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Vol. 286, Issue 1, 61-69, July 1998
Department of Psychiatry and Human Behavior (J.K.R, K.M.W, W.L.W.), Department of Pharmacology and Toxicology (K.M.W., W.L.W.), University of Mississippi Medical Center, Jackson, Mississippi
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Abstract |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Low, nonreinforcing doses of heroin have been shown to shift the dose-response function of cocaine leftward in rhesus monkeys trained under a progressive-ratio schedule of i.v. drug injection. Our study sought to determine 1) whether a reciprocal enhancement of heroin self-administration would be observed when heroin was combined with low, nonreinforcing doses of cocaine, and 2) whether self-administration of cocaine-heroin combinations could be antagonized by the opioid antagonist naltrexone. Rhesus monkeys (n = 4) were prepared with i.v. catheters and trained to self-administer cocaine under a progressive-ratio schedule. The initial response requirement of this schedule was fixed-ratio 120, which doubled across the session to a maximum of 1920. Injections were separated by a 30-min time out. Cocaine dose-response functions (6.4-100 µg/kg/injection) for injections/session and breakpoints were monophasic, i.e., increased with dose until responding reached a maximum. Heroin dose-response functions (1.6-25 µg/kg/injection) either increased to a peak and then decreased or reached an asymptote. When nonreinforcing doses of cocaine (3.2-25 µg/kg/injection) were combined with heroin, the heroin dose-response function was shifted to the left, without change in maximum injections/session. Presession treatments with naltrexone (3.2-1600 µg/kg, i.m., 10-min presession) antagonized self-administration of heroin and heroin + cocaine combinations in a dose-dependent fashion. However, naltrexone treatment had no effect on cocaine self-administration. Antagonism by naltrexone of self-administration of heroin and heroin + cocaine was surmounted by increasing the dose of heroin either alone or in the heroin + cocaine combination. In vivo apparent pA2 and pKB analyses of these data revealed values of approximately 8.0, consistent with a role for mu opioid receptors in the self-administration of heroin and cocaineheroin (i.e., "speedball") combinations.
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Introduction |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Many polydrug
abusers inject cocaine in combination with heroin by mixing the drugs
in solution and injecting them simultaneously. This combination is
referred to as a "speedball," and the abuse of speedballs has
increased worldwide along with the rise in cocaine and heroin abuse
(Darke and Hall, 1995
; Frank and Galea, 1996). In the United States,
recent epidemiological findings show that up to 92% of heroin abusers
also inject cocaine (Office of National Drug Control Policy, 1997).
Clinical observations have revealed that speedball abuse is associated
with a higher incidence of psychopathology and a greater risk for
contracting AIDS than either cocaine or heroin abuse alone (Battjes
et al., 1994; Meandzija et al., 1994; Brooner
et al., 1997).
Despite the prevalence and detrimental consequences of speedball abuse,
relatively little is known concerning the pharmacological mechanisms
underlying this form of polydrug abuse. Mechanisms that have been
advanced to account for combined cocaine-opioid abuse have been based
primarily on anecdotal observations from polydrug abusers, and include
mutual enhancement of effects of the individual drugs or reduction in
aversive effects of the drugs when combined (Tutton and Crayton, 1993).
Empirically based hypotheses have been developed from recent controlled
clinical studies evaluating the subjective effects of cocaine in
combination with mu opioid agonists. The subjective effects
of various dose combinations of cocaine and mu agonists were
greater than those produced by either drug alone on key measures, such
as positive ratings of "drug liking" and "high"
(e.g., Foltin and Fischman, 1992; Walsh et al.,
1996). Consistent with these findings, results with drug discrimination
procedures, generally considered to be predictive of subjective effects
in people, have shown that morphine and similar drugs can enhance the
discriminative stimulus effects of cocaine in monkeys and rats
(Spealman and Bergman, 1992, 1994; Suzuki et al., 1997; but
see Broadbent et al., 1995). Taken together, these findings
suggest that administration of mu agonists enhance the
subjective and discriminative stimulus effects of cocaine, which in
turn may play a role in the high prevalence of speedball abuse.
A preclinical approach for studying self-administration of
cocaine-opioid combinations is to mimic the typical pattern of speedball abuse by people, who characteristically mix the two drugs and
inject them i.v. Using this approach, Rowlett and Woolverton (1997)
demonstrated a leftward shift in the dose-response function of cocaine
when combined with relatively low, nonreinforcing doses of heroin in
monkeys trained under a PR schedule of i.v. drug injection. In another
study, Mello et al. (1995) demonstrated that combination of
relatively high heroin doses with lower, nonreinforcing doses of
cocaine resulted in an increase in self-administration. Both Mello
et al. (1995) and Hemby et al. (1996), however,
demonstrated that self-administration of higher dose combinations of
cocaine and heroin was reduced relative to cocaine alone. Collectively, the results of these studies suggest that combining cocaine and heroin
results in an enhancement of self-administration relative to the
component drugs alone, at least when relatively low doses are combined,
probably via enhanced reinforcing effects.
Preclinical characterization of the abuse-related effects of
cocaine-opioid combinations should allow collection of meaningful data
regarding the understanding of the pharmacological basis of speedball
abuse. A useful method for investigating pharmacological mechanisms
underlying behavioral effects is to conduct antagonism studies (see
Mello and Negus, 1996, for review). Few studies have assessed
antagonism of the abuse-related effects of cocaine-opioid combinations.
Recently, Walsh et al. (1996) examined the ability of the
general opioid antagonist naltrexone to attenuate subjective effects of
cocaine-hydromorphone combinations. Naltrexone blocked the subjective
effects of hydromorphone, but not cocaine, and attenuated
hydromorphone-induced enhancement of cocaine's effects (Walsh et
al., 1996). Regarding self-administration of speedballs, Hemby
et al. (1996) demonstrated a reduction of heroin-induced changes in cocaine self-administration by naltrexone. As mentioned, however, cocaine-heroin interactions were studied at relatively high
doses that resulted in decreased self-administration compared to the
constituent drugs alone. At this time, the extent to which opioid
receptors are involved in the self-administration of low dose
cocaine-heroin combinations in which self-administration is enhanced is
not known. In addition, no studies have included quantitative analysis
of naltrexone antagonism (i.e., in vivo apparent
pA2 analysis) to determine the possible
involvement of mu vs. other subtypes of opioid
receptors.
Because our earlier experiments revealed an enhancement of cocaine
self-administration by otherwise inactive doses of heroin (Rowlett and
Woolverton, 1997), the present study sought to extend this finding by
determining whether a reciprocal enhancement of heroin
self-administration would result when combined with ineffective doses
of cocaine. The role of opioid receptors in the self-administration of
cocaine-heroin combinations was assessed by conducting antagonism studies with the opioid receptor blocker naltrexone. The present experiments extended the results of Hemby et al. (1996) by
evaluating low instead of high dose combinations and by quantitatively
assessing the role of opioid receptor subtypes by use of in
vivo apparent pA2/pKB
analyses (cf., Negus et al., 1993). A PR schedule
of drug injection similar to the one used by Rowlett and Woolverton
(1997) was used, which allowed examination of potential changes in the relative reinforcing potency (lateral shifts in dose-response functions) and reinforcing efficacy (maximum responding maintained by a
drug) of heroin after combination with cocaine and/or naltrexone (Rowlett et al., 1996; Rowlett and Woolverton, 1997).
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Materials and Methods |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Animals and apparatus.
Subjects were one adult female
(monkey 11084) and three adult male (monkeys RIk2, 9002, AP13) rhesus
monkeys (Macaca mulatta) with body weights between 6.1 and
12 kg during the course of the experiments. One monkey (AP13) was
experimentally naïve at the beginning of the studies. Monkeys
RIk2 and 9002 participated in the previous study involving
self-administration of cocaine and heroin combinations (Rowlett and
Woolverton, 1997), whereas monkey 11084 had a history of
self-administration of i.v. cocaine and selective D1 dopamine agonists
under a fixed-ratio schedule. For the present experiments, each monkey
was fitted with a stainless-steel restraint harness and tether which
was attached to the rear of an experimental cubicle (90 cm wide × 90 cm deep × 90 cm high) in which the monkey lived for the
duration of the studies. Two response levers (BRS/LVE, PRL-001,
Beltsville, MD) were mounted on the inside of the transparent front of
each cubicle, 10 cm above the floor. Four jeweled stimulus lights, two
red and two white, were mounted directly above each lever. Drug
injections were delivered by a peristaltic infusion pump (Cole-Parmer
Co., Chicago, IL) located outside the cubicle. All programming and recording of experimental events was accomplished using a Macintosh II
computer and associated interfaces located in an adjacent room. Water
was available continuously and each monkey was fed, between 7:00 and
7:30 A.M. each morning, a sufficient amount of monkey chow
(Ralston-Purina Co., St. Louis, MO), fresh fruit and vegetables to
maintain a stable body weight. In addition, each monkey was given a
chewable vitamin tablet 3 days per week. Experiments were conducted
during the light cycle (lights on 7:00 A.M. to 10:00 P.M.), 7 days per week.
General procedure. After adapting to the cubicle and restraint system, each monkey received injections of a combination of ketamine (1.0 mg/kg, i.m.) and atropine (.04 mg/kg, i.m.) followed in 20 to 30 min by inhaled isoflurane. When anesthesia was adequate, a catheter was surgically implanted into a major vein. For femoral and jugular (internal and external) veins, a silicone catheter (.076 cm, i.d., .26 cm o.d.; Cole-Parmer Co.) was used. For brachial veins, the catheter was Micro-Renethane (.1 cm i.d., .2 cm o.d.; Braintree Scientific, Braintree, MA) drawn to a tapered tip after heating. An antibiotic was injected locally to the incision site and was administered i.m. twice daily for 7 days to prevent infection.
After surgery the monkey was returned to the cubicle and the catheter was threaded through the tether, out the back of the cubicle and connected to the infusion pump. If a catheter became nonfunctional during the experiment, a new catheter was implanted as described above following a 1- to 2-wk period to allow any infection to clear. Catheters were filled with drug solution 30 min before the session and with a solution of 20 U/ml heparin after the session to prevent clotting at the catheter tip. A short-acting barbiturate (methohexital, 3.0 mg/kg, i.v.) was administered periodically to assess catheter patency. Catheters were considered to be patent if evidence of anesthesia occurred within 30 sec of the injection. Details of the PR procedure have been reported previously (Rowlett et al., 1996). Experimental sessions, signaled by the
illumination of the white lever lights, started at noon each day.
During initial sessions, one lever press on the right lever resulted in
an injection of cocaine (100 µg/kg/injection administered over 10 sec). The white lights were turned off and the red lights were
illuminated during drug infusion. Once the monkey began pressing the
lever, the PR schedule was initiated with a TO, in which the lights
were extinguished and responding had no programed consequences, and a
LH, in which a preset length of time was allowed to complete a response
requirement, equal to 60 sec. The response requirements and TO/LHs were
gradually increased to the terminal conditions of the PR schedule. The
PR schedule consisted of five components, each made up of four trials
(i.e., 20 trials total). Each trial within a component had
the same response requirement. Thus, the response requirement in the
first component was FR 120 and doubled in successive components to a
maximum of FR 1920 in the fifth component. A trial ended with an
injection or the expiration of a 15-min LH. After an injection or
expiration of the LH, all stimulus lights were extinguished and
responding had no consequences during a 30-min TO. A session ended when
the response requirement was not met within the LH for two consecutive
trials or when all 20 trials had been completed. Thus, in order to
complete a component and progress to the next FR, at least two trials
had to be completed within the component.
Once the final conditions of the PR schedule were reached, a
single-alternation procedure was initiated in which the maintenance dose of cocaine (100 µg/kg/injection) was available alternating with
sessions of saline availability. Training under this single-alternation sequence occurred until a 6-day sequence was achieved in which 1)
injections/session for saline were 5 or less for three saline sessions,
2) mean injections/session for saline were ± one
injection/session with no upward or downward trends for three saline
sessions in the sequence, and (3) mean injections/session for cocaine
were ± one injection/session with no upward or downward trends
for three cocaine sessions in the sequence. Once the above criteria were met, testing began according to the following four-session cycles:
DSTD, SDTD; where "D" represents the maintenance drug, "S"
equals saline and "T" represents a test session. The sequences for
the four-session cycles were chosen so that each test session was
preceded by either drug or saline with equal frequency and so that
sessions with the maintenance drug occurred after the test session.
This latter condition was used to assess if any effects of the
treatments incurred during the test session carried over to the day
after testing. Test sessions were conducted if injections/session
during the two preceding sessions were within the range of the
previously determined stable performance. If these criteria were not
met, testing was stopped and the monkey was returned to the
single-alternation sequence until the 6-day criteria described above
were again met. Each dose and dose combination condition was determined
twice. Second determinations occurred in consecutive 4-session cycles
for approximately half of the conditions, for the remaining conditions
the second determination occurred after intervening test sessions with
different doses or dose combinations.
Cocaine-heroin combination experiments.
To compare
self-administration of cocaine-heroin combinations to
self-administration of the drugs singly, dose-response functions for
cocaine and heroin alone were determined initially for each monkey. On
intervening sessions (i.e., sessions 1, 2 and 4 of the
four-session cycle), saline, doses of cocaine (100 µg/kg/injection) or heroin (6.4 µg/kg/injection) were available. The doses of cocaine and heroin were determined previously to maintain maximum
injections/session and breakpoints under the PR sequence used in this
study (Rowlett and Woolverton, 1997). Saline or various doses of
cocaine alone (6.4-100 µg/kg/injection) or heroin alone (1.6-25
µg/kg/injection) were made available during test sessions (session 3 of the four-session cycle). These doses were chosen based on our
previous study to represent primarily ascending limb doses of both
drugs under the conditions of this study (Rowlett and Woolverton,
1997).
), the dose of cocaine to be mixed with heroin was determined in
the monkeys on an individual basis. Initially, a dose of cocaine was
chosen, based on initial dose-response determinations, that was 4-fold
below the lowest dose that maintained behavior above saline levels.
This cocaine dose then was combined with the lowest dose of heroin
tested that did not maintain behavior above saline levels. Next, the
dose of cocaine in the mixture was either increased or decreased on an
individual basis in each monkey until responding maintained by the
combination was above saline levels for two test sessions. Finally,
holding the nonreinforcing dose of cocaine constant, the dose of heroin
in the combination was decreased until responding was at saline levels
and increased until responding reached a peak or asymptote. In this
fashion, a dose-response function for the cocaine-heroin combination
was constructed in each monkey with fixed and relatively low doses of
cocaine plus varying doses of heroin.
Naltrexone antagonism experiments. Various doses of naltrexone were administered prior to maintenance doses of cocaine, heroin or their combination to establish naltrexone's ability to antagonize self-administration of cocaine-heroin combinations relative to the constituent drugs alone. Either saline, cocaine (100 µg/kg/injection), heroin (6.4 or 13 µg/kg/injection) or a cocaine-heroin combination was used as the maintenance drug condition on sessions 1, 2 and 4 of the four-session cycle. The cocaine-heroin combination was chosen as the lowest dose combination that maintained responding above saline levels when combined but not when the constituent drugs were tested alone. Each maintenance drug condition was in effect until the 6-day stability criteria described above were met. The maintenance condition was then tested with presession treatments of various doses of naltrexone (6.4-1600 µg/kg) or saline (0.1 ml/kg), injected i.m. 10 min before the beginning of session 3 of the four-session cycle. The order of naltrexone test dose was counter-balanced across the four monkeys and all test conditions were determined twice.
After the establishment of effective naltrexone doses, heroin and cocaine-heroin dose-response functions were redetermined in monkeys RIk2, 11084 and AP13 in the presence of various doses of naltrexone (1.6-50 µg/kg, i.m., 10-min presession). Higher doses of heroin (50 and 100 µg/kg/injection), alone or in the cocaine-heroin combinations, also were added to the redeterminations of dose-response functions to assess whether blockade by naltrexone was surmountable. Monkey 9002 was not available for this phase of the study. Determinations of dose-response functions were repeated for monkeys RIk2, 11084 and AP13 after completion of all test conditions. This second determination was conducted to control for baseline changes for heroin alone, which were evident in our initial study (Rowlett and Woolverton, 1997). The second determinations were conducted with
submaximal and peak doses of cocaine and heroin only, because the only
change in sensitivity to heroin previously observed was with
low-to-intermediate doses of heroin.
Drugs. Cocaine HCl, heroin HCl and naltrexone HCl were provided by the National Institute on Drug Abuse, mixed in 0.9% saline solution and sterilized by filtration (0.2-µm filter, Nalge Co., Rochester, NY). Combinations of cocaine and heroin were prepared in the same saline solution. Cocaine, heroin and cocaine-heroin injections occurred over a 10-sec period in a volume of approximately 1 ml. Naltrexone was injected into a quadriceps muscle at a volume of 0.1 ml/kg. All drug doses are expressed as the salt form of the drug.
Data analysis.
Injections/session, averaged for the two
determinations, was the dependent measure, with the corresponding FR
breakpoint also noted. Previous research has indicated that
injections/session provides a reliable measure of self-administration
of a drug that, in contrast to breakpoint, does not violate assumptions
of standard statistical tests (Depoortere et al., 1993;
Rowlett et al., 1996). Each monkey served as its own
control, and doses of cocaine, heroin and cocaine-heroin combinations
were considered to maintain self-administration if the mean
injections/session for the two determinations was above the range of an
individual monkey's mean injections/session after saline
determination.
.05. ED50 values for cocaine alone were
calculated as described above except that the maximum injections/session maintained by cocaine was used as the
Imax value in the calculation.
For naltrexone antagonism of cocaine-heroin self-administration,
apparent pA2 analysis was conducted. The method
of Arunlakshana and Schild (1959) was used with drug doses in mol/kg
substituted for drug concentrations. Linear regression analysis was
conducted to obtain the slope values (to test whether the slope
differed from -1.0 using a one-sample t test, Tallarida
et al., 1979), and the x-intercept (apparent
pA2 value). For naltrexone antagonism of heroin
self-administration, apparent pKB analysis was
conducted according to the method described by Negus et al.
(1993). Apparent pKB values were calculated
according to the equation: pKB = -log[B/(X-1)]. In this equation, "B" is the dose in mol/kg and "X" is the dose ratio (ED50 of the agonist combined with
antagonist divided by the ED50 of the agonist
alone).
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Self-administration of cocaine and heroin, alone and combined. During the course of the study, all monkeys completed one to four injections/session (breakpoint = 120) when saline was available (table 1). When doses of cocaine were available, injections/session and breakpoints increased as the dose of cocaine increased, with saline-like levels maintained from 6.4 to as high as 25 µg/kg/injection (table 1). At the largest dose of cocaine tested (100 µg/kg/injection), injections/session were 16 to 19 with breakpoints of 960 and 1920 responses. Redetermination of the cocaine dose-response functions for monkeys RIk2, 11084 and AP13 at the end of the study revealed injections/session that varied by approximately one injection/session at every dose with no consistent trend for an increase or decrease in responding (data not shown). Comparison of the mean ED50 values (table 2) revealed no apparent difference from the first to second determinations [first determination (mean, 95% CI, n): 36, 8.1, 4; second determination: 38, 14, 3].
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Self-administration of cocaine, heroin and cocaine plus heroin after presession naltrexone. Presession naltrexone treatments did not alter self-administration of 100 µg/kg/injection of cocaine over the 250-fold dose range tested (6.4-1600 µg/kg, data not shown). At the highest dose of naltrexone tested (1600 µg/kg), the mean injections/session was 16 (S.E.M. = 1.0), which was the same as the mean of 16 injections/session (S.E.M. = 2.0) maintained by cocaine after presession i.m. injection with saline.
Presession naltrexone treatments reduced self-administration of 6.4 µg/kg/injection of heroin (monkeys RIk2, 9002, 11084) or 13 µg/kg/injection of heroin (monkey AP13) to saline levels in a dose-dependent fashion in all monkeys (fig. 2, filled symbols). When combinations of cocaine and heroin at the peak of the combination dose-response functions were tested after presession treatments with naltrexone, injections/session and breakpoints were also reduced to saline levels in a dose-dependent fashion in all monkeys (fig. 2, open symbols).
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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In our study, combination of low, normally ineffective doses of
cocaine with a range of doses of heroin resulted in an enhancement of
self-administration compared to heroin alone. The overall effect was a
leftward and approximately parallel shift in the heroin dose-response
function relative to the dose-response function for heroin alone.
Moreover, nonreinforcing doses of heroin combined with nonreinforcing
doses of cocaine resulted in injections/session greater than observed
when saline was available for self-administration. These results
confirm and extend our earlier data in which combining low doses of
heroin with cocaine resulted in an overall shift to the left in the
cocaine dose-response function (Rowlett and Woolverton, 1997). In our
previous study, however, the dose-response functions for heroin alone
were shifted to the left in two monkeys when tested after exposure to
the various cocaine-heroin combinations, raising the possibility that
the enhancement of cocaine self-administration by heroin was due, at
least in part, to changes in sensitivity to heroin alone that may have
developed over the course of our study. Our findings indicate that this
likely is not the case, because no changes in self-administration were
observed upon redetermination of dose-response functions of heroin
alone. Collectively, the results of the present and our previous study
indicate that combinations of low doses of cocaine and heroin result in
a reciprocal enhancement of the reinforcing potency of the combinations
compared to either drug alone.
In addition to changes in sensitivity to heroin, in our previous study interanimal differences were observed for the change in position and shape of the cocaine dose-response functions after combination with heroin. Specifically, one monkey showed a marginal leftward and downward shift in the cocaine dose-response function, which clearly differed from the robust parallel leftward shifts in the dose-response functions of the other animals. By contrast, in our study relatively few interanimal differences were observed, except that monkey AP13 showed higher ED50 and lower Imax values for heroin and heroin-cocaine combinations compared to the other animals. Moreover, monkey AP13 required the lowest dose of cocaine to shift the heroin dose-response function to the left in comparison to the other monkeys. It is interesting to note that this monkey was experimentally naïve, whereas the other animals had extensive experience with cocaine, heroin or related drugs, raising the possibility that experimental history may be a factor in determining sensitivity to cocaine-heroin combinations. Regardless of individual differences in ED50 values, Imax values and dose of cocaine required to enhance the effects of heroin, the overall effect of a leftward and parallel shift in the heroin dose-response function after combination with cocaine was evident in all monkeys tested in our study.
As with our previous results, the shift in the heroin dose-response
functions was not accompanied by a corresponding change in the maximum
injections/session (Imax) or breakpoints compared to heroin alone. If one posits that Imax reflects
the relative reinforcing efficacy of a drug, then our findings suggest
that the relative reinforcing efficacy (as compared to potency) of heroin was not altered in combination with cocaine. This possibility needs to be viewed cautiously, however, because the dose-response functions for heroin tended to be biphasic, as was clearly observed in
our previous study (Rowlett and Woolverton, 1997). It is conceivable, therefore, that the tendency of high doses of heroin to suppress responding may have interfered with detection of any cocaine-induced increase in Imax. Interestingly, in a recent
study by Mattox et al. (1997), behavioral economic analysis
of speedball interactions revealed that "demand" for cocaine-heroin
combinations self-administered by smoke inhalation was increased
relative to smoked heroin base, which may reflect an increase in
relative reinforcing efficacy of the speedball mixture compared to
heroin alone. Consistent with this view, under conditions in which the
cocaine and cocaine-heroin dose-response functions were monophasic,
Imax values for cocaine-heroin combinations were
reliably greater than the Imax values for heroin alone (Rowlett and Woolverton, 1997). Together, these results raise the
possibility that the reinforcing efficacy, in addition to the potency,
of heroin may increase when combined with active doses of cocaine.
However, only the reinforcing potency of heroin appears to be increased
when combined with normally inactive doses of cocaine. The extent to
which any changes in reinforcing efficacy produced by combining cocaine
and heroin are determined by rate-suppressing effects, scheduling
conditions, or doses in the mixture remains to be determined.
Consistent with previous research with opioid antagonists combined with
mu agonists (Harrigan and Downs, 1978; Ettenberg et al., 1982; Bertalmio and Woods, 1989; Winger et al.,
1992), presession administration with naltrexone reduced heroin
self-administration in our study. Increasing the heroin dose surmounted
naltrexone's antagonism of heroin self-administration, resulting in a
shift to the right in the dose-response function. In vivo
apparent pKB analysis of this rightward shift
revealed a pKB value of 8.0, consistent with
apparent pA2 values obtained in previous
behavioral and physiological studies in rhesus monkeys treated with
naltrexone combined with prototypic mu agonists
(e.g., 8.3 for morphine in drug discrimination, France
et al., 1990; 7.8 for alfentanil antinociception, Gerak
et al., 1994). Moreover, our findings with naltrexone
complement and extend a previous study by Bertalmio and Woods (1989),
in which quadazocine antagonized self-administration of the
mu selective agonist alfentanil with an apparent
pA2 value of 7.6. Evidence of surmountable
antagonism of heroin self-administration by naltrexone at an apparent
affinity value consistent with interaction at the mu
receptor supports the view that stimulation of mu receptors is a primary mechanism underlying the reinforcing effects of heroin and
other mu opioid agonists. The pharmacological activity of heroin, however, is thought to be due to the action of its metabolites 6-monoacetylmorphine and morphine (Inturrisi et al., 1983).
Thus, interpretation of
pA2/pKB analyses is
complicated by the possibility that self-administration was mediated by
either morphine or 6-monoacetylmorphine, or both, rather than the
parent compound. Although we cannot at present state definitively which
metabolite modulates the reinforcing effects of heroin, our results
suggest that regardless of the metabolite, mu receptor
stimulation plays a prominent role in heroin self-administration.
In contrast to the interaction of naltrexone with heroin, presession
treatments of naltrexone did not alter cocaine self-administration over
an approximately 300-fold dose range. This observation is concordant
with previous findings that opioid antagonists do not consistently
alter the reinforcing effects of cocaine (e.g., Killian et al., 1978; Ettenberg et al., 1982; Winger
et al., 1992). The lack of antagonism by naltrexone of
cocaine self-administration in our study over a relatively broad dose
range supports the notion that opioid receptor stimulation does not
play a primary role in mediating the reinforcing effects of cocaine
(cf., Ettenberg et al., 1982). Interestingly,
some reports have noted decreases in cocaine self-administration after
treatments with opioid antagonists in rats (De Vry et al.,
1989; Corrigall and Coen, 1991), as well as opioid antagonist-induced
decreases in cocaine conditioned place preference (Houdi et
al., 1989) and cocaine's effects on electrical brain stimulation
(Bain and Kornetsky, 1987). The reasons for these different findings
with naltrexone are not clear but may reflect species and/or procedural
differences.
Evaluation of the effects of naltrexone on self-administration of
heroin and cocaine alone allowed determination of whether naltrexone's
effects on cocaine-heroin combinations were similar to its effects on
heroin (i.e., surmountable antagonism) or on cocaine
(i.e., no effect) self-administration. Naltrexone
pretreatment resulted in a dose-dependent suppression of responding
maintained by cocaine-heroin combinations, at doses similar to those
that suppressed self-administration of heroin alone. Moreover,
increasing the dose of heroin in the cocaine-heroin mixture resulted in
an increase in cocaine-heroin self-administration, such that the dose-response function was shifted to the right (i.e.,
surmountable antagonism). When differing doses of naltrexone were
administered prior to determination of speedball dose-response
functions, rightward shifts were observed that increased in magnitude
as the dose of naltrexone was increased. Despite individual differences
in the dose combinations that maintained behavior, the observed shifts in speedball dose-response functions produced by naltrexone were similar across animals, and in vivo apparent
pA2 analysis of these data revealed apparent
affinity estimates of 7.9 to 8.2 (mean pA2 = 8.0). This apparent pA2 value is within the range
of pA2 values obtained with naltrexone combined
with other prototypic mu agonists in behavioral studies with
monkeys (France et al., 1990; Gerak et al., 1994;
Gerak and France, 1996). This pA2 value also is
identical to the in vivo apparent pKB
value obtained with naltrexone combined with heroin alone in our study.
Overall, our results are consistent with previous data showing
attenuation of the reinforcing, discriminative stimulus and subjective
effects of speedball combinations by naltrexone (Spealman and Bergman, 1992; Hemby et al., 1996; Walsh et al., 1996) and
extend previous results by illustrating involvement of the
mu receptors in the enhanced self-administration of
cocaine-heroin combinations. Finally, it is important to emphasize that
naltrexone antagonism of self-administration of cocaine-heroin
combinations occurred under conditions in which naltrexone did not
block cocaine self-administration and in which a nonreinforcing dose of
cocaine shifted the heroin dose-response function to the left. Thus,
the apparent mu-mediated self-administration of heroin did
not appear to be influenced by the presence or absence of cocaine, a
result concordant with the notion that the reinforcing effects of
cocaine and heroin reflect separate pharmacological mechanisms
(cf., Ettenberg et al., 1982).
As mentioned, the finding of naltrexone-reversible enhancement of the
effects of speedballs compared to the constituent drugs is consistent
with results from other behavioral paradigms (Spealman and Bergman,
1992; Hemby et al., 1996; Kimmel and Holtzman, 1997). Although neuropharmacological mechanisms underlying enhancement of the
behavioral effects of cocaine by opioid agonists have not been
established definitively, our study provides support for the
involvement of mu receptors as has been proposed previously (Brown et al., 1991; Spealman and Bergman, 1992). We cannot,
however, rule out a possible role for delta receptors in
mediating the enhanced self-administration of cocaine-heroin
combinations. Concordant with a possible role for delta
receptors in abuse-related effects of speedballs, previous studies have
shown that the delta antagonist naltrindole attenuated both
the discriminative stimulus effects of cocaine and cocaine-induced
conditioned place preference in rats (Menkens et al., 1992;
Suzuki et al., 1994). In addition, the delta
agonists TAN-67 and SNC-80 have been shown to enhance the
discriminative stimulus effects of cocaine in both rats and squirrel
monkeys (Rowlett and Spealman, in press; Suzuki et al., 1997), and delta receptors apparently are involved in the
antinociceptive effects of 6-monoacetylmorphine (Rady et
al., 1997). Regardless of the exact mechanisms underlying
interactions between cocaine and opioids, our results suggest that
mutual enhancement of the self-administration of cocaine and heroin may
serve as the pharmacological basis for the persistence of speedball
abuse.
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Acknowledgments |
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The authors thank J. Weems and S. Kearney for technical assistance. We are grateful to Drs. R. D. Spealman and D. M. Platt for helpful comments on an earlier version of this manuscript and to Dr. S. S. Negus for helpful discussions concerning pA2/pKB analyses.
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Footnotes |
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Accepted for publication March 6, 1998.
Received for publication October 24, 1997.
1 This work was supported by National Institute on Drug Abuse Grant DA10352 (W.L.W.) and National Research Scientist Award DA05625 (J.K.R.). The animals used in this study were maintained in accordance with the United States Public Health Service "Guide for Care and Use of Laboratory Animals" and all procedures were approved by the University of Mississippi Medical Center Institutional Animal Care and Use Committee.
2 Current address: Harvard Medical School, New England Regional Primate Research Center, Box 9102, One Pine Hill Drive, Southborough, MA 01772-9102.
Send reprint requests to: Dr. James K. Rowlett, Harvard Medical School, New England Regional Primate Research Center, Box 9102, One Pine Hill Drive, Southborough, MA 01772-9102.
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Abbreviations |
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AIDS, acquired-immune deficiency syndrome; CI, confidence interval; ED50, dose that produced 50% of the maximum injections/session produced by drug alone; FR, fixed-ratio; Imax, maximum injections/session, reinforcing efficacy; LH, limited hold; PR, progressive-ratio; TO, time-out.
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References |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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21-29[Medline].This article has been cited by other articles:
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