreatment with the anxiolytic agent,
diazepam—an effect later replicated in an emotional
strain of mice (Geist and Ettenberg, 1997; David et al.,
2001a).
The current study was devised to test the hypothesis that
the negative anxiogenic state associated with cocaine may
serve to motivate some cocaine users to add heroin as a
means of self-medication (i.e., negative reinforcement). As
the peak positive experience with cocaine wanes and is
followed by growing anxiety or cravings, the delayed onset
of heroin’s actions may serve to curtail the aversive
experience. This notion, that cocaine produces an initial
positive state, followed temporally by a negative or aversive
state, is consistent with the opponent-process theory of drug
action (Koob et al., 1997; Solomon and Corbit, 1974). It is
hypothesized that it is this latter negative or aversive effect
that may motivate cocaine users to self-medicate by
simultaneously administering cocaine and heroin. In the
operant runway, we would therefore operationally predict
that the number of approach–avoidance bretreatsQwould
decrease in cocaine+heroin-reinforced animals compared to
those running the alley for cocaine alone.
2. Methods
2.1. Subjects
Thirty-one male albino Sprague–Dawley rats (weighing
340–470 g at the time of surgery) were obtained from
Charles River Laboratories and served as subjects. Each
animal was individually housed in metal wire cages
located in a temperature-controlled (23 8C), 12-h light–
dark vivarium environment (lights on at 0700 h). Animals
were provided ad libitum access to food (Purina Rat
Chow) and water throughout the experiment. The
animals’ care and all experimental procedures were
reviewed and approved by the University of California
at Santa Barbara’s Institutional Animal Care and Use
Committee for compliance with the National Institutes of
Health Guide for the Care and Use of Laboratory
Animals.
2.2. Surgery
Each animal was surgically implanted with a chronic
silastic jugular catheter under deep isoflurane-induced
anesthesia (4% for induction and 1.5–2.5% maintenance
continuously) administered via inhalation. Rats were also
injected with atropine (0.04 mg/kg, i.m.) to prevent
respiratory congestion and flunixin meglumine (FluMe-
glumine) (2.0 mg/kg, s.c.) as a general nonopiate
analgesic. One end of the catheter was inserted into the
jugular vein, while the other end was passed subcuta-
neously to the animal’s back where it was fused to a
threaded cannula (Item 313G; Plastics One) that exited
through an opening (3 mm diameter) made using a
biopsy punch. The cannula was cemented to a 2-cm
square of surgical Mersilene mesh that was laid flat on
the animal’s back and secured in place. In between drug
treatments, a cap (Item 313DC; Plastics One) was
inserted into guide cannula to prevent infection. Immedi-
ately following surgery, all animals were given the
antibiotic ticarcillin disodium and clavulanata potassium
(Timentin) (50 mg/0.25 ml) through the catheter to
prevent infection, followed by an injection of heparin
(1000 IU/0.1 ml) to maintain catheter patency. Beginning
the day after surgery and maintained daily throughout the
remainder of the experiment, each subject was injected
with Timentin (20 mg/0.1 ml, i.v.) followed by heparin
(1000 IU/0.1 ml, i.v.), upon completion of runway
testing. Drug reinforcement training did not begin until
at least 7 days postsurgery. Twice during the experiment,
animals were injected with a low dose of methohexital
dosium (Brevital) (0.1 mg/kg, i.v.) to confirm catheter
patency. Brevital is a fast-acting barbiturate that causes
immediate sedation in animals.
2.3. Runway apparatus
All trials were conducted in four identical wooden
straight arm runways (measuring 155 cm long15 cm
wide40 cm high). Attached to one end of each runway
was a start box (242540 cm) with a goal box of the
same dimensions attached to the opposite end. The
runway floor consisted of small-diameter steel rods
D. Guzman, A. Ettenberg / Pharmacology, Biochemistry and Behavior 79 (2004) 317–324318
arranged in parallel (1.2 cm apart) along the entire
runway, including start and goal boxes. Suspended in
parallel (3 cm apart) above and along the length of the
runway apparatus were two long bar magnets. These
magnets were aligned in such a manner as to repel a pot
magnet attached to the underside of a flow-through
swivel assembly that was positioned between the two
magnetic rails. Thus, the rails provided a track along
which the swivel could float with extremely low friction.
As a subject traversed the alley, it pulled behind and
above it the swivel assembly that connected the animal to
the drug delivery apparatus and permitted freedom of
movement within the alley (for a more complete
description of the runway apparatus, see Geist and
Ettenberg, 1990).
Imbedded in the walls along the length of the runway
were 13 pairs of infrared photodetector-emitters whose
output was fed into a Windows-based personal computer
and thereby identified the animals’ position in the
apparatus at all times during each trial. The first photo-
detector–emitter pair was located within the start box and
the final pair was located within the goal box. The
remaining 11 photodetector emitters were set equally
spaced along the walls of the alley. A sliding door allowed
access from the start box to the runway. Five seconds after
the animal was placed into the start box, the door was
automatically dropped and the trial initiated. The animals
were then free to travel the length of the alley to the goal
box. Upon goal box entry, a sliding door was automati-
cally raised from below the floor to prevent retracing and
an IV injection was automatically initiated.
2.4. Procedure
2.4.1. Cocaine self-administration
The first phase of the experiment consisted of cocaine
hydrochloride (cocaine) self-administration training for all
animals. Each animal was connected to the swivel drug
delivery system by threading a male internal cannula
(Item 313I; Plastics One) into the external cannula
mounted on the animal’s back. The internal cannula
was connected via PE 20 tubing to a 10-ml syringe
containing a solution of (1.0 mg/kg/0.1 ml) cocaine
mixed in physiological saline (0.9%). The syringe was
placed in a Razel pump set to infuse at a rate of 0.1 ml
over a 4-s period. Once the animal was connected to the
swivel, it was placed in the start box of one of the four
runways (each animal was tested in the same runway for
the entire experiment). After 5 s, the start door dropped
and the trial was initiated. Subjects were permitted up to
15 min to traverse the runway and enter the goal box.
Upon goal box entry, the goal door closed and, 3 s later,
the IV drug reinforcer (1.0 mg/kg/injection) was deliv-
ered. The animal remained in the goal box for 5 min
postinjection after which it was removed and returned to
its home cage.
Each subject was tested in the runway one trial per
day for 14 consecutive days. During each trial, the
number and location of approach–avoidance bretreatsQ
were counted by computer. A bretreatQwas defined as a
stop in forward movement, a turn, and retreat back
towards the start box. The pivot point in the runway, or
where the animal began to traverse back towards the start
box, was identified as the blocationQof each retreat. As
reviewed in the Introduction, bretreatsQhave been shown to
occur when goal box events have mixed positive+negative
attributes (Geist and Ettenberg, 1997). Start latencies, the
time to leave the start box and enter the alley, were also
recorded for each animal on each trial. Goal times were not
recorded since our own previous work has shown them to be
confounded by and highly correlated with retreat behaviors
(e.g., Ettenberg and Geist, 1991). That is, subjects that
bretreatQin the runway necessarily take longer to enter the
goal box.
2.4.2. Speedball (cocaine+heroin) trials
After 14 days/trials of cocaine self-administration, the
subjects were each assigned to one of three groups. The
groups were matched for mean number of retreats during
the 14-day training period to ensure comparable baseline
conditions. A cocaine (n=11) group (COC) was tested in
the same manner as already described for seven additional
trials, each culminating in an IV injection of cocaine (1.0
mg/kg). One cocaine+heroin (n=10) group received an IV
injection of cocaine (1.0 mg/kg)+low-dose (0.025 mg/kg)
diacetylmorphine (heroin) reinforcement upon goal box
entry [COC+HER (L)]. A final cocaine+heroin (n=10)
group received the IV cocaine reinforcer (1.0 mg/
kg)+high-dose (0.1 mg/kg) heroin [COC+HER (H)].
Doses of heroin were chosen based on previous work
from our laboratory showing that rats given an IV
injection of 0.025 mg/kg heroin did not produce reliable
conditioned place preferences, while a dose of 0.1 mg/kg
resulted in a robust and significant preference for the
drug-paired side (Walker and Ettenberg, 2001). Retreat
and start latencies data were collected during each trial
over eight consecutive days.
3. Results
Custom software using data from the infrared photo-
detector-emitter cells that line the alley provided a pictorial
representation of each subject’s behavior during each trial.
Fig. 1 provides a spatio-temporal record of a representative
cocaine-reinforced animal and a cocaine+heroin (high dose)
animal on the final trial (21). The abscissa represents real
time during a single trial, while the ordinate represents the
rat’s location in the runway with location 1 being just
outside the start box door and location 11 just outside the
goal box. Note that both rats moved toward and away from
the goal box several times (represented as bpeaksQin the
D. Guzman, A. Ettenberg / Pharmacology, Biochemistry and Behavior 79 (2004) 317–324 319
chart) before finally entering the goal box. The number of
peaks in the graph yields retreat frequency and their value
on the ordinate scale represents retreat location in the alley.
The cocaine-only animal made 11 such retreats and took 9.8
min to enter the goal box, while the bspeedballQsubject
made fewer retreats and hence entered the goal box sooner
(i.e., after 3.3 min).
Fig. 2 depicts the mean (+S.E.M.) retreat frequencies of
the three treatment groups during weeks 1, 2, and 3. Note
that while the figure shows the data for each group during
weeks 1 and 2, all animals (n= 31) received cocaine-only
treatment during that time and were not assigned to one of
the three groups [i.e., COC, COC+HER (L), or COC+HER
(H)] until completion of trial 14. Hence, all bars are
represented by the same shade during weeks 1 and 2 (left
panel of Fig. 2). A two-factor mixed analysis of variance
(ANOVA) (GroupWeek) on the data depicted in Fig. 2
confirmed the following reliable results: a main effect for
Week [ F(2,56)=15.72, pb0.01; reflecting the increase in
overall retreat frequency over trials]; a significant Group-
Week interaction [ F(4,56)=3.21, pb0.05]; no group
differences were observed. During the final week of testing,
the addition of heroin to the cocaine solution prevented the
further increase in retreat behavior that occurred in the
cocaine-only subjects. The right panel of Fig. 2 (speedball
trials) clearly shows that retreat frequency continued to rise
in the COC group (GroupWeek interaction) but held at
week 2 levels in the COC+HER (L) and the COC+HER (H)
groups. Although the occasional rat did not exhibit a retreat
on a given trial, all subjects were included in the data
analysis.
Fig. 3 depicts the mean (+S.E.M.) group retreat
frequency per trial at each location within the alley during
week 3 of testing. A two-factor ANOVA (GroupLocation)
computed on these data revealed a reliable main effect for
Group [ F(2,18)=7.268, pb0.01], a reliable main effect for
retreat Location [ F(8,144)=22.22, pb0.001], and a reliable
(GroupLocation) interaction [ F(16,144)=3.63, pb0.001].
Thus, while retreats tended to occur predominately just
outside the goal box entry for all groups (main effect for
Location), the tendency to emit such retreats was greatest in
the COC group (main effect for Group), whose subjects’
relatively greater propensity to retreat increased with
proximity to the goal box (GroupLocation interaction).
Start latencies did not differ between groups during the
final week of testing. A one-way between-group ANOVA
computed on the mean start latencies of the three groups
Fig. 2. Mean (+S.E.M.) retreat frequency for each of the three groups
during weeks 1, 2, and 3 of the study. Note that all groups were treated
identically during the first 2 weeks of the study (left panel) when all
subjects ran for cocaine only. During this phase of the experiment, retreats
increased equivalently in all three groups. During week 3 (trials 15–21;
right panel), the continued increase in retreats that was observed in the COC
animals was prevented by the addition of heroin.
Fig. 1. Two representative spatio-temporal records from different rats: one
running for IV cocaine (1.0 mg/kg/injection) and a second rat running for
an IV bspeedballQcombination (1.0 mg/kg/injection cocaine+0.1 mg/kg/
injection heroin) on the final day of testing (trial 21). The graphs depict the
location of the rat in the runway ( y-axis) expressed as a function of time (x-
axis) within the trial. Location 1 corresponds to a location just outside the
start box, while location 11 is just outside the goal box. The slope of the
curve indicates running speed with more gentle slopes representing slower
running. In these examples, the subjects ran quickly down the alley, stopped
(typically just outside the goal box entry), and ran quickly all the way back
to the start box. Note that the cocaine subject made 11 such retreats before
finally entering the goal box just after 9.8 min into the trial, while the
bspeedballQ-reinforced rat made only five such retreats before entering the
goal box 3.3 min into the trial.
D. Guzman, A. Ettenberg / Pharmacology, Biochemistry and Behavior 79 (2004) 317–324320
confirmed that all three groups approached the goal (i.e., left
the start box) with equivalent intensity [F(2,28)=1.88,
pN.05].
4. Discussion
Human users describing the effects of cocaine often
report that the initial positive euphoria is followed by an
aversive state of anxiety and strong craving (Washton and
Gold, 1984; Anthon et al., 1989; Cox et al., 1986; Spotts
and Shontz, 1984). It was therefore hypothesized that this
late-onset aversive state motivates some cocaine users to
administer cocaine and heroin simultaneously such that
the addition of heroin serves as a negative reinforcer by
taking the bedgeQoff of the cocaine or reducing the
bcrashQfollowing cocaine use (Foltin and Fischman,
1992). An animal runway model of cocaine self-admin-
istration previously established in our laboratory has been
shown to be sensitive to cocaine’s dual-opponent pro-
cesses and thus provides an appropriate model to test this
hypothesis (Ettenberg and Geist, 1991; Geist and Etten-
berg, 1997). The current study confirmed the develop-
ment of approach–avoidance retreat behaviors in rats
approaching a goal box previously associated with IV
cocaine presentation (see Figs. 1–3). Hence, the subjects
exhibited ambivalence about entering a location putatively
associated with both positive and negative aspects of
cocaine action. Furthermore, as predicted by conflict
theory (e.g., Miller, 1994), the location of these retreats
was not spread randomly within the alley but rather was
clustered outside the bchoiceQpoint, at the entry of the
goal box (see Figs. 1 and 3).
The primary finding in this research was that adding
heroin to a cocaine reinforcer prevented further increases in
retreat behaviors during the last seven trials of the experi-
ment. As shown in Fig. 2, the cocaine-reinforced animals
made increasingly more retreats than either of the two
cocaine+heroin groups. Based on these findings, we con-
clude that the addition of heroin to the cocaine solution
prevented the further increase in ambivalence about entering
the goal box observed in the cocaine-only animals. Note that
the drug reinforcers are presented on a single trial per day
after the completion of the operant runway response. Hence,
the observed changes in retreat frequency over trials and the
differences between groups cannot be attributed to direct
motoric or other effects of the drugs since animals are
undrugged at the time of testing. The precise means by which
the opiate produced the changes in cocaine-induced retreat
behaviors remains unclear. The current results could have
been due to either an increase in the approach component of
the runway behavior (e.g., additive or synergistic positive
effects of cocaine and heroin relative to cocaine alone), or a
decrease of the avoidance component of the behavior (e.g.,
heroin-induced decreases in the negative effects of cocaine),
or both. Indeed, human users have reported both these
positive and negative reinforcing actions as motivating
factors for the combined use of opiates and cocaine (Foltin
and Fischman, 1992; Tutton and Crayton, 1993).
We had expected to observe a dose–response effect of
heroin based on our previous work with IV heroin in the
conditioned place preference test (Walker and Ettenberg,
2001). In fact, both the blowQand the bhighQdoses of heroin
produced comparable effects on cocaine-induced bretreats.Q
While it is unclear precisely why there was no dose–
response effect, these data might suggest that heroin’s
actions in this study were due to processes other than reward
(e.g., anxiolytic effects) since the two doses differed
substantially in their ability to produce conditioned place
preferences. Additionally, our results demonstrated that the
subjects’ motivation to approach the goal box (i.e., to leave
the start box) were the same for all three groups. Only the
bretreatQbehaviors differed across conditions. This again
suggests that heroin may have altered the ambivalence or
conflict exhibited by the cocaine-experienced rats, and not
brewardQper se.
Fig. 3. The figure depicts the daily group mean (+S.E.M.) frequency of retreats (pivot points) during the last week of testing (trials 15–21) for each location in
the runway. The location of each retreat is represented on the x-axis, with position 3 corresponding to a point just outside the start box, and position 11
corresponding to a point just outside the goal box. Retreat frequency dramatically increased in all groups with proximity to the goal box.
D. Guzman, A. Ettenberg / Pharmacology, Biochemistry and Behavior 79 (2004) 317–324 321
Preclinical investigations up to this point have focused
on the benhanced reward hypothesis,Qalthough evidence
for an increase in reinforcement by heroin/cocaine combi-
nations compared to cocaine or heroin alone has been
somewhat inconsistent. For example, Mello et al. (1995)
reported that self-administration response patterns for
heroin and cocaine combinations in rhesus monkeys were
similar to response patterns for either cocaine or heroin
alone, suggesting that the reinforcing effects of speedball
administration were not different from the reinforcing
effects of either drug alone. Comparable results were found
in a study by Mattox et al. (1997). In contrast, Rowlett and
Woolverton (1997) and David et al. (2001b) reported a
leftward shift in the self-administration dose–response
function for IV cocaine when heroin was added, indicating
a heroin-induced potentiation of the reinforcing effects of
cocaine in primates and mice. Furthermore, in the Rowlett
and Woolverton (1997) experiment, it was also found that
low doses of heroin or cocaine that alone failed to
maintain self-administration behavior did so when tested
in combination—a finding later replicated by Duvachelle
et al. (1998) in rats. Further evidence to support the notion
of synergistic or additive rewarding effects of stimulant/
opiate combinations has come from experiments using the
conditioned place preference paradigm. For example,
Brown et al. (1990) found that doses of buprenorphine, a
partial A-receptor agonist, and doses of cocaine that were
individually unable to induce preferences for drug-paired
environments did so when given together. Bilsky et al.
(1992) found similar results with methadone/cocaine
combinations—a result that may account for the high
incidence of cocaine use within methadone-treated pop-
ulations (Hartell et al., 1996; Grella et al., 1997). Addi-
tionally, Masukawa et al. (1993) found that morphine
combined with either cocaine or amphetamine induced
greater place preferences than that produced by either
stimulant alone.
The notion of a synergistic action between cocaine and
heroin on perceived drug reward is also consistent with the
results of preliminary neurochemical studies. There is
mounting evidence to suggest that the reinforcing effects
of both cocaine and heroin, like many other drugs of abuse,
are believed to be in part mediated by elevations in
extracellular dopamine levels in the nucleus accumbens
(for review, see Leshner and Koob, 1999). While cocaine
appears to increase dopamine levels by inhibiting its
reuptake by the dopamine transporter (DAT) in the NAcc,
heroin seems to induce dopamine release by binding directly
on opiate receptors in the ventral tegmental area, resulting in
a disinhibition of dopamine neurons (Giros et al., 1996;
Johnson and North, 1992). Based on the putative role of
dopamine in drug reinforcement, Hemby et al. (1999)
hypothesized that the increased euphoric effects of cocaine
and heroin reported by speedball users may involve
dopamine levels in the NAcc. These investigators used in
vivo microdialysis to compare dopamine levels in the
nucleus accumbens following either an IV injection of
cocaine alone, heroin alone, or their combination in rats.
While cocaine produced a 300% elevation in dopamine
levels above baseline, heroin only raised levels 70% above
baseline. However, the combined administration of cocaine
plus heroin raised dopamine levels 1000% above baseline,
indicating a synergistic interaction. Nearly identical results
were later reported in a study using intraperitoneal injections
of heroin and cocaine and their combination in rats
(Gerasimov and Dewey, 1999). The increased dopamine
levels found in the NAc in these investigations may be the
mechanism by which enhanced reinforcement, often
reported by human speedball users, is mediated (Tutton
and Crayton, 1993).
While preclinical evidence for the enhanced reward
hypothesis is increasing, there are also data suggesting
that opiates may act to reduce the negative side effects of
cocaine administration in human drug users (Foltin and
Fischman, 1992; Walsh et al., 1996). Indeed, dual actions
(i.e., positive and negative effects) of cocaine are well
established in both the animal and human literature
(Washton and Gold, 1984; Anthon et al., 1989; Cox et
al., 1986; Spotts and Shontz, 1984; Rogerio and
Takahashi, 1992; Simon et al., 1994; Yang et al., 1992;
Geist and Ettenberg, 1997; David et al., 2001a). In our
own laboratory, we have further shown that these dual
effects follow a temporal sequence consistent with the
opponent-process theory of drug action (Koob et al.,
1997; Solomon and Corbit, 1974). For example, we have
shown that while the immediate effects of IV cocaine are
positive and hence able to establish conditioned place
preferences, cocaine–place pairings that occur 15 min post
IV injection result in learned avoidance of the conditioned
environment (Ettenberg et al., 1999; Knackstedt et al.,
2002). These results suggest that while the immediate
consequences of cocaine administration are positive, the
effects present 15 min postinjection are negative. These
results are consistent with recent cocaine and heroin
pharmacokinetic findings. For example, Booze et al.
(1997) reported a distribution half-life (t
1/2a
)ofb1 min
for IV cocaine (1.0 mg/kg) in rats, while (t
1/2h
) was found
to be 13 min. Thus, while the initial positive effects of
cocaine (i.e., those producing conditioned place prefer-
ences) are associated with high levels of plasma cocaine,
the aversive effects (i.e., those producing conditioned
place aversions) are associated with dropping levels of
cocaine. In this context, the presence of heroin in a
speedball preparation may act to curtail the aversive
experience. Heroin has been reported to be rapidly
absorbed into the brain and then converted to morphine
very quickly upon reaching the brain (Inturrisi et al.,
1983; Oldendorf, 1978). Morphine, which is well estab-
lished to have anxiolytic actions (Motta and Brandao,
1993; Rex et al., 1998), has in turn been found to have an
elimination half-life (t
1/2h
) of 25.3 min following IV
administration in rats (Dahlstrom and Paalzow, 1978).
D. Guzman, A. Ettenberg / Pharmacology, Biochemistry and Behavior 79 (2004) 317–324322
Hence, at a point in time when cocaine’s negative
properties have been demonstrated to alter behavior (i.e.,
15 min post IV injection), morphine levels remain high
and hence able to counteract the aversive cocaine crash.
In summary, the present study was able to replicate our
previous findings showing that rats trained to traverse an
alley for IV cocaine reinforcement come to exhibit
increased levels of an approach–avoidance behavior as
trials proceed (Ettenberg and Geist, 1991; Geist and
Ettenberg, 1997). In the current study, the ambivalence
about entering a cocaine-associated goal box continued to
rise throughout the 3 weeks of daily runway testing. In
contrast, the addition of heroin to the self-administered
cocaine solution (speedball) truncated the further develop-
ment of retreat behaviors in the runway. These data are
consistent with the hypothesis that the net affective
response to cocaine is improved (i.e., less negative) when
heroin is added. As such, these results confirm the self-
report data provided by human bspeedballQusers in the
clinical literature (Tutton and Crayton, 1993; Foltin and
Fischman, 1992; Walsh et al., 1996).
References
Anthon JC, Tien AY, Petronis KR. Epidemiological evidence on cocaine
use and panic attacks. Am J Epidemiol 1989;129:543 – 9.
Bilsky EJ, Montegut MJ, Delong CL, Reid LD. Opioidergic modulation of
cocaine conditioned place preferences. Life Sci 1992;50(14):85 – 90.
Booze RM, Lehner AF, Wallace DR, Welch MA, Mactutus CF. Dose–
response cocaine pharmacokinetics and metabolite profile following
intravenous administration and arterial sampling in unanesthetized,
freely moving male rats. Neurotoxicol Teratol 1997;19(1):7 – 15.
Brown EE, Finaly JM, Wong JT, Damsma G, Fibiger HC. Behavioral and
neurochemical interactions between cocaine and buprenorphine: impli-
cations for the pharmacotherapy of cocaine abuse. J Pharmacol Exp
Ther 1990;256:119 – 25.
Cox BJ, Norton GR, Swinson RP, Endler NS. Substance abuse and
panic-related anxiety: a critical review. Behav Res Ther 1986;28:
385 – 393.
Dahlstrom BE, Paalzow L, 1978. In: Adler ML, Manara L, Samanin R,
editors. Factors affecting the action of narcotics. New York7Raven
Press; 1978. p. 233 – 48.
David V, Gold LH, Koob GF, Cazala P. Anxiogenic-like effects limit
rewarding effects of cocaine in BALB/cByJ mice. Neuropsychophar-
macology 2001a;24(3):300 – 18.
David V, Polis I, McDonald J, Gold LH. Intravenous self-adminis-
tration of heroin/cocaine combinations (speedball) using nose-poke
or lever-press operant responding in mice. Behav Pharmacol 2001b;
12:25 – 34.
Diaz T, Chu SY, Byers RH, Hersh BS, Conti L, Rietmeijer CA, et al. The
types of drugs used by HIV-infected injection drug users in a multistate
surveillance project: implications for intervention. Am J Public Health
1994;84(12):171 – 5.
Dolan MP, Black JL, Malow RM, Penk WE. Clinical differences among
cocaine, opioid, and speedball users in treatment. Psychol Addict Behav
1991;5(2):78 – 84.
Duvachelle CL, Sapoznik T, Kornetsky C. The synergistic effects of
combining cocaine and heroin (bspeedballQ) using a progressive-ratio
schedule of drug reinforcement. Pharmacol Biochem Behav 1998;
61(3):297 – 302.
Ettenberg A, Geist TD. Animal model for investigating the anxiogenic
effects of self-administered cocaine. Psychopharmacology (Berl)
1991;103(4):455 – 61.
Ettenberg A, Raven MA, Danluck DA, Necessary BD. Evidence for
opponent-process actions of intravenous cocaine. Pharmacol Biochem
Behav 1999;64(3):507 – 12.
Foltin RW, Fischman MW. The cardiovascular and subjective effects of
intravenous cocaine and morphine combinations in humans. J Pharma-
col Exp Ther 1992;261:623 – 32.
Frank B, Galea J. Cocaine trends and other drug trends in New York City,
1986–1994. J Addict Dis 1996;15(4):1 – 12.
Geist TD, Ettenberg A. A simple method for studying intravenous drug
reinforcement in a runway. Pharmacol Biochem Behav 1990;36:
703 – 6.
Geist TD, Ettenberg A. Concurrent positive and negative goal box events
produce runway behaviors comparable to those of cocaine-reinforced
rats. Pharmacol Biochem Behav 1997;57:145 – 50.
Gerasimov MR, Dewey SL. Gamma-vinyl GABA-aminobutyric acid
attenuates the synergistic elevations of nucleus accumbens dopamine
produced by cocaine/heroin (speedball) challenge. Eur J Pharmacol
1999;380:1 – 4.
Giros B, Jaber M, Jones SR. Hyperlocomotion and indifference to cocaine
and amphetamine in mice lacking the dopamine transporter. Nature
1996;379:606 – 12.
Grella CE, Anglin MD, Wugalter SE. Patterns and predictors of cocaine and
crack use by clients in standard and enhanced methadone maintenance
treatment. Am J Drug Alcohol Abuse 1997;23(1):15 – 42.
Hartell DM, Schoenbaum EF, Selwyn PA, Friedland GH, Klein RS,
Drucker E. Patterns of heroin, cocaine, and speedball injection among
Bronx (USA) methadone maintenance patients: 1978–1988. Addict Res
1996;3(4):323 – 40.
Hemby SE, Conchita CO, Dworkin SI, Smith JE. Synergistic elevations in
nucleus accumbens extracellular dopamine concentrations during self-
administration of cocaine/heroin combinations bspeedballQin rats.
J Pharmacol Exp Ther 1999;288:274 – 80.
Inturrisi CE, Schultz M, Shin S, Umans JG, Angel L, Simon EJ. Evidence
from opiate binding studies that heroin acts through its metabolites. Life
Sci 1983;33:773 – 6 [Supplement].
Johnson SW, North RA. Opioids excite dopamine neurons by hyper-
polarization of local interneurons. J Neurosci 1992;12:483 – 8.
Knackstedt LA, Samimi MM, Ettenberg A. Evidence for opponent-process
actions of intravenous cocaine and coacethylene. Pharmacol Biochem
Behav 2002;72(4):931 – 6.
Koob GF, Caine SB, Parsons L, Markou A, Weiss F. Opponent process
model and psychostimulant addiction. Pharmacol Biochem Behav
1997;57(3):513 – 21.
Leshner AJ, Koob GF. Drugs of abuse and the brain. Proc Assoc Am
Physicians 1999;111(2):99 – 108.
Malow RM, West JA, Corrigan SA, Pena JM, Lott WC. Cocaine and
speedball users: differences in psychopathology. J Subst Abuse Treat
1992;9:287 – 91.
Masukawa Y, Suzuki T, Misawa M. Differential modification of the
rewarding effects of methamphetamine and cocaine by opioids and
antihistimines. Psychopharmacology 1993;111(2):139– 43.
Mattox AJ, Thompson SS, Carroll ME. Smoked heroin and cocaine base
(speedball) combinations in rhesus monkeys. Exp Clin Psychopharma-
col 1997;5(2):113 – 8.
Mello NK, Negus SS, Mendelson JH, Sholar JW, Drieze J. A primate model
of polydrug abuse: cocaine and heroin combinations. J Pharmacol Exp
Ther 1995;274(3):1325 – 37.
Miller NE. Experimental studies of conflict. In: McHunt IV, editor.
Personality and the behavior disorders. New York7Ronald Press;
1994. p. 431 – 65.
Motta V, Brandao ML. Aversive and antiaversive effects of morphine in the
dorsal periaqueductal gray of rats submitted to the elevated plus-maze
test. Pharmacol Biochem Behav 1993;44(1):119– 25.
D. Guzman, A. Ettenberg / Pharmacology, Biochemistry and Behavior 79 (2004) 317–324 323
Oldendorf WH. In: Adler ML, Manara L, Samanin R, editors. Factors
affecting the action of narcotics. New York7Raven Press; 1978.
p. 221 – 31.
Ranaldi R, Munn E. Polydrug self-administration in rats: cocaine–heroin is
more rewarding than cocaine alone. NeuroReport 1998;9:2463 – 6.
Rex A, Voigt JP, Voits M, Fink H. Pharmacological evaluation of a
modified open-field test sensitive to anxiolytic drugs. Pharmacol
Biochem Behav 1998;59(3):677 – 93.
Rogerio R, Takahashi RN. Anxiogenic properties of cocaine in the rat
elevated pluz-maze. Pharmacol Biochem Behav 1992;43:631 – 3.
Rowlett JK, Woolverton WL. Self-administration of cocaine and heroin
combinations by rhesus monkeys responding under a progressive-ratio
schedule. Psychopharmacology 1997;133:363– 71.
Shutz CG, Vlahov D, Anthony JC, Graham NH. Comparison of self-
reported injection frequencies for past 30 days and 6 months among
intravenous drug users. J Clin Epidemiol 1994;47:191– 5.
Siegal HA, Carlson RG, Wang J, Falck RS, Stephans RC, Nelson ED.
Injection drug users in the Midwest: an epidemiological comparison
of drug use patterns in four Ohio cities. J Psychoact Drugs 1994;
26:265 – 75.
Simon P, Dupuis R, Costentin J. Thigmotaxis as an index of anxiety in
mice: influence of dopaminergic transmissions. Behav Brain Res
1994;61:59 – 64.
Solomon RL, Corbit JD. An opponent-process theory of motivation: 1
Temporal dynamics of affect. Psychol Rev 1974;81:119 – 45.
Spotts JV, Shontz FC. Drug-induced ego states: 1. Cocaine phenomenology
and implications. Int J Addict 1984;19:119 – 51.
Tutton CS, Crayton JW. Current pharmacotherapies for cocaine abuse: a
review. J Addict Dis 1993;12(2):109 – 27.
Walker BM, Ettenberg A. Benzodiazepine modulation of opiate reward.
Exp Clin Psychopharmacol 2001;9(2):191 – 7.
Walsh SL, Sullivan JT, Preston KL, Garner JE, Bigelow GE. Effects of
naltrexone on response to intravenous cocaine, hydromorphone and
their combination in humans. J Pharmacol Exp Ther 1996;279:
524 – 538.
Washton AM, Gold MS. Chronic cocaine abuse: evidence for adverse
effects on health and functioning. Psychiatr Ann 1984;14:733 – 43.
Yang XM, Gorman AL, Dunn AJ, Goeders NE. Anxiogenic effects of acute
and chronic cocaine administration: neurochemical and behavioral
studies. Pharmacol Biochem Behav 1992;41:643 – 50.
D. Guzman, A. Ettenberg / Pharmacology, Biochemistry and Behavior 79 (2004) 317–324324
