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BEHAVIORAL PHARMACOLOGY
New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts
Received January 29, 2007; accepted March 8, 2007.
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Abstract |
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; Koob, 1992), and speedballs may engender their effects by an interaction of these two neurotransmitter systems (for review, see Leri et al., 2003).
Although cocaine acts generally at monoamine systems (i.e., DA, serotonin, and norepinephrine systems), considerable evidence suggests that the abuse-related effects of cocaine itself are due primarily to its action at DA systems (for review, see Woolverton and Johnson, 1992; Platt et al., 2002). Moreover, cocaine and heroin have been shown to share abuse-related effects (e.g., discriminative stimulus effects), and these shared effects probably involve DA and not serotonergic or noradrenergic systems (Rowlett et al., 2004). Cocaine binds to recognition sites associated with the DA transporter, resulting in inhibition of DA transport and, as a consequence of vesicular release of DA, accumulation of this neurotransmitter in the synapse. Extracellular DA then binds to and stimulates DA receptors. Two main families of DA receptors ("D1-like", consisting of D1 and D5 subtypes, and "D2-like", consisting of D2,D3, and D4 subtypes) have been described previously (Civelli et al., 1991; Schwartz et al., 1992), and both D1-like and D2-like receptor mechanisms have been implicated in the effects of cocaine related to its abuse (Woolverton and Johnson, 1992; Platt et al., 2002).
Although considerable research has focused on the role of D1-like and D2-like receptors in cocaine self-administration, the role of DA receptor subtypes in the ability of cocaine to enhance heroin self-administration has received relatively less attention. The available evidence suggests that DA receptors are involved in the ability of cocaine to modulate heroin self-administration. Hemby et al. (1996), for example, showed that the DA D2-like antagonist eticlopride reversed cocaine-induced alterations in heroin self-administration in rats. In addition, Mello and Negus (1999) observed attenuation of speedball self-administration by the nonselective DA antagonist flupenthixol when combined with relatively low, ineffective doses of an opioid antagonist. Using a different approach, the present study aimed to evaluate the capacity of agonists with selectivity for D1-like and D2-like receptor subtypes to alter the self-administration of heroin. To investigate D1-like receptor mechanisms, we chose the representative agonists SKF 82958 and SKF 81297, both of which show high affinity for D1-like receptors in rhesus monkey brain as well as approximately 20- (SKF 82958) to 1000-fold (SKF 81297) selectivity for D1-like versus D2-like receptors (Weed et al., 1998). To investigate D2-like mechanisms, we chose the representative agonists R-(-)-propylnorapomorphine (NPA) and quinpirole, both of which have very high degrees of selectivity for D2-like versus D1-like receptors (i.e., >400-fold; Gao et al., 1990; Doll et al., 1999). In addition, NPA has been shown to exhibit relatively high affinity at the D2-like receptor in binding studies with rhesus monkey brain, whereas quinpirole, but not NPA, has modest selectivity for D3 compared with D2 receptor subtypes (Malmberg and Mohell, 1995; Ranaldi et al., 2001). We postulated that if D1-like and/or D2-like receptors underlie the ability of cocaine to enhance the reinforcing effects of heroin, then a subtype-selective agonist should engender enhancement that is qualitatively similar to that of cocaine combined with heroin.
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Materials and Methods |
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, 2005). Monkeys were housed in colony rooms with a 12-h light/dark cycle (lights on at 6:30 AM), they had unrestricted access to water, and they were fed Harlan Teklad Monkey Diet, supplemented by fresh fruit (Harlan Teklad, Madison, WI). All procedures were conducted with the approval and under the supervision of the Harvard University Institutional Animal Care and Use Committee. The monkeys were cared for according to the Guide for Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, 1996).
Each monkey was prepared with a chronic indwelling venous catheter according to the general procedures described by Platt et al. (2005). A polyvinyl chloride catheter (Tygon; inner diameter, 0.65 mm; outer diameter, 1.35 mm) was implanted in a jugular (internal or external), femoral, or brachial vein under isoflurane anesthesia and aseptic conditions. The proximal end of the catheter terminated above the right atrium, and the distal end was passed subcutaneously to exit in the midscapular region. Experimental sessions began 7 days after surgery.
Apparatus. Monkeys were housed individually in stainless steel primate cages that also served as the experimental chambers. A removable panel was placed on the front of each cage and contained four stimulus lights (two red and two white; 3 cm, 1.1 W; MED Associates, St. Albans, VT) and a response lever (MED Associates). Each monkey was fitted with a nylon-mesh jacket (Lomir Biomedical Inc., Malone, NY) that was connected to a 1-m stainless steel flexible tether (Lomir Biomedical Inc.). The monkey's catheter was routed through the tether and attached to a fluid swivel (Lomir Biomedical Inc.) on top of the cage. The swivel was attached to an injection pump (MED Associates) located on top of the cage, which could infuse drug solutions at a rate of 0.2 ml/s. The stimulus lights, response levers, and infusion pump were connected to interfaces (MED Associates) and PC-compatible computers located in an adjacent room.
Procedure. Monkeys were trained to self-administer cocaine under a PR schedule of i.v. drug injection according to the procedures described by Rowlett et al. (2002). Experimental sessions began daily at 12:00 PM. At the beginning of the session, the white stimulus lights above the lever were illuminated to signal the start of a trial. Upon completion of the response requirement, the white lights were extinguished and the red stimulus lights were illuminated for 1 s, coinciding with a 1-s infusion of drug or saline. Each trial ended with either an injection or the expiration of a 30-min limited hold. Trials were separated by a 30-min time-out period, during which all lights were extinguished, and responding had no programmed consequences.
Experimental sessions consisted of five components made up of four trials each, for a possible maximum of 20 trials per session. The response requirement remained constant during each of the four trials within a component, and it doubled across successive components of the session. The initial response requirement was 100 and increased to 200, 400, 800, and 1600 responses per injection. The session ended when a monkey self-administered a maximum of 20 injections or when the response requirement was not completed for two consecutive trials.
Under training conditions, cocaine (0.1 or 0.18 mg/kg/injection, depending on the monkey) or an equivalent volume of saline was available for self-administration on alternate days. Stable self-administration was defined by the following criteria: 1) the number of injections/session maintained by cocaine was greater than or equal to 11 for at least three sessions of cocaine availability, and the number of injections/session maintained by saline was less than or equal to 5 for at least three sessions of saline availability; and 2) no upward or downward trends in the number of injections were observed across either type of session. Once self-administration was stable, test sessions (T) were added to the alternating sequence of cocaine (C) and saline (S) sessions according to the following sequence: STSCTCTCST, and so on.
Initially, dose-response functions for individual compounds were determined in one-half log increments with the following ranges (milligrams per kilogram per injection): cocaine (0.01-0.3), SKF 82958 (0.003-0.1), SKF 81297 (0.01-0.3), NPA (0.0003-0.01), quinpirole (0.003-0.1). For drug combination studies, a dose-response function for heroin (0.0003-0.01) was determined first, followed next by combination with one of two doses of the following compounds (milligrams per kilogram per injection): cocaine (0.01 and 0.03), SKF 82958 (0.003 and 0.01), SKF 81297 (0.01 and 0.03), NPA (0.0003 and 0.001), and quinpirole (0.003 and 0.01). Drug combination studies were conducted by mixing the dose of the test drug with each dose of heroin in the same syringe. All drug combinations were tested in an irregular order across subjects (n = 3-6), with the restriction that all doses of heroin or the drug combination were studied before testing the next drug combinations.
To evaluate the extent to which potential interactions between heroin with D1-like and D2-like agonists were unique to heroin self-administration, we conducted an additional study in which either the D1-like agonist SKF 81297 or the D2-like agonist NPA was combined with cocaine, rather than heroin. For these studies, a dose-response function for cocaine (0.01-0.1 mg/kg/injection) was determined first, followed next by combination with one of two doses of SKF 81297 (0.01 and 0.03 mg/kg/injection) or NPA (0.0003 and 0.001 mg/kg/injection). Other details of these studies are as described above.
Drugs. Cocaine HCl, SKF 81297, SKF 82958, NPA, and quinpirole HCl were obtained from commercial sources (Sigma-Aldrich, St. Louis, MO). Heroin HCl was obtained from the National Institute on Drug Abuse (Bethesda, MD). All drugs were dissolved in 0.9% saline solution (cocaine) or saline solution containing small amounts of 0.1 N HCl (titrated to pH 6-7) or ethanol (
10%), and filter-sterilized (0.2 µm) before administration. Doses were expressed, where noted, as the salt form of the drugs.
Data Analysis. The number of injections/session and the break points were determined for individual monkeys under each test condition. The mean number of injections/session for each drug when tested alone was analyzed by separate repeated measures analysis of variance (ANOVA). Combinations of doses were analyzed by two within, repeated measures ANOVA with drug and dose as the two factors. For all ANOVAs, multiple comparisons were made using Bonferroni t tests (
level, p < 0.05). Break point, defined as the highest response requirement completed during a test session, was used to calculate the maximal break point irrespective of dose (BPmax), a measure of the maximal reinforcing effects of the drug. Because break point data characteristically violate assumptions of homogeneity of variance and normality, the BPmax data were transformed to log10 values. The log10(BPmax) data were analyzed using repeated measures ANOVA and Bonferroni t tests.
To determine the extent to which drug combinations resulted in effects that differed from dose additivity, isobolographic analyses were conducted as described by Rowlett et al. (2001). Dose additivity is defined as the combined effect occurring when dose combinations of two drugs produce effects equal to the effect produced by the sum of the individual doses (for review, see Woolverton, 1987). For isobolographic analyses, the dose needed to engender 50% of the maximal number of injections/session maintained by heroin (ED50) was calculated for individual monkeys by log linear regression analysis based on at least three points representing the linear portion of the dose-response function. For each drug combination, a theoretical line of dose additivity was plotted in a two-dimensional graph as a diagonal line between the ED50 values for each drug alone. The predicted ED50 values were divided by the ED50 values of the combinations for individual animals (obtained using linear regression analysis). The ratios (expressed as mean ± S.E.M. for the group of monkeys) were compared with the population value of 1.0 using one-sample t tests (Rowlett et al., 2001) as adapted from Gessner (1974). For this analysis, ratios equal to 1.0 indicate additive effects, ratios greater than 1.0 indicate a supra-additive interaction, and ratios less than 1.0 indicate an infra-additive interaction.
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Results |
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The average maximal reinforcing effect, measured by BPmax determinations, was highest for cocaine (mean BPmax ± S.E.M. = 1333 ± 167), followed by NPA (560 ± 98), SKF 82958 (500 ± 101), SKF 81297 (450 ± 126), and quinpirole (400 ± 0). Analysis of the log10(BPmax) revealed differences in the maximal reinforcing effects of the five drugs [F(4,12) = 13.42; p < 0.05]. Multiple comparison tests showed that the mean log10(BPmax) value for cocaine was higher than the mean log10(BPmax) values for all of the DA agonists (Bonferroni t tests).
Combination of Cocaine with Heroin. When self-administered alone, heroin engendered a dose-dependent increase in the mean number of injections/session, with a maximal average of 13 injections/session (S.E.M. = 3.1) at 0.003 mg/kg/injection (Fig. 2, filled circles). To determine the effects of combining cocaine with heroin, the heroin dose-response function was redetermined with an ineffective and a minimally effective dose of cocaine (0.01 and 0.03 mg/kg/injection, respectively). As can be seen in Fig. 2, the overall effect of combining cocaine with heroin was a leftward and upward shift in the heroin dose-response function by cocaine. Analysis of the number of injections/session following cocaine-heroin combinations revealed a main effect of heroin dose [F(3,9) = 17.4; p < 0.05], a main effect of cocaine dose [F(2,6) = 29.7; p < 0.05], and a heroin dose x cocaine dose interaction [F(6,18) = 5.3; p < 0.05]. These ANOVA results are consistent with an enhancement of the effects of heroin combined with cocaine that was dependent on the dose combination. Specifically, enhancement of heroin by combination with cocaine typically was observed at lower dose combinations (Fig. 2). Multiple comparison tests revealed that the mean number of injections/session maintained by combinations of cocaine with lower doses of heroin (e.g., 0.0003 mg/kg/injection of heroin plus 0.01 mg/kg/injection of cocaine) were reliably higher than the corresponding dose of heroin alone (Bonferroni t tests, p < 0.05), whereas combinations of cocaine with the higher doses of heroin (0.003 and 0.01 mg/kg/injection) were not reliably different from the number of injections/session maintained by heroin alone. Finally, the average maximal reinforcing effects of the cocaine-heroin combinations, measured by log10(BPmax) determinations, did not differ from the average maximal reinforcing effects of heroin alone (data not shown).
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Combination of D1-Like Agonists with Heroin. To determine the effects of combining the D1-like agonists SKF 82958 and SKF 81297 with heroin, the heroin dose-response function was redetermined with ineffective and minimally effective doses of the two D1-like agonists (Fig. 3, a and b). Analysis of the number of injections/session following SKF 82958-heroin combinations revealed a main effect of heroin dose [F(3,9) = 14.3; p < 0.05], a main effect of SKF 82958 dose [F(2,6) = 5.8; p < 0.05], and a heroin dose x SKF 82958 dose interaction [F(6,18) = 11.4; p < 0.05; note that the heroin dose 0.01 mg/kg/injection was not included in the analysis]. As with cocaine-heroin combinations, these results are consistent with a SKF 82958-induced enhancement of heroin self-administration that depended on the dose combination (Fig. 3a). Multiple comparison tests revealed that the mean number of injections/session maintained by combinations of SKF 82958 with 0.0003 and 0.001 mg/kg/injection of heroin were reliably higher than the corresponding dose of heroin alone (0.003 mg/kg/injection of SKF 82958 plus 0.001 mg/kg/injection of heroin versus heroin alone; 0.01 mg/kg/injection of SKF 82958 plus 0.0003 and 0.001 mg/kg/injection of heroin compared with heroin alone; Bonferroni t tests, p < 0.05). In contrast, combinations of SKF 82958 with the higher dose of heroin (0.003 mg/kg/injection) were not reliably different from the number of injections/session maintained by this dose of heroin alone. As with cocaine-heroin combinations, the average maximal reinforcing effects of the SKF 82958-heroin combinations, measured by log10(BPmax) determinations, did not differ from the average maximal reinforcing effects of heroin alone (data not shown).
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A similar pattern of effects was observed for combinations of SKF 81297 and heroin (Fig. 3b). Analysis of the number of injections/session following SKF 81297-heroin combinations revealed a main effect of heroin dose [F(3,9) = 13.5; p < 0.05], a heroin dose x SKF 81297 dose interaction [F(6,18) = 3.4; p < 0.05], but no main effect of SKF 81297 dose [F(2,6) = 3.6; p = 0.096; note that the heroin dose 0.01 mg/kg/injection was not included in the analysis]. These ANOVA results suggest an effect of combining SKF 81297 with heroin that depended on the dose of the D1-like agonist (Fig. 3b). Multiple comparison tests revealed that the mean number of injections/session maintained by combinations of SKF 81297 with 0.0003 and 0.001 mg/kg/injection of heroin was reliably higher than the corresponding doses of heroin alone (0.01 mg/kg/injection of SKF 81297 plus 0.001 mg/kg/injection of heroin versus this dose of heroin alone; 0.03 mg/kg/injection of SKF 81297 plus 0.0003 and 0.001 mg/kg/injection of heroin compared with these doses of heroin alone; Bonferroni t tests, p < 0.05). In contrast, the number of injections/session maintained by combinations of SKF 81297 with the higher dose of heroin (0.003 mg/kg/injection) was not reliably different from the number of injections/session maintained by this dose of heroin alone. As with cocaine-heroin and SKF 82958-heroin combinations, the average maximal reinforcing effects of the SKF 81297-heroin combinations, measured by log10(BPmax) determinations, did not differ from the average maximal reinforcing effects of heroin alone (data not shown).
Combination of D2-Like Agonists with Heroin. The effects of combining the D2-like agonists with heroin were strikingly different from combining cocaine or D1-like agonists with heroin. In this regard, combination of an ineffective and minimally effective dose of D2-like agonist with heroin overall resulted in predominantly rightward and downward shifts in the heroin dose-response function (Fig. 4, a and b). For NPA (Fig. 4a), the repeated measures ANOVA revealed a main effect of heroin dose [F(4,16) = 13.9; p < 0.05] and a reliable NPA dose x heroin dose interaction [F(8,32) = 11.0; p < 0.05], but no main effect of NPA dose [F(2,8) = 3.2; p = 0.094]. These ANOVA results probably reflect attenuation of the effects of heroin by combination with NPA, even at a dose (0.001 mg/kg/injection) of NPA that maintained self-administration when tested alone. Multiple comparison tests showed that three dose combinations (0.0003 mg/kg/injection NPA plus 0.001 mg/kg/injection heroin, 0.001 mg/kg/injection NPA plus 0.001 mg/kg/injection heroin; 0.001 mg/kg/injection NPA plus 0.003 mg/kg/injection heroin) resulted in average numbers of injections/sessions that were reliably lower than those observed with heroin alone (Bonferroni t tests, p < 0.05). With respect to maximal reinforcing effects, analysis of log10(BPmax) values did not reveal a significant difference for NPA-heroin combinations compared with heroin alone (data not shown).
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For quinpirole (Fig. 4b), the repeated measures ANOVA revealed a main effect of heroin dose [F(4,16) = 10.8; p < 0.05] and a reliable quinpirole dose x heroin dose interaction [F(8,32) = 4.4; p < 0.05], but no main effect of quinpirole dose [F(2,8) = 2.5; p = 0.144]. As with the NPA analysis, these ANOVA results probably reflect an overall attenuation of the effects of heroin by combination with quinpirole. Multiple comparison tests showed that two dose combinations (0.003 mg/kg/injection quinpirole plus 0.003 mg/kg/injection heroin and 0.01 mg/kg/injection quinpirole plus 0.003 mg/kg/injection heroin) resulted in reliably lower average numbers of injections/sessions compared with the corresponding doses of heroin alone (Bonferroni t tests, p < 0.05). As with NPA-heroin combinations, the average maximal reinforcing effects of the quinpirole-heroin combinations, measured by log10(BPmax) determinations, did not differ from the average maximal reinforcing effects of heroin alone (data not shown).
Combination of SKF 81297 or NPA with Cocaine. To determine the extent to which the different modulatory effects of D1-like and D2-like agonists are unique to combinations with heroin, we repeated the studies using SKF 81297 and NPA combined with cocaine. As can be seen in Fig. 5a, the effects of combining SKF 81297 with cocaine were similar to the effects of combining this D1-like agonist with heroin, in that self-administration of an ineffective dose of cocaine was enhanced by combination with SKF 81297. Analysis of the number of injections/session following SKF 81297-cocaine combinations revealed a main effect of cocaine dose [F(3,6) = 5.3; p < 0.05], a main effect of SKF 81297 dose [F(2,4) = 21.8; p < 0.05], but no interaction between cocaine dose x SKF 81297 [F(6,12) = 1.7, p > 0.05], indicative of an overall increase in self-administration engendered by both cocaine and SKF 81297. Multiple comparison tests showed that self-administration of the combination of 0.01 mg/kg/injection and 0.03 mg/kg/injection of SKF 81297 with 0.03 mg/kg/injection of cocaine was reliably greater than self-administration of this dose of cocaine alone (Fig. 5a).
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Isobolographic Analysis. Isobolograms were calculated for the lower of the two doses of cocaine or DA agonist combined with heroin, because combination with the higher doses of cocaine or DA agonist typically did not result in points associated with 50% of the maximal number of injections/session. The isobolographic analyses of combinations with heroin are summarized in Table 1. Combinations of heroin with cocaine, SKF 82958, and SKF 81297 resulted in additive effects (comparison of the ratio of predicted to obtained ED50 values for the combinations; one-sample t test, p < 0.05). In contrast, combination of heroin with 0.0003 mg/kg/injection of NPA as well as combinations of heroin with 0.003 mg/kg/injection of quinpirole resulted in reliable infra-additive interactions (one-sample t tests, p < 0.05; Table 1).
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Isobolograms were calculated for the lower doses of SKF 81297 or NPA in combination with cocaine (Table 2). Combinations of cocaine with SKF 81297 resulted in additive effects (comparison of the ratio of predicted to obtained ED50 values for the combinations; one-sample t test, p > 0.05). In contrast, combination of cocaine with 0.0003 mg/kg/injection of NPA resulted in a reliable infra-additive interaction (one-sample t test, p < 0.05; Table 2).
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Discussion |
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Although our findings with DA agonists generally are congruent with previous reports using PR procedures (e.g., Weed et al., 1997; Woolverton and Ranaldi, 2002), several differences among the present results and previous reports are noteworthy. For example, Weed et al. (1997) showed that the relative reinforcing effectiveness of SKF 82958, but not SKF 81297, was similar to that of cocaine. In the present study, however, both D1-like agonists were less effective reinforcers compared with cocaine. In addition, in the Woolverton and Ranaldi (2002) report, NPA was a much less effective reinforcer compared with the findings from our studies. The reasons for these differences in self-administration with very similar PR procedures are unclear, although one possibility might be the different experimental histories of the monkeys. In the Weed et al. (1997) and Woolverton and Ranaldi (2002) studies, the monkeys had extensive experience self-administering DA agonists, stimulants, and local anesthetics. In contrast, monkeys in our studies had extensive histories primarily with opioid receptor agonists and cocaine-opioid receptor agonist combinations. Self-administration history has previously been shown to play a key role in the extent to which the D2-like agonist quinpirole was self-administered by rhesus monkeys (Sinnott et al., 1999).
Self-administration of cocaine-heroin combinations in our study was enhanced compared with heroin alone (Rowlett and Woolverton, 1997; Rowlett et al., 1998, 2005). A consistent finding across the present and previous studies is that doses of cocaine and heroin that did not maintain self-administration above saline levels when tested alone resulted in significant self-administration when available in combination. When assessed via isobolographic analysis, the combined effects of cocaine and heroin were found to be largely dose-additive. This finding is consistent with a recent report by Negus (2005), in which combining cocaine and heroin in a choice procedure often resulted in dose-additive effects. One interpretation of additive drug effects is that the two drugs act via a common mechanism (Wessinger, 1986; Woolverton, 1987), an interpretation consistent with the idea that the combined effects of cocaine and heroin are modulated by coactivation of the mesolimbic DA systems (Rowlett et al., 1998, 2005; Smith et al., 2006). Cocaine and heroin both have been shown to increase mesolimbic DA neurotransmission, the former by blockade of DA transport, and the latter by µ opioid receptor activation of mesolimbic DA neurons (for review, see Di Chiara and North, 1992).
In the present study, two agonists with selectivity for D1-like receptors enhanced self-administration of relatively low doses of heroin. These results were qualitatively similar to the findings with combinations of cocaine and heroin. That is, doses of the D1-like agonists and heroin that did not maintain reliable self-administration when tested alone resulted in significant self-administration when combined. As with cocaine-heroin combinations, effects were not observed at relatively high dose combinations (as determined via the BPmax measure). Moreover, isobolographic analyses showed that the combined effects of the D1-like agonists with heroin were dose-additive. If additive effects of cocaine-heroin combinations reflect overlapping mechanisms of action, presumably by stimulation of DA neurotransmission; then the present findings raise the possibility that D1-like receptor stimulation is a key mechanism of action underlying speed-ball self-administration.
In contrast to the effects of combining D1-like agonists with heroin, the combination of the D2-like agonists NPA and quinpirole with heroin resulted in an attenuation of self-administration. That is, combinations of the D2-like agonists with heroin reduced self-administration compared with heroin alone, resulting in overall rightward and downward shifts of the heroin dose-response function. Surprisingly, this attenuation of the reinforcing effects of heroin also occurred with doses of NPA or quinpirole that were self-administered when available alone. Isobolographic analyses of the combined effects of heroin with NPA and quinpirole revealed significant infra-additive interactions. Infra-additive effects occur when the combined effects of two drugs are less than predicted based on dose additivity (Wessinger, 1986; Woolverton, 1987). Pharmacological mechanisms underlying infra-additive interactions are incompletely understood, although one potential mechanism is functional antagonism (Wessinger, 1986; Woolverton, 1987). However, the likelihood of D2-like agonists acting as functional antagonists of heroin seems remote, because there are no known reports of these D2-like agonists interacting with opioids at the receptor level. Nevertheless, our findings show that D2-like agonists inhibit the reinforcing effects of heroin when administered together, suggesting a functional antagonism at least at the level of the final common pathway involved in the process of reinforcement.
Another possible explanation for intra-additive interactions between D2-like agonists and heroin is that the D2-like compounds induced nonspecific inhibitory effects on operant lever pressing. To examine the specificity of the effects of combining DA agonists with heroin, we conducted a control study in which cocaine was combined with the same doses of either SKF 81297 or NPA that differentially altered heroin self-administration. Similar to SKF 81297-heroin combinations, the combination of SKF 81297 with cocaine resulted in enhanced self-administration of relatively low doses of cocaine compared with these doses of cocaine alone. These results differ from those of other studies in which D1-like agonists were administered as pretreatments followed by a period of cocaine self-administration. In these studies, D1-like agonists generally suppress cocaine self-administration (for review, see Platt et al., 2002). The reason for this discrepancy is not clear, although differences in species and schedules of reinforcement are possible contributing factors. Moreover, it is noteworthy that the D1-like agonist in the present study was combined with cocaine, i.e., its administration was response-contingent, in contrast to being administered as a pretreatment.
In contrast to the findings with D2-like agonists combined with heroin, evidence for an enhancement of the effects of cocaine when combined with NPA was obtained. This enhancement occurred at a dose of NPA that when combined with heroin, clearly attenuated self-administration of the opioid agonist. A potentially important implication of these findings is that D2-like agonists do not invariably induce a nonspecific inhibition of lever pressing.
Although NPA combination enhanced cocaine self-administration at the higher of the two NPA doses (0.001 mg/kg/injection), isobolographic analysis revealed an infra-additive interaction between cocaine and the lower dose of NPA (0.0003 mg/kg/injection). That is, isobolographic analysis predicted that the lower dose of NPA should have enhanced self-administration of cocaine, yet no effect on cocaine self-administration was observed. This finding is similar to the results of combining NPA with heroin, and, in general, these findings suggest that D2-like agonists can under suitable conditions attenuate the reinforcing effects of cocaine.
Although the finding that self-administered doses of D2-like agonists suppressed heroin self-administration and interacted with cocaine in an infra-additive manner is at first glance unexpected, evidence for attenuation of other behavioral effects of both heroin and cocaine by these compounds does exist (Cook and Beardsley, 2004; Witkin et al., 2004). For example, Cook and Beardsley (2004) showed that quinpirole and 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT), a D2-like agonist that binds preferentially to D3 receptors, attenuated the discriminative stimulus effects of heroin, consistent with earlier research demonstrating that this D3-preferring agonist attenuated the antinociceptive effects of morphine (Cook et al., 1999). In another study, the convulsant effects of cocaine were blocked by a series of D2-like agonists in a manner consistent with action at D3 receptors (Witkin et al., 2004). Based on this research, an intriguing speculation is that the ability of D2-like agonists to attenuate the reinforcing effects of heroin and to interact with cocaine in an infra-additive fashion may involve primarily actions mediated by the D3 receptor.
Speedball abuse consistently is associated with a higher rate of failure in detoxification and treatment compared with abuse of the individual drugs (Marrero et al., 2005). No medications are currently available for treatment of speed-ball abuse, and, in fact, the use of methadone to treat heroin dependence is often associated with high rates of cocaine abuse (Meandzija et al., 1994). Our results suggest that DA receptors might be viable targets for development of pharmacotherapies for speedball abuse, in particular, D2-like receptors based both on their ability to attenuate the abuse-related effects of heroin and to interact with cocaine in an infra-additive manner.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: DA, dopamine; SKF 81297, 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine HCl; SKF 82958, 6-chloro-N-allyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine; NPA R-(-)-propylnorapomorphine; T, test; C, cocaine; S, saline; ANOVA, analysis of variance; BPmax, maximal break point irrespective of dose; PR, progressive ratio; 7-OH-DPAT, 7-hydroxy-2-dipropylaminotetralin.
Address correspondence to: Dr. James K. Rowlett, New England Primate Research Center, Harvard Medical School, Box 9102, One Pine Hill Dr., Southborough, MA 01772-9102. E-mail: james_rowlett{at}hms.harvard.edu
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References |
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Civelli O, Bunzow JR, Grandy DK, Zhou Q-Y, and Van Tol HHM (1991) Molecular biology of the dopamine receptors. Eur J Pharmacol 207: 277-286.[CrossRef][Medline]
Cook CD and Beardsley PM (2004) Modulation of the discriminative stimulus effects of mu opioid agonists in rats: II. Effects of dopamine D2/3 agonists. Behav Pharmacol 15: 75-83.[CrossRef][Medline]
Cook CD, Rodefer JS, and Picker MJ (1999) Selective attenuation of the antinociceptive effects of mu opioid by the putative dopamine D3 agonist 7-OH-DPAT. Psychopharmacology 144: 239-247.[CrossRef][Medline]
Di Chiara G and North RA (1992) Neurobiology of opiate abuse. Trends Pharmacol Sci 13: 185-193.[CrossRef][Medline]
Doll MKH, Nichols DE, Kilts JD, Prioleau C, Lawler CP, Lewis MM, and Mailman RB (1999) Synthesis and dopaminergic properties of benzo-fused analogues of quinpirole and quinelorane. J Med Chem 42: 935-940.[CrossRef][Medline]
Gao Y, Baldessarini RJ, Kula NS, and Neumeyer JL (1990) Synthesis and dopamine receptor affinities of enantiomers of 2-substituted apomorphines and their N-n-propyl analogues. J Med Chem 33: 1800-1805.[CrossRef][Medline]
Gessner PK (1974) The isobolographic method applied to drug interactions, in Drug Interactions (Morselli PL, Garattini S, and Cohen SN eds) pp 349-362, Wiley-Liss, Inc., New York.
Hemby SE, Smith JE, and Dworkin SI (1996) The effects of eticlopride and naltrexone on responding maintained by food, cocaine, heroin and cocaine/heroin combinations in rats. J Pharmacol Exp Ther 277: 1247-1258.
Koob GF (1992) Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci 13: 177-184.[CrossRef][Medline]
Leri F, Bruneau J, and Stewart J (2003) Understanding polydrug use: review of heroin and cocaine co-use. Addiction 98: 7-22.[CrossRef][Medline]
Malmberg A and Mohell N (1995) Characterization of [3H]quinpirole binding to human dopamine D2A and D3 receptors: effects of ions and guanine nucleotides. J Pharmacol Exp Ther 274: 790-797.
Marrero CA, Robles RR, Colón HM, Reyes JC, Matos TD, Sahai H, Calderón JM, and Shepard EW (2005) Factors associated with drug treatment dropout among injection drug users in Puerto Rico. Addict Behav 30: 397-402.[CrossRef][Medline]
Meandzija B, O'Connor PG, Fitzgerald B, Rounsaville BJ, and Kosten TR (1994) HIV infection and cocaine use in methadone maintained and untreated intravenous drug users. Drug Alcohol Depend 36: 109-113.[CrossRef][Medline]
Mello NK and Negus SS (1999) Effects of flupenthixol and quadazocine on self-administration of speedball combinations of cocaine and heroin by rhesus monkeys. Neuropsychopharmacology 21: 575-588.[CrossRef][Medline]
Negus SS (2005) Interactions between the reinforcing effects of cocaine and heroin in a drug-vs-food choice procedure in rhesus monkeys: a dose-addition analysis. Psychopharmacology (Berl) 80: 115-124.
Platt DM, Carey GJ, and Spealman RD (2005) Intravenous self-administration techniques in monkeys, in Current Protocols in Neuroscience (Enna S, Williams M, Ferkany J, Kenakin T, Porsolt R, and Sullivam J eds) Unit 9.21, Wiley-Liss, Inc., New York.
Platt DM, Rowlett JK, and Spealman RD (2002) Behavioral effects of cocaine and dopaminergic strategies for preclinical medication development. Psychopharmacology (Berl) 163: 265-282.[CrossRef][Medline]
Ranaldi R, Wang Z, and Woolverton WL (2001) Reinforcing effects of D2 dopamine receptor agonists and partial agonists in rhesus monkeys. Drug Alcohol Depend 64: 209-217.[CrossRef][Medline]
Rowlett JK, Platt DM, and Spealman RD (2004) Cocaine-like discriminative stimulus effects of heroin: modulation by selective monoamine transport inhibitors. J Pharmacol Exp Ther 310: 342-348.
Rowlett JK, Rodefer JS, and Spealman RD (2002) Self-administration of cocaine, alfentanil, and nalbuphine under progressive-ratio schedules: consumer demand and labor supply analyses of relative reinforcing effectiveness. Exp Clin Psychopharmacol 10: 367-375.[CrossRef][Medline]
Rowlett JK, Rodefer JS, and Spealman RD (2005) Self-administration of cocaine-opioid combinations by rhesus monkeys: evaluation of the role of µ receptor efficacy using labor supply analysis. J Pharmacol Exp Ther 312: 1289-1297.
Rowlett JK, Spealman RD, and Platt DM (2001) Similar enhancement of the discriminative stimulus effects of cocaine and GBR 12909 by heroin in squirrel monkeys. Psychopharmacology (Berl) 157: 313-319.[CrossRef][Medline]
Rowlett JK, Wilcox KM, and Woolverton WL (1998) Self-administration of cocaine-heroin combinations by rhesus monkeys: antagonism by naltrexone. J Pharmacol Exp Ther 286: 61-69.
Rowlett JK and Woolverton WL (1997) Self-administration of cocaine and heroin combinations by rhesus monkeys responding under a progressive-ratio schedule. Psychopharmacology 133: 363-371.[CrossRef][Medline]
Schwartz JC, Giros B, Martres MP, and Sokoloff P (1992) The dopamine receptor family: molecular biology and pharmacology. Neuroscience 4: 99-108.[Medline]
Sinnott RS, Mach RH, and Nader MA (1999) Dopamine D2/D3 receptors modulate cocaine's reinforcing and discriminative stimulus effects in rhesus monkeys. Drug Alcohol Depend 54: 97-110.[CrossRef][Medline]
Smith JE, Co C, Coller MD, Hemby SE, and Martin TJ (2006) Self-administered heroin and cocaine combinations in the rat: additive reinforcing effects: supra-additive effects on nucleus accumbens extracellular dopamine. Neuropsychopharmacology 31: 139-150.[Medline]
Weed MR, Paul IA, Dwoskin LP, Moore SE, and Woolverton WL (1997) The relationship between reinforcing effects and in vitro effects of D1 agonists in monkeys. J Pharmacol Exp Ther 283: 29-38.
Weed MR, Woolverton WL, and Paul IA (1998) Dopamine D1 and D2 receptor selectivities of phenyl-benzazepines in rhesus monkey striata. Eur J Pharmacol 361: 129-142.[CrossRef][Medline]
Wessinger WD (1986) Approaches to the study of drug interactions in behavioral pharmacology. Neurosci Biobehav Rev 10: 103-113.[CrossRef][Medline]
Witkin JM, Dijkstra D, Levant B, Akunne HC, Zapata A, Peters S, Shannon HE, and Gasior M (2004) Protection against cocaine toxicity in mice by the dopamine D3/D2 agonist R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol [(+)-PD 128,907]. J Pharmacol Exp Ther 308: 957-964.
Woolverton WL (1987) Analysis of drug interactions in behavioral pharmacology, in Neurobehavioral Pharmacology (Thompson T, Dews PB, and Barrett JE eds) vol 6, pp 275-302, Erlbaum, Hillsdale, NJ.
Woolverton WL and Johnson KM (1992) Neurobiology of cocaine abuse. Trends Pharmacol Sci 13: 193-200.[CrossRef][Medline]
Woolverton WL and Ranaldi R (2002) Comparison of the reinforcing efficacy of two dopamine D2-like receptor agonists in rhesus monkeys using a progressive-ratio schedule of reinforcement. Pharmacol Biochem Behav 72: 803-809.[CrossRef][Medline]
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