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Vol. 288, Issue 1, 274-280, January 1999
Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina
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Abstract |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The abuse of cocaine/opiate combinations (speedball) represents a growing trend in illicit drug use. Delineation of neurobiological substrates mediating the reinforcing effects of the combination may increase our knowledge of reinforcement mechanisms and provide useful new information for the development of pharmacotherapies. Several studies suggest dopaminergic innervations of the nucleus accumbens (NAc) have a central role in the brain processes underlying drug reinforcement. The present study was undertaken to determine the relationship between the self-administration of cocaine/heroin combinations and NAc extracellular dopamine concentrations ([DA]e) using in vivo microdialysis and microbore high-pressure liquid chromatography. Rats were assigned randomly to one of three groups to self-administer i.v. cocaine (125, 250, and 500 µg/infusion; n = 5), heroin (4.5, 9, and 18 µg/infusion; n = 5), or cocaine/heroin combinations (125/4.5; 250/9, and 500/18 µg/infusion; n = 4) under a fixed ratio (FR) 10: 20-s time-out schedule of reinforcement/multicomponent dosing session. After stable rates of responding were engendered and maintained, microdialysis samples were collected in 10-min intervals during the self-administration session. Self-administration of cocaine/heroin combinations produced synergisitic elevations in NAc [DA]e (1000% baseline) compared with cocaine (400% baseline) and heroin (not significantly different from baseline levels). Neither the number of infusions nor the interinfusion intervals was significantly different between the groups across the self-administration session. Moreover, cocaine concentrations were not significantly different between the cocaine and cocaine/heroin groups. These results demonstrate that heroin interacts with cocaine to produce synergistic elevations in [DA]e, providing a neurochemical basis for understanding the abuse liability of cocaine/opiate combinations.
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Introduction |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Users
of cocaine and opiate combinations (termed "speedball") represent a
growing subset of the drug abuse population (Greberman and Wada, 1994
).
In addition to the illicit use of cocaine/heroin combinations, several
studies report significant use of cocaine by patients in methadone and
levo-alpha-acetylmethadol (LAAM) maintenance treatment programs
(Dunteman et al., 1992; Schottenfeld et al., 1997). Despite the
prevalence of this problem, the underlying neurobiological substrates
mediating the effects of speedball have been understudied. Several
hypotheses have been set forth to explain the combined use of these
substances, including 1) enhancement of the positive effects of
either drug, 2) a reduction in the magnitude or duration of undesired
side effects; 3) production of a positive feeling or state not
available with either drug alone, or 4) nonadditive effects even though
the drugs are administered concurrently (Kosten et al., 1987; Foltin
and Fischman, 1992; Hemby et al., 1996). The hypothesis of
enhanced euphorigenic effects is paralleled in preclinical studies,
demonstrating that cocaine and heroin potentiate the reinforcing
effects of one another in the self-administration paradigm (Mattox et
al., 1997; Rowlett and Woolverton 1997). The question remains as to the
neurobiological substrates mediating the reinforcing effects of
cocaine/heroin combinations.
The mesolimbic dopamine system is a critical substrate for the
reinforcing effects of drugs of abuse (Wise and Bozarth, 1987). Administration of abused drugs appears to activate this pathway and
stimulate dopamine neurotransmission in the nucleus accumbens (NAc) in
humans, nonhuman primates, and rodents (Porrino, 1993; Lyons et al.,
1996; Volkow et al., 1997), an effect associated with the abuse
liability of these substances (Koob and Bloom, 1988). However, a
growing body of literature suggests that the reinforcing effects of
cocaine are mediated by dopamine, whereas opiate receptors mediate the
reinforcing effects of heroin and morphine (see for review, Koob and
Bloom, 1988; Hemby et al., 1997b). For example, several laboratories
have demonstrated that NAc extracellular dopamine concentration
([DA]e) is elevated during cocaine
self-administration sessions in rodents as measured by in vivo
microdialysis (Pettit and Justice, 1989; 1991; Wise et al., 1995b;
Hemby et al., 1997a). The in vivo neurochemical data are complemented
by numerous studies demonstrating that dopamine receptor antagonists
increase responding maintained by high-unit doses of cocaine
under fixed ratio (FR) schedules of reinforcement, effects that are
interpreted generally as an attenuation of the reinforcing effects of
the drug. In contrast, administration of dopamine antagonists does not
affect heroin self-administration (see for review, Hemby et al.,
1997b). The lack of direct dopaminergic involvement in heroin
self-administration is complimented by a recent study demonstrating
that NAc [DA]e was not
elevated during heroin self-administration sessions (Hemby et al.,
1995). Summarily, these studies indicate that cocaine and heroin
self-administration are mediated by dopamine-dependent and
dopamine-independent mechanisms, respectively. Interestingly, Brown et
al. (1991) have reported that acute experimenter-administered
combinations of cocaine and buprenorphine (opiate receptor mixed
agonist/antagonist) produced synergistic elevations in NAc
[DA]e. These results suggest that coadministration of cocaine and heroin may produce similar effects, although the involvement of NAc dopamine in the reinforcing effects of
the cocaine/heroin combinations has not been determined to date.
The suggested role of dopamine neurons in drug reinforcement, combined with the reported increase in euphorigenic effects of cocaine/heroin combinations reported by humans suggests involvement of NAc [DA]e in cocaine/heroin self-administration. The authors hypothesize that the potentiated euphorigenic effects in humans and the corresponding potentiation of reinforcing effects in animal models are based on an augmented neurochemical response in brain pathways underlying reinforcement processes. To this end, the effect of i.v. self-administered cocaine, heroin, and cocaine/heroin combinations were examined in [DA]e and cocaine concentrations ([COC]) in the NAc of the rat using in vivo microdialysis.
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Materials and Methods |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Subjects and Surgical Procedures. Male Fisher F-344 rats (90-150 days; 275-350 g; SASCO, Lincoln, NE) were housed individually in acrylic cages in a temperature-controlled vivarium on a 12-h reversed light/dark cycle (lights on: 5:00 PM.) with food and water available ad libitum, except during experimental sessions. Self-administrations occurred during the dark phase of the cycle.
Rats were pretreated with atropine sulfate (10 mg/kg, i.p.), and anesthesia was induced by administration of sodium pentobarbital (Nembutal, 40 mg/kg, i.p.). While anesthetized, rats were implanted with chronic indwelling venous catheters followed by implantation of guide cannulas, as described previously (Hemby et al., 1995; 1997a).
The catheter was implanted into the right jugular vein to extend to the
right atrium and was anchored to surrounding muscle. The opposite end
of the catheter was guided s.c. to the back and threaded through a
plastic oval backplate residing above the scapulae. The skin was
sutured over the backplate. Two Teflon screws attached the backplate to
a shoulder harness, which was attached to a spring leash. The catheter
was threaded through the shoulder harness and spring leash and was
connected to a single fluid channel swivel. Following catheter
implantation, rats were secured in a Kopf stereotaxic frame (David Kopf
Instruments, Tujunga, CA) and implanted unilaterally with
20-gauge (Plastics One Inc., Roanoke, VA) stainless steel guide
cannulas, with the side of placement counter-balanced within groups.
Cannula tips were aimed for the dorsal surface of the NAc (+9.5 mm from
, ±1.3 mm lateral from the midline, and 
5.0 mm ventral from dura;
König and Klippel, 1974). Guide cannulas were secured with skull
screws and dental acrylic cement; obturators (28 gauge; Plastics One
Inc.), cut flush with the bottom of the cannulas, and inserted to
prevent blockage. Penicillin G procaine (75,000 U/0.25 ml, i.m.) was
administered immediately after surgery. After surgery, rats were
transferred immediately to their respective home cages where they
received hourly infusions of heparinized saline (1.7 U/ml, 200 µl/h)
to maintain functional catheters. Infusions of methohexital (100 µl,
10 mg/kg, i.v.) were administered as needed to assess catheter patency.
The health of the rats was monitored daily by the experimenter and
weekly by institutional veterinarians according to the guidelines issued by the Bowman Gray Animal Care and Use Committee and by the
National Institutes of Health.
Self-Administration. For self-administration sessions, rats were transferred to operant-conditioning chambers that were enclosed in sound-attenuated chambers containing an exhaust fan, an 8-ohm speaker, a tone source, a house light, and a 20-ml syringe pump attached to the outside. Extraneous noise was masked by the exhaust fan and by white noise delivered continually through the speaker. The front panel of the operant chamber contained a fixed lever centered between the side panels and positioned 2.5 cm above the floor; a cue light was located 6 cm above the lever. Levers required approximately 0.25 N to operate, and the cue light was covered with red translucent cover. A counterbalanced arm containing a single-channel liquid swivel was located 8.5 cm above the chamber and attached to the outside of the front panel. IBM-compatible computers were used for session programming and data collection (Med Associates, Inc., East Farfield, VT).
Rats were assigned randomly to groups to self-administer cocaine, heroin, or cocaine/heroin combinations. Responding was engendered under a FR 1: time-out (TO) 20-s schedule of three 1-h components. The ratio was gradually increased to 10. Subjects were allowed to self-administer cocaine i.v. (125, 250, and 500 µg/infusion; n = 5), heroin (4.5, 9, and 18 µg/infusion; n = 5), or cocaine/heroin combinations (cocaine/heroin: 125/4.5, 250/9.0, and 500/18 µg/infusion; n = 4). Each dose was available during a different component, and doses were presented in ascending order. The infusion volume for the first component was 50 µl infused over 1.4 s, and the volumes for the successive components were 100 µl for component two (infused over 2.8 s) and 200 µl for component three (infused over 5.6 s). Before each component, a 10-min blackout was followed by a priming infusion of the dose to be administered in the succeeding component. After an additional 10-min blackout period, the lever was activated, and the cue light above the lever was illuminated. Upon completion of the response requirement, a drug infusion was delivered, the lever light extinguished, a tone was generated, and the house light was illuminated. During the 20-s TO after the infusion, responses on the lever were recorded but had no scheduled consequence. A minimum of 10 days of stable responding (less than 10% variation in the number of infusions) at FR10 in all components was required before microdialysis procedures were initiated.In Vivo Microdialysis and High-Pressure Liquid Chromatography
(HPLC) Procedures.
The microdialysis procedures and probe
construction have been described previously (Hemby et al., 1995;
1997a). Briefly, two pieces of fused silica were inserted into 6 mm of
regenerated cellulose membrane (250 µm o.d., 5000 mol wt
cutoff; Spectra/Por, Los Angeles, CA). For the present experiment, the
active portion of the probes was 2 mm, defined by the distance between
the ends of the fused silica. The inlet silica line was connected to a syringe filled with artificial cerebrospinal fluid, which was used as
the perfusion medium. This artificial cerebrospinal fluid perfusate
consisted of 145 mM NaCl, 1.2 mM CaCl2, 2.8 mM KCl, 1.2 mM
MgCl2, 5.4 mM D-glucose, and 1.25 mM
NaH2PO4 (pH = 7.2).
80°C until analysis.
Three microliters of the sample was assayed for dopamine using
microbore HPLC with electrochemical detection, while the remaining 3 µl was assayed for cocaine using microbore HPLC with ultraviolet detection. The HPLC for dopamine analysis consisted of a syringe pump
(model LC-260D; Isco, Lincoln, NE), an air-actuated injection valve
(model ACI4UW; Valco Instruments, Houston, TX), with a 1.0-µl sample
loop, a Spherisorb microbore column (0.5 mm i.d. × 100 mm, 5 µm
C18 silica), a dual glassy carbon working
electrode (model PM; EG&G Princeton Applied Research, Princeton, NJ), a
reference electrode (RE-1; Bioanalytical Systems Inc., West Lafayette,
IN), and an electrochemical detector (model 400; EG&G Princeton Applied Research). Columns were packed in the laboratory with silica purchased from Phase Separations, Inc. (Norwalk, CT). The applied potential was
+700 mV as referenced to Ag/AgCl. The mobile phase consisted of 27.2 mM
sodium phosphate-monobasic, 10% v/v methanol, 4.9 mM triethylamine, 13 mM disodium-EDTA, and 0.99 mM sodium octyl sulfate, with the pH
adjusted to 5.75 with 0.1 N phosphoric acid. The flow rate of the
mobile phase was 10 to 12 µl/min, and the detection limit for
dopamine was 100 pM. Quantification of dopamine was achieved by
comparing samples with standards of known concentration. The HPLC for
cocaine analysis consisted of a HPLC pump (model 222D; Scientific
Systems, Inc., State College, PA) adapted for microbore use, a Rheodyne
injection valve (model 7520; Rohnert Park, CA) with a 0.5-µl
sample loop, a Spherisorb microbore column (0.5 mm i.d. × 100 mm, 3 µm C18), and an analytical variable
wavelength detector (model 3200, Thermo Instruments, Inc., Riveria
Beach, FL) customized for microbore chromatography. The wavelength was 235 nm, and the absorbance was 0.0001, full scale. The mobile phase
consisted of 50 mM sodium phosphate monobasic, 10 mM triethylamine, 17% acetonitrile, and 10% methanol, with the pH adjusted to 5.6 with
a flow rate of 25 µl/min. The detection limit for cocaine was 200 nM.
Quantification of cocaine was achieved by comparing samples with
standards of known concentration.
Histology. Verification of guide cannula tracts and assessment of gliosis at the probe site were determined in all subjects. Brains were removed, and coronal stions (20 µm) were taken from 100 µm rostral to 100 µm caudal to the cannula tract. Sections were fixed in 4% paraformaldehyde and stained with cresylecht violet. Probe placements were verified by light microscopy in a "blind" manner to reduce experimenter bias of the results. Probe placements were within the NAc for all subjects in this study (Fig. 1).
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Drugs. Cocaine HCl and heroin HCl were kindly provided by the National Institute on Drug Abuse. Atropine sulfate was purchased from Sigma Chemical Co. (St. Louis, MO), sodium pentobarbital was purchased from Abbott Laboratories (North Chicago, IL), penicillin G procaine was purchased from Butler Company (Columbus, OH), and methohexital was purchased from Eli Lilly and Company (Indianapolis, IN). Cocaine doses are expressed as the weight of the salt, whereas heroin doses are expressed as the weight of the free base. Cocaine and heroin were dissolved in heparinized 0.9% saline.
Data Analysis. Behavioral and microdialysis data were analyzed using a two-way repeated measures analysis of variance (ANOVA) with group and dose as the fixed effects and time as the repeated measure. For behavioral analysis, dependent measures included the number of infusions, interinfusion interval, postreinforcement pause (time elapsed between the end of the 20-s TO and the first response of the next ratio), latency to the first reinforcer of each component, and ratio run time (time elapsed between the first and last response of the ratio). [DA]e and [COC] were the dependent measures for the microdialysis data. Post hoc analyses were conducted as needed using Fisher's least significant difference test. The null hypothesis was rejected when P < .05.
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Baseline [DA]e
A schematic representation of probe placements from subjects included in this experiment is shown in Fig. 1. Histological examination revealed that probe placements for all subjects were located in the NAc, medial to the anterior commissure. Baseline values of dopamine were assessed in each subject by collecting three samples before the beginning of the self-administration session. All subsequent samples were expressed as the mean (±S.E.M.) of the percent variation of the mean baseline value. There were no statistically significant differences in baseline [DA]e between the groups (cocaine: 7.4 ± 2.5 nM; heroin: 7.7 ± 1.1 nM; cocaine/heroin: 9.3 ± 1.7 nM).
Self-Administration
Behavioral Data.
The selected doses of cocaine, heroin, and
cocaine/heroin combinations engendered and maintained rates and
patterns of responding typically observed under FR schedules of
reinforcement (Fig. 2; Hemby et al.,
1995, 1996). The dose-effect curves (number of infusions and
interinfusion intervals) for the groups self-administering cocaine and
heroin were not significantly different from the group self-administering cocaine/heroin combinations (Fig.
3). However, for both measures, there was
significant main effect of dose [infusions: F(2,22)=26.13,
P < .001; interinfusion interval: F(2,22)=36.34, P < .001]. There was a significant dose-dependent
effect on the number of infusions for cocaine [F(2,12)=7.32;
P < .009], heroin [F(2,12)=4.10;
P < .045], and cocaine/heroin combinations
[F(2,9)=24.39; P < .001]. The number of
infusions was inversely proportional to the dose
self-administered in all groups, characteristic of the
descending limb of the dose-effect function. In contrast, interinfusion
intervals were related linearly to the self-administered dose(s) for
the cocaine [F(2,12)=16.9; P < .001] and
cocaine/heroin groups [F(2,9)=122.95; P < .001].
For postreinforcement pause, timed from the end of the TO period
following each infusion until the first response of the subsequent
ratio, there was a significant main effect of drug [F(2,10)=5.89,
P < .025] and dose [F(2,20)=91.51, P < .001] as well as a significant drug × dose interaction [F(4,20)=6.68, P < .0015].
Postreinforcement pauses were linearly related to dose(s) for the
cocaine (109.1 ± 34.9, 264.3 ± 24.8, 543.3 ± 17.0 s for 125, 250 and 500 µg/infusion; [F(2,12)=68.56,
P < .001]) and cocaine/heroin groups (144.8 ± 16.0, 397.0 ± 17.3, 636.7 ± 35.4 s for 125/4.5;
250/9.0 and 500/18.0 µg/infusion; [F(2,9)=100.32, P < .001], indicating that the initiation of
responding after each infusion was dependent on the dose infused. In
addition, there was a significant main effect of dose on latency to the first reinforcer [F(2,22)=3.55, P < .047] where
the cocaine group exhibited the only significant dose-dependent effect
[F(2,12)=4.89, P < .03]. There was no
significant effect on ratio run-time, measured as the elapsed time
between the first and last response of the ratio, in any of the groups
tested. These data indicate that responding, once initiated, was not
differentially altered by the three doses investigated in each group.
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Microdialysis Data. NAc [DA]e were significantly different between all groups (Fig. 4, top panel) for the self-administration session [F(2,330)=16.61, P < .001]. In addition, there was a significant drug X dose interaction[F(60,330)=11.3, P < .001]. Post hoc analyses revealed significant differences between all groups; however, there were no significant differences in [DA]e between doses of the same drug. Self-administration of all of the cocaine/heroin combinations tested resulted in a greater than 2-fold increase in NAc [DA]e compared with cocaine alone and a greater than additive effect for the individual doses of cocaine and heroin combined. Both cocaine/heroin combinations and cocaine produced consistent large elevations in [DA]e compared with no change for heroin. NAc [DA]e were elevated approximately 1000% of baseline in the cocaine/heroin combination group and approximately 400% of baseline in the cocaine group, whereas [DA]e were not significantly different from baseline levels during the heroin self-administration session. Elevations observed in the cocaine/heroin and cocaine groups were sustained throughout the self-administration session and there were no significant differences between components for either group. During the hour following the end of the self-administration session, [DA]e declined from 1000% to approximately 200% for the cocaine/heroin group and from 400% to approximately 100% of baseline for the cocaine group.
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Dopaminergic projections to the NAc are known to play an important
role in the reinforcing effects of abused drugs (Wise and Bozarth,
1987). The present study was undertaken to compare in vivo changes in
NAc [DA]e during self-administration sessions of cocaine, heroin, and cocaine/heroin combinations.
Self-administration of cocaine and cocaine/heroin combinations produced
substantial elevations in NAc [DA]e during the
self-administration session that were paralleled by similar elevations
in [COC] in the groups self-administering cocaine and cocaine/heroin
combinations. Differences in [DA]e between the
cocaine and cocaine/heroin groups can not be attributed to alterations
in the bioavailability of cocaine since the [COC] were not
significantly different between the two groups. This point is supported
by a previous study in humans which reported that the disposition of
cocaine or morphine was not affected by the presence of the other drug
(Foltin and Fishman, 1992). To our knowledge, this is the first
published report on in vivo neurochemical changes during the
self-administration of cocaine/opiate combinations and the first report
of synergisitic elevations in NAc [DA]e for
self-administered illicit drug combinations. The results from the
cocaine self-administration session confirm previous studies (Pettit
and Justice, 1989, 1991; Wise et al., 1995b; Hemby et al., 1997a) and
extend them by demonstrating elevations in
[DA]e for multiple doses of the drug presented
in the same session. In contrast, heroin self-administration failed to
significantly alter NAc [DA]e at the doses
tested, in confirmation of a previous study (Hemby et al., 1995). It
should be noted that the selected doses of heroin were shown to
reliably engender and maintain responding under the present
experimental conditions. These results obtained in the present study
are inconsistent with the hypothesis proposed by Wise and Bozarth
(1987). Mounting evidence suggests the reinforcing effects of opiates
are mediated by opiate receptors postsynaptic to dopamine terminals in
the NAc (Van Ree and Ramsey, 1987; Hemby et al., 1997b). The present
results demonstrate that self-administered heroin and cocaine interact
in a synergistic manner to elevate NAc [DA]e.
The neurochemical data from cocaine and cocaine/heroin combination
self-administration sessions support a substantial body of
pharmacological data indicating a role for dopamine in drug reinforcement (see for review, Hemby et al., 1997b). Systemic and
central administration of selective dopamine receptor antagonists increase rates of cocaine self-administration maintained under FR
schedules of reinforcement and decrease break points under progressive
ratio schedules, indicative of a decrease in the reinforcing effects of
cocaine. Similarly, selective destruction of presynaptic dopamine
terminals in the NAc produce extinction-like responding in rats trained
to self-administer cocaine (Roberts et al., 1980; Pettit et al., 1984).
The pharmacological relevance of the synergistic elevations in
[DA]e observed in the present study is offered
by a recent study in which pretreatment with the D2 receptor-selective antagonist eticlopride increased the self-administration of
cocaine/heroin combinations (Hemby et al., 1996). Eticlopride exerted
similar effects on cocaine self-administration but was not effective in altering heroin self-administration. In contrast, naltrexone
pretreatment increased cocaine/heroin and heroin self-administration,
but had no effect on cocaine self-administration. The increase in
self-administration after antagonist administration is considered a
compensatory response to the receptor antagonism, such that more drug
is available to compete with the antagonist at the receptor. These data
indicate that the self-administration of cocaine/heroin combinations is dependent on both dopamine and opiate receptor mechanisms.
The lack of change in NAc [DA]e during the
heroin self-administration confirms a previous study from our
laboratory (Hemby et al., 1995). This finding is supported by other
studies demonstrating that pharmacological and neurochemical
manipulations that alter the functional integrity of the mesolimbic
dopamine pathway do not affect the acquisition or maintenance of opiate
self-administration (Pettit et al., 1984, Gerrits and Van Ree, 1996).
Furthermore, several studies have shown that heroin self-administration
in rats is not altered by systemic (Ettenberg et al., 1982; Van Ree and
Ramsey, 1987; Hemby et al., 1996) or intra-NAc (Van Ree and Ramsey,
1987) administration of dopamine receptor antagonists. The reinforcing
effects of heroin appear to be mediated by opiate receptors in the NAc,
inasmuch as intra-NAc administration of either opiate receptor
antagonists (Koob et al., 1984; Corrigall and Vaccarino, 1988) or
agents that produce excitotoxic lesions (Zito et al., 1985) alter i.v.
heroin self-administration in a manner consistent with this premise.
Collectively, these results support the hypothesis that heroin
self-administration is mediated in a dopamine-independent manner. In
contrast to the present findings, one group has reported NAc
[DA]e to be increased during heroin self-administration sessions (Kiyatkin et al., 1993; Wise et al., 1995a). However, the differences between these studies are probably due
to a number of contributing factors, including analytical procedures,
self-administration procedures, and behavioral histories of the rats
(see for review, Hemby et al., 1997b). As previously discussed, a
significant volume of pharmacological data support the present
neurochemical data on heroin self-administration and indicate
that opiate reinforcement is mediated in a dopamine-independent manner.
In light of the contrasting effects of cocaine and heroin
self-administration on [DA]e,
self-administration of cocaine/heroin combinations produced synergistic
elevations in [DA]e. However, the question
remains as to the functional significance of the observed elevation.
The neurochemical effects could arguably be ascribed to the reinforcing
effects of the combination or to increased general motor activity.
Overt behavioral changes, such as increased motor activation or
stereotypy, were not observed in the cocaine/heroin combination group
compared with the cocaine and heroin groups. Similarly, there was no
evidence of differences in measures of operant responding (responding
during the time-out period after infusions, the amount of time required
to complete the ratio, the latency to the first response after an
infusion, etc.). Therefore, the elevated [DA]e
observed during the cocaine/heroin self-administration did not produce
significant differences in the behavioral effects of cocaine or heroin
alone. Under the present experimental procedures, combined doses of
cocaine and heroin did not produce changes in the total number of
infusions obtained or in the pattern of responding compared with the
doses of cocaine and heroin alone. Previously, the authors and others
have reported a leftward shift in the dose-effect function when cocaine
and heroin were combined (Hemby et al., 1996; Rowlett and Woolverton,
1997), suggesting that the cocaine/heroin combinations were more potent
than either drug alone. The difference in the present results and those
published previously (Hemby et al., 1996) is probably due to the manner
in which responding was engendered and/or the dose combinations chosen
to be studied in the respective experiments. Experiments have been
initiated to further test the hypothesis that relative reinforcing
efficacy and/or potency is greater for the combination than for either drug alone (e.g., progressive ratio schedules and choice procedures).
Due to the paucity of pharmacological data on cocaine/heroin
self-administration, the apparent mechanism by which heroin augments the dopaminergic response of cocaine remains unclear. The
administration of cocaine decreases whereas morphine increases the
firing rate of mesolimbic dopaminergic neurons (Matthews and German,
1984; Einhorn et al., 1988). Cocaine inhibits the reuptake of dopamine, resulting in increased extracellular concentrations (Harris and Baldessarini, 1973). In turn, elevated dopamine levels activate autoreceptors on the dopamine cell bodies, leading to hyperpolarization and decreased cell firing (Aghajanian and Bunney, 1974). In contrast, heroin activates µ opiate receptors on 
-aminobutyric acid
(GABA) interneurons in the ventral tegmental area,
resulting in hyperpolarization of these neurons and a concomitant
disinhibition of dopamine cell firing (Johnson and North, 1992).
Increased dopaminergic cell firing results in increased uptake, a
voltage-dependent process which occurs during the repolarization phase
of the action potential (Rudnick and Clark, 1993). The synergistic
effect of cocaine/heroin combinations on NAc
[DA]e could result from the increased firing of
dopamine neurons by opiates and the direct effect of cocaine on
dopamine reuptake. However, the lack of significant increase in
[DA]e during heroin self-administration alone
suggests that the synergy is not additive and that the specific
mechanism requires further investigation. The neurochemical synergy is
significant as the magnitude of such elevations in
[DA]e cannot be obtained with cocaine alone
with the procedures used, without inducing significant seizure
activity. Further studies are warranted to determine the physiological
and pharmacological bases of the synergistic neurochemical effect of
cocaine/heroin self-administration.
The present result that cocaine and heroin interact to produce a
synergistic effect on a neurotransmitter relevant to reinforcement provides a neurochemical basis to support the hypothesis that the
combination of cocaine and heroin produce an effect not available with
either drug alone. The relationship of the synergisitic elevations in
NAc [DA]e to alterations in the reinforcing
efficacy/potency of the combination remains to be studied. The present
data also suggest a neurochemical basis for the significant incidence
of cocaine use among individuals in methadone or LAAM maintenance programs (Dunteman et al., 1992; Schottenfeld et al., 1997). The development of pharmacological adjuncts for substance abuse treatment is based primarily on a fundamental understanding of the
neuropharmacological and neurochemical basis of the subjective and
reinforcing effects. Improved pharmacological treatments for clinical
intervention of cocaine/heroin combination abuse may result from
increased understanding of the neurobiological substrates mediating the behavioral effects of the drug combination.
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Acknowledgments |
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We appreciate the comments and suggestions of Charles O'Brien, Gary Aston-Jones, Sam Deadwyler, and Linda Porrino in the preparation of the manuscript.
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Footnotes |
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Accepted for publication August 13, 1998.
Received for publication May 14, 1998.
1 This research was supported in part by the U.S. Public Health Service Research Grants DA-06634, DA-00114, and DA-03628. Parts of this study were presented at the College on Problems of Drug Dependence, 1995.
Send reprint requests to: Dr. Scott E. Hemby, Yerkes Regional Primate Research Center, Department of Pharmacology, 95113 Rolling Research Center, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322. E-mail: hemby{at}pharm.med.upenn.edu
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Abbreviations |
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[DA]e, extracellular dopamine concentrations; NAc, nucleus accumbens; [COC], cocaine concentrations; FR, fixed ratio; ANOVA, analysis of variance; TO, time-out.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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), heroin (
), and
cocaine/heroin combinations (
) on [DA]e (top panel)
and [COC] (bottom panel) in the NAc during self-administration
sessions. Data are expressed as mean percentage of baseline
[DA]e ± S.E.M. and mean [COC] ± S.E.M. Samples were
collected in 10-min intervals. The first three filled circles in the
top panel represent baseline [DA]e samples collected
before the self-administration session. Each 1-h component was preceded
by a 10-min blackout period, an infusion of the dose available in the
subsequent session, and another 10-min blackout period (vertical gray
bars). After collection of the sixth sample in the final component, the
response lever was retracted, and the response lever light was
extinguished. Samples were collected for an additional 60 min (open
symbols). Note the fifth and sixth [COC] samples for the
cocaine/heroin group were below the limit of detection. There was a
significant main effect of Drug on [DA]e for the session
F(2,330) = 16.61, P = .0005, and a significant
interaction of drug over time F(60,330)=11.3, P < .0001. Post hoc analyses revealed significant differences between all
groups (P < .05). However, there was no
significant difference in [COC] between the two groups during or
after the self-administration session.