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BEHAVIORAL PHARMACOLOGY
Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont, Massachusetts (S.S.N., N.K.M.); Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina (B.E.B.); and Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (M.H.B., R.B.R.)
Received May 4, 2006; accepted October 26, 2006.
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Abstract |
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; Vocci et al., 2005). One potential approach to the treatment of cocaine dependence has been suggested by the effective treatment of opioid dependence with opioid agonists such as methadone and of tobacco dependence with formulations of nicotine. These medications share pharmacological mechanisms of action with the abused drug and produce some effects in common with the abused drug, and they have been referred to as "agonist" medications (Rothman and Glowa, 1995). Cocaine blocks the reuptake of dopamine, serotonin, and norepinephrine, and the abuse-related effects of cocaine are thought to be mediated primarily by its dopaminergic effects (Woolverton and Johnson, 1992). Consequently, both indirect and direct dopamine agonists have been evaluated as candidate agonist medications (Mello and Negus, 1996; Carroll et al., 1999; Newman and Kulkarni, 2002; Platt et al., 2002; Rothman et al., 2002; Grabowski et al., 2004). As one example, chronic treatment with the monoamine releaser d-amphetamine, which selectively releases dopamine and norepinephrine, produced a dose-dependent and sustained decrease in cocaine self-administration under second-order, progressive-ratio and choice schedules in rhesus monkeys (Negus, 2003; Negus and Mello, 2003a,b). Moreover, amphetamine-induced decreases in cocaine self-administration were relatively selective, in that cocaine self-administration was reduced by amphetamine doses that had lesser effects on responding maintained by a nondrug reinforcer (food pellets) and that produced little other evidence of toxicity. Amphetamine maintenance also decreased cocaine use with low toxicity in clinical trials (Grabowski et al., 2001, 2004), and effective doses in humans were almost identical to doses that reduced cocaine self-administration in nonhuman primates.
These results suggest that amphetamine may be a promising lead compound in the development of agonist medications for cocaine abuse and dependence. However, amphetamine is itself a drug of abuse, and its high abuse potential limits its utility as a candidate medication for addiction treatment. One strategy for building on these results with amphetamine is to identify other monoamine releasers that have lower abuse potential than amphetamine but that retain amphetamine's ability to produce sustained and selective decreases in cocaine self-administration. A growing body of literature suggests that a reduction in the selectivity of monoamine releasers to release dopamine/norepinephrine versus serotonin is associated with a reduction in reinforcing effects (Locke et al., 1996; Rothman et al., 2005; Wee et al., 2005). Serotonergic activity also seems to limit the reinforcing effects of monoamine reuptake inhibitors (Czoty et al., 2002). Less is known about the degree to which selectivity for release of different monoamines influences the effects of monoamine releasers on cocaine self-administration. In one study, acute administration of an appropriate dose combination of phentermine (which selectively releases dopamine/norepinephrine >> serotonin) and fenfluramine (which selectively releases serotonin >> dopamine/norepinephrine) decreased cocaine self-administration more than food-maintained responding in rhesus monkeys; however, phentermine alone reduced cocaine self-administration with even lesser effects on food-maintained responding (Glowa et al., 1997). Likewise, chronic administration of the nonselective releaser PAL-287 produced a marginally selective decrease in cocaine self-administration versus food-maintained responding in rhesus monkeys, but more selective reductions in cocaine self-administration were achieved with chronic amphetamine treatment (Negus and Mello, 2003b; Rothman et al., 2005). Taken together, these results suggest that reducing the dopamine/norepinephrine versus serotonin selectivity of releasers may reduce their abuse potential, but this may also reduce their ability to produce behaviorally selective reductions in cocaine- versus food-maintained responding.
The purpose of the present study was to further investigate the degree to which dopamine/norepinephrine versus serotonin selectivity would influence the cocaine-like abuse-related effects of monoamine releasers and the ability of these compounds to produce selective reductions in cocaine self-administration. Five compounds were selected for study, ranging from PAL-353 (selectively releases DA/NE >> 5HT) to the serotonin-selective releaser fenfluramine. Figure 1 shows the chemical structures of these five drugs, and Table 1 shows potency and selectivity data for the drugs to serve as substrate-type releasers at dopamine, norepinephrine, and serotonin transporters. As is commonly true for existing monoamine releasers, the potency of these compounds to release norepinephrine was similar to or higher than potency to release dopamine, and compounds with exclusive selectivity for dopamine or norepinephrine release are not yet available (Rothman et al., 2001). All compounds were evaluated first in an assay of cocaine discrimination in rhesus monkeys to assess the relative potency and efficacy of these compounds to produce cocaine-like discriminative stimulus effects. These studies provide one measure of the ability of these compounds to produce cocaine-like abuse-related effects. Second, all compounds were evaluated for their effects on cocaine- and food-maintained responding under a second-order schedule that has been used previously to assess the effects of amphetamine (Negus and Mello, 2003b) and other candidate medications (Negus et al., 1997, 1999; Mello and Negus, 1998; Negus and Mello, 2002). Preclinical studies with this procedure have shown good concordance with clinical trials (Mello, 2005). We hypothesized that decreases in selectivity for dopamine/norepinephrine versus serotonin release would be associated with decreases in cocaine-like discriminative stimulus effects and decreases in the selectivity of reductions in cocaine self-administration.
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Materials and Methods |
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Animal maintenance and research were conducted in accordance with the guidelines provided by the National Institutes of Health Committee on Laboratory Animal Resources. The facility was licensed by the United States Department of Agriculture, and protocols were approved by the Institutional Animal Care and Use Committee. The health of the monkeys was periodically monitored by consulting veterinarians. Monkeys had visual, auditory, and olfactory contact with other monkeys throughout the study. Operant procedures and foraging toys provide an opportunity for environmental manipulation and enrichment.
Drug Discrimination Procedures
Apparatus. Each monkey was housed individually in a well ventilated stainless steel chamber (56 x 71 x 69 cm). The home cages of all monkeys were modified to include an operant panel (28 x 28 cm) mounted on the front wall. Three round translucent response keys (5.1 cm in diameter) were arranged 3.5 cm apart in a horizontal row 9 cm from the top of the operant panel. Each key could be transilluminated by red or green stimulus lights (SuperBright LEDs; Fair-child Semiconductor, San Jose, CA). In addition, three circular translucent panels (1.9 cm in diameter) were located in a vertical column below the center response key and could be transilluminated by red or green stimulus lights. The operant panel also supported an externally mounted pellet dispenser (model G5210; Gerbrands, Arlington, MA) that delivered 1-g food pellets to a food receptacle mounted on the cage beneath the operant response panel. Operation of the operant panel and pellet dispenser and data collection were accomplished with custom-written software operating on microprocessors and software purchased from MED Associates (Georgia, VT) and located in a separate room.
Discrimination Training. Subjects were trained to discriminate cocaine (0.4 mg/kg i.m.) from saline using procedures identical to those used for our previous studies of the effects of indirect and direct dopamine agonists (Lamas et al., 1996; Negus et al., 1999). Discrimination sessions consisted of multiple 20-min cycles and were conducted 5 days per week. Each cycle consisted of a 15-min time-out period followed by a 5-min response period. During the time-out, all stimulus lights were off and responding had no scheduled consequences. During the response period, the right and left response keys were transilluminated red or green, and monkeys could receive up to 10 food pellets by responding under a fixed ratio (FR) 30 schedule of food presentation. For three of the six monkeys, the left key was illuminated green and the right key was illuminated red. For the other three monkeys, the colors of the response keys were reversed. The center key was not illuminated at any time, and responding on the center key had no scheduled consequences. If all available food pellets were delivered before the end of the 5-min response period, the stimulus lights transilluminating the response keys were turned off, and responding had no scheduled consequences for the remainder of that response period.
On training days, monkeys were given an i.m. injection of either saline or 0.40 mg/kg cocaine 5-min after the beginning of each timeout period (i.e., 10 min before the response period). Following administration of saline, responding on only the green key (the saline-appropriate key) produced food, whereas following administration of 0.40 mg/kg cocaine, only responding on the red key (the drug-appropriate key) produced food. Responses on the inappropriate key reset the FR requirement. Daily sessions consisted of one to five cycles, and if the training dose of cocaine was administered, it was administered only during the last cycle.
During the response period of each cycle, three dependent variables were determined: 1) percentage of injection-appropriate responding before delivery of the first reinforcer [(injection-appropriate responses emitted before first reinforcer ÷ total responses emitted before first reinforcer) x 100]; 2) percentage of injection-appropriate responding for the entire response period [(injection – appropriate responses emitted during response period ÷ total responses emitted during response period) x 100]; and 3) response rate (total responses emitted during response period ÷ total time stimulus lights were illuminated).
Monkeys were considered to have acquired cocaine discrimination when the following three criteria were met for seven of eight consecutive training sessions: 1) the percentage of injection-appropriate responding before delivery of the first reinforcer was greater than or equal to 80% for all cycles; 2) the percentage of injection-appropriate responding for the entire cycle was greater than or equal to 90% for all cycles; and 3) at least one pellet was earned during all training cycles.
Discrimination Testing. Once monkeys met criterion levels of cocaine discrimination, testing began. Test sessions were identical to training sessions except that responding on either key produced food, and test compounds were administered using a cumulative dosing procedure. In this procedure, increasing doses of the test compound were administered at the beginning of each successive 20-min cycle, instead of saline or the cocaine training dose, and each successive dose increased the total cumulative dose by 0.5 log units. Each drug was tested in a group of five monkeys, and testing in each monkey was conducted up to a dose that produced >90% cocaine-appropriate responding (i.e., full substitution) or that eliminated responding. Note that an original group of five monkeys was used to test cocaine, PAL-353, PAL-314, PAL-287, and fenfluramine. One monkey died of causes unrelated to the study before methamphetamine could be tested. Accordingly, a sixth monkey was used to test cocaine and methamphetamine.
Test sessions were usually conducted on Tuesday and Friday, and training sessions were usually conducted on Monday, Wednesday, and Thursday. Test sessions were conducted only if the three criteria listed above were met during the training day immediately preceding the test day. If responding did not meet criterion levels of discrimination performance, then training was continued until criterion levels of performance were obtained for at least two consecutive days.
Data Analysis. Where possible, an ED50 value for each drug in each monkey was defined as the dose of a test compound that produced 50% cocaine-appropriate responding. Log ED50 values were calculated by log-linear interpolation from individual subject dose-effect curves. Log ED50 values were averaged to yield mean values, and these log values were converted to linear values for presentation. In addition, the percentage of cocaine-appropriate responding and the percentage of control response rate were determined for the highest dose of each compound tested in each monkey. These data were averaged and are reported in tabular form. For determination of the percentage of control response rate, the control response rate was determined for each monkey as the mean response rate during saline training cycles immediately preceding test sessions throughout the study. For graphical display, the cumulative percentage of monkeys in which full substitution (>90% cocaine-appropriate responding) was observed is shown as a function of drug dose.
Drug Self-Administration
Apparatus. Each monkey was housed individually in a well ventilated stainless steel chamber (64 x 64 x 79 cm). The home cages of all monkeys were modified to include an operant panel and pellet dispenser identical to those described above for drug discrimination studies. In addition, a double-lumen catheter was surgically implanted into each monkey under aseptic conditions as described previously (Negus et al., 1999; Negus and Mello, 2003b). The intravenous catheter was protected by a tether system consisting of a custom-fitted nylon vest connected to a flexible stainless steel cable and fluid swivel (Lomir Biomedical, Malone, NY). Two syringe pumps (model B5P-lE; Braintree Scientific, Braintree, MA; or model 980210, Harvard Apparatus, South Natick, MA) were mounted above each cage for delivery of saline or drug solutions through the two lumen of the intravenous catheters. One syringe pump (the self-administration pump) was used to deliver self-administered cocaine injections. The second syringe pump (the treatment pump) was used for noncontingent delivery of saline or test drugs. The treatment pump delivered injections every 20 min from 10:30 AM each day until 9:30 AM. the next morning for a total of 3 injections/h and 69 injections/day. No treatment injections were delivered between 9:30 AM and 10:30 AM. During this period, monkeys received their morning ration of food, and their health status was evaluated by the technical staff. Catheter patency was periodically evaluated by i.v. administration of 5 mg/kg ketamine or the short-acting barbiturate methohexital (3 mg/kg) through the catheter lumen. The catheter was considered to be patent if i.v. administration of ketamine or methohexital produced a loss of muscle tone within 10 s. Operation of the operant panel, pellet dispenser, and drug pumps and the collection of data were accomplished with custom-written software operating on microprocessors and software purchased from MED Associates and located in a separate room.
Training Procedure. Procedures for the evaluation of cocaine- and food-maintained responding were identical to those used in our previous studies of indatraline and amphetamine (Negus et al., 1999; Negus and Mello, 2003b). Alternating daily sessions of food and cocaine availability were associated with different colored stimulus lights projected on the center response key of the operant response panel. Red stimulus lights signaled food availability, and green stimulus lights signaled the availability of cocaine injections (delivered in a volume of 0.1 ml in 1 s). Under the terminal schedule, the completion of a variable ratio of 16 responses on the center response key resulted in the illumination for 1 s of an appropriately colored stimulus light (red for food, green for drug) underneath the center key (VR16:S). In addition, completion of this VR response requirement at FR2 resulted in delivery of the available reinforcer and the initiation of a 10-s time-out period, during which the stimulus light illuminating the center response key was turned off and responding had no scheduled consequences. This terminal second-order schedule is designated as FR2(VR16:S). The two side keys were not transilluminated during sessions of food and cocaine availability, and responding on these keys had no scheduled consequences. Four food sessions and four drug sessions were conducted during each experimental day. Food sessions began at 11:00 AM, 3:00 PM, 7:00 PM, and 6:00 AM. the next morning, and drug sessions began at 12:00 PM, 4:00 PM, 8:00 PM, and 7:00 AM. the next morning. At all other times, responding had no scheduled consequences. Each food and drug session lasted 1 h or until 25 food pellets or 20 injections had been delivered, whichever occurred first. Thus, monkeys could earn a maximum of 100 food pellets per day and 80 injections per day. Studies were conducted 7 days per week.
During initial training, responding was maintained by delivery of 1-g food pellets during food sessions and by 0.032 mg/kg/injection of cocaine during drug sessions. Training continued until monkeys met the following criteria for stable food and cocaine self-administration under the terminal schedule: 1) three consecutive days during which the number of drug injections/day differed by no more than 20% from the mean number of drug injections/day during those 3 days, and there was no upward or downward trend; and 2) during the same three consecutive days, the mean number of both drug injections per day and food pellets per day was greater than 50.
Testing Procedures. Once cocaine- and food-maintained responding stabilized, testing began. Each dose of each drug was tested for a period of seven consecutive days. During the 7-day test period, the unit dose of cocaine was changed to 0.01 mg/kg/inj, and saline or a dose of a test drug was administered by the treatment pump through one lumen of the double lumen catheter as described above (one injection every 20 min from 10:30 AM each day until 9:30 AM the next day unless stated otherwise). A unit dose of 0.01 mg/kg/injection cocaine was used for these studies, because previous studies have demonstrated that this is the lowest dose to reliably maintain high rates of cocaine self-administration in all monkeys, and because behavior maintained by this unit dose of cocaine is sensitive to the effects of pretreatment compounds (Negus et al., 1999; Negus and Mello, 2003b). The infusion rate for test drugs was identical to that used in our previous studies with amphetamine and opioids, and a similar infusion rate was used in the present study to permit direct comparison with those previous studies (Negus et al., 1997; Mello and Negus, 1998; Negus and Mello, 2002, 2003a,b; Negus, 2003; Pereira Do Carmo et al., 2006). The dose ranges for each test drug were as follows: PAL-353 (0.032–0.32 mg/kg/h), methamphetamine (0.01–0.056 mg/kg/h), PAL-314 (0.32–1.0 mg/kg/h), PAL-287 (0.1–1.0 mg/kg/h), and fenfluramine (0.1–1.0 mg/kg/h). For all drugs except PAL-314, these dose ranges were empirically determined to cover a range from doses that produced little or no effect to doses that decreased rates of cocaine self-administration to less than 20% of control. The dose range for PAL-314 was limited by the solubility of the drug. In particular, delivery of 1.0 mg/kg/h PAL-314 required an increase in infusion rate from 0.3 ml/h (0.1 ml every 20 min) to 1.2 ml/h (0.1 ml every 5 min). Doses higher than 1.0 mg/kg could not be reliably tested, because sustained use of higher infusion rates placed undue strain on the catheter. At the conclusion of each test period, the maintenance dose of cocaine (0.032 mg/kg/inj) and saline control treatment were reinstated for a period of at least 4 days and until the number of reinforcers per day maintained by cocaine and food returned to baseline levels. This interval between successive treatments was designed to reduce the possibility of carryover effects from one treatment condition to the next.
Both PAL-353 and methamphetamine produced relatively selective decreases in responding maintained by 0.01 mg/kg/injection of cocaine versus food. To evaluate the effects of these two drugs on self-administration maintained by a higher unit dose of cocaine, a follow-up study was conducted. Specifically, the highest dose of each of these drugs (0.32 mg/kg/h PAL-353 and 0.056 mg/kg/h methamphetamine) was tested during availability of 0.032 mg/kg/injection of cocaine. These experiments were identical to those described above, except for the higher cocaine unit dose.
The effects of each test drug on cocaine- and food-maintained responding were evaluated in groups of three to four monkeys. In general, all doses of one drug were tested in a given monkey before initiation of studies with another drug. Both the sequence of drug doses and the sequence of drugs were mixed across monkeys. It should also be noted that results with PAL-287 were described previously (Rothman et al., 2005).
Data Analysis. The primary dependent variables were the total injections per day and total pellets per day delivered during the last 3 days of treatment with saline or each dose of each test drug. For statistical analysis, values for cocaine- and food-maintained responding during drug treatments were expressed as a percentage of control values for cocaine- and food-maintained responding obtained during saline treatment. Test drug effects were then analyzed by two-factor analysis of variance, with test drug dose as one factor, and reinforcer type (cocaine or food) as the other factor. A significant analysis of variance was followed by individual means comparison using simple effects or the Duncan's post hoc test. ED50 values for each drug to reduce cocaine- and/or food-maintained responding were also determined. The ED50 was defined as the dose of test drug that reduced levels of cocaine- or food-maintained responding to 50% of control levels. ED50 values to reduce cocaine- and food-maintained responding were determined in each monkey using log-linear interpolation, and these ED50 values were compared by t test. In the event that a drug reduced cocaine self-administration but not food-maintained responding to levels below 50% of control, a conservative estimate of the ED50 value to reduce food-maintained responding was determined by assuming that the next incremental dose would have eliminated food-maintained responding. For all analyses, the criterion for significance was set at p < 0.05, and all analyses were conducted using commercially available software (CLRANOVA; Clear Lakes Research, Houston, TX). In addition to these statistical analyses, levels of cocaine- and food-maintained responding are also displayed for all 7 days of treatment with saline and the highest dose of each drug.
Drugs
Cocaine HCl was obtained from the National Institute on Drug Abuse (National Institutes of Health, Bethesda, MD) and was dissolved in sterile saline. PAL-287, PAL-314, and PAL-353 were provided by B. Blough. d-Methamphetamine HCl and dl-fenfluramine HCl were purchased from Sigma-Aldrich (St. Louis, MO). All drug solutions were dissolved in water and were filter-sterilized using a 0.22-µm Millipore filter (Millipore Corporation, Billerica, MA). Doses were calculated using the salt forms of the drugs given above.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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cocaine PAL-353 PAL-314 PAL-287 fenfluramine. The rank order of maximal cocaine-like discriminative stimulus effects (defined as maximal percentage monkeys in which complete substitution was observed; Fig. 2) was cocaine = PAL-353 = methamphetamine > PAL-314 = PAL-287 > fenfluramine.
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; Negus and Mello, 2003b). During control saline treatment in the present study, monkeys usually self-administered the maximum numbers of 80 cocaine injections per day and 100 food pellets per day during availability of both 0.01 and 0.032 mg/kg/injection of cocaine. Specifically, during the last 3 days of 7-day control treatments with saline, monkeys responded for 79.2 ± 0.8 cocaine injections per day and 95.3 ± 2.5 food pellets per day during availability of 0.01 mg/kg/injection cocaine and for 78.6 ± 1.0 cocaine injections per day and 97.2 ± 2.8 food pellets per day during availability of 0.032 mg/kg/injection of cocaine.
Figure 3 shows percentage of control levels of responding for 0.01 mg/kg/injection of cocaine and food during treatment with each of the monoamine releasers (results with PAL-287 reported previously; Rothman et al., 2005). Results of statistical analysis are reported in Table 3, and ED50 values for each drug to reduce cocaine- and food-maintained responding are shown in Table 4. PAL-353, methamphetamine, PAL-287, and fenfluramine produced dose-dependent decreases in cocaine self-administration. However, the relative effects on food maintained responding varied. PAL-353 and methamphetamine significantly reduced cocaine self-administration at doses that either did not affect food-maintained responding, or that decreased food-maintained responding significantly less than cocaine self-administration. ED50 analysis indicated that both drugs were at least 3-fold more potent in decreasing cocaine self-administration than in decreasing food-maintained responding. PAL-287 at a dose of 1.0 mg/kg/h was the lowest dose to significantly decrease both cocaine- and food-maintained responding, but cocaine self-administration was decreased more than foodmaintained responding. ED50 analysis indicated that PAL-287 was less than 2-fold more potent in decreasing cocaine self-administration than food-maintained responding, and this small difference in ED50 values was not statistically significant. Finally, fenfluramine produced virtually identical effects on cocaine- and food-maintained responding. A dose of 1.0 mg/kg/h was the lowest dose to significantly decrease responding maintained by either reinforcer, and the magnitude of this decrease was similar for both reinforcers. ED50 analysis also indicated similar potencies of fenfluramine to decrease cocaine- and food-maintained responding. PAL-314 did not significantly alter cocaine or food-maintained responding relative to baseline across the dose range tested (Table 3), and higher doses could not be tested due to the limited solubility of the drug. However, at the highest dose of 1.0 mg/kg/h PAL-314, cocaine- and food-maintained responding were 57.1 ± 6.6 and 98.8 ± 2.7% of control, respectively, indicating a trend for this compound to produce at least a marginally selective decrease in cocaine- versus food-maintained responding.
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Figure 4 shows levels of cocaine self-administration and food-maintained responding during all 7 days of treatment with saline or the highest dose of each monoamine releaser. In general, monkeys responded at high, stable levels for both cocaine and food reinforcement during saline treatment. During treatment with monoamine releasers, maximal decreases in cocaine self-administration were achieved within 2 to 5 days, and decreases in cocaine self-administration were generally sustained for the duration of the treatment. The only exception was PAL-314, and levels of cocaine self-administration seemed to recover toward baseline on day 7 of treatment with 1.0 mg/kg/h PAL-314. As noted above, effects on food-maintained responding varied across monoamine releasers. The smallest effects were observed with PAL-353 and methamphetamine, and the greatest effects were observed fenfluramine.
Figure 5 shows the effects of the highest doses of PAL-353 (0.32 mg/kg/h) and methamphetamine (0.056 mg/kg/h) on responding maintained by food and a higher unit dose of 0.032 mg/kg/injection of cocaine. Results of statistical analysis are reported in Table 3. Results were similar to those reported during availability of the lower unit dose of 0.01 mg/kg/injection of cocaine. Specifically, 0.32 mg/kg/h PAL-373 significantly decreased both 0.032 mg/kg/injection cocaine self-administration and food-maintained responding, but cocaine self-administration was decreased more than food-maintained responding. A dose of 0.056 mg/kg/h methamphetamine significantly decreased 0.032 mg/kg/injection cocaine self-administration, but it did not significantly alter food-maintained responding.
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Discussion |
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Effects of Monoamine Releasers in the Assay of Cocaine Discrimination. The results of the present study agree with previous findings that dopamine/norepinephrine-selective releasers substitute more effectively than serotonin-selective releasers for a cocaine training stimulus in drug discrimination studies. For example, amphetamine substituted for cocaine in rats and rhesus monkeys trained to discriminate cocaine from saline, whereas fenfluramine did not (D'Mello and Stolerman, 1977; Schuster and Johanson, 1985; Wood and Emmett-Oglesby, 1988). Likewise, cocaine and amphetamine produced relatively similar profiles of discriminative and subjective effects in humans, whereas fenfluramine did not produce stimulant-like subjective effects (Chait et al., 1986; Oliveto et al., 1998). The present results also provide some insight into the degree of dopamine/norepinephrine versus serotonin selectivity that is required to produce reliable cocaine-like discriminative stimulus effects. Specifically, methamphetamine (which is approximately 31-fold selective for dopamine versus serotonin release in assays of monoamine release; Table 1) produced full substitution for cocaine in all monkeys, whereas PAL-314 and PAL-287 (which have 6.1-fold selectivity and 0.27-fold selectivity, respectively) did not substitute for cocaine in all monkeys. The present results also agree with the finding that reductions in selectivity for dopamine/norepinephrine versus serotonin release are associated with reductions in the reinforcing efficacy of monoamine releasers in rhesus monkeys (Locke et al., 1996; Rothman et al., 2005; Wee et al., 2005). Interestingly, PAL-314 and PAL-287 produced similar degrees of substitution for cocaine in the present study (i.e., full substitution in four of five monkeys). However, these compounds displayed very different abilities to maintain self-administration, with PAL-314 maintaining self-administration more reliably than PAL-287 (Rothman et al., 2005; Wee et al., 2005). Thus, despite the general concordance between these drug discrimination and drug self-administration results, there remain potentially important differences in the pharmacological mechanisms responsible for production of cocaine-like discriminative stimulus versus reinforcing effects. Specifically, reinforcing effects of monoamine releasers may be more vulnerable than cocaine-like discriminative stimulus effects to increases in serotonergic activity.
Effects of Monoamine Releasers on Cocaine- versus Food-Maintained Responding. With regard to the preclinical evaluation of candidate pharmacotherapies for drug dependence, we have argued previously that optimal medications might be those that produce sustained decreases in self-administration of the target drug of abuse across a wide range of drug unit doses while producing lesser effects on responding for a nondrug reinforcer (e.g., food) and minimal evidence of undesirable effects (Mello and Negus, 1996; Mello, 2005). By these criteria, dopamine/norepinephrineselective monoamine releasers produce a more promising profile of effects than less-selective or serotonin-selective releasers as candidate medications for cocaine dependence. In the present study, the dopamine/norepinephrine-selective releasers PAL-353 and methamphetamine produced sustained decreases in cocaine self-administration across a 0.5 log unit range of cocaine unit doses while having significantly lesser effects on food-maintained responding. Amphetamine, which also has high selectivity for dopamine/norepinephrine versus serotonin release, also produced decreases in cocaine self-administration that were sustained (for up to 28 days), apparent across a 30-fold range of cocaine doses, and selective for cocaine- versus food-maintained responding under three different schedules of reinforcement (Negus, 2003; Negus and Mello, 2003a,b). Possible mechanisms underlying these effects were discussed previously (Negus and Mello, 2003b).
These findings are concordant with earlier preclinical studies that chronic amphetamine treatment produced rightward/downward shifts in cocaine discrimination and self-administration dose-effect curves in rodents (Peltier et al., 1996), and with clinical findings that amphetamine may serve as a relatively safe and effective maintenance medication for the treatment of cocaine dependence in humans (Grabowski et al., 2001, 2004). By contrast, monoamine releasers with lower pharmacological selectivity for dopamine/norepinephrine versus serotonin release displayed less behavioral selectivity in reducing cocaine- versus food-maintained responding. These results suggest that nonselective or serotonin-selective releasers may have decreased cocaine self-administration by producing a nonselective reduction in the reinforcing effects of both cocaine and food (e.g., Higgins and Fletcher, 2003), a reduction in stimulus control, or nonselective motoric effects that impaired the ability of the subjects to respond. This conclusion based on these chronic treatment studies is consistent with results of a previous study that examined the acute effects of phentermine and fenfluramine administered either alone or in combination in monkeys responding for cocaine and food (Glowa et al., 1997). In that study, the most selective decreases in cocaine self-administration were accomplished with phentermine alone.
Prospects for the Use of Monoamine Releasers as Treatments for Cocaine Dependence. We have interpreted the results of the present study to suggest that dopamine/norepinephrine-selective monoamine releasers may reduce cocaine use with fewer undesirable effects than nonselective or serotonin-selective releasers. However, several caveats to this conclusion warrant mention. First, it is well established that monoamine releasers with relatively high selectivity for dopamine/norepinephrine versus serotonin function as strong reinforcers in drug self-administration studies, and drugs such as amphetamine and methamphetamine have acknowledged abuse liability. Although agonist medications for other forms of drug dependence also have high abuse liability (e.g., methadone for the treatment of opioid abuse), the abuse liability of dopamine/norepinephrine-selective monoamine releasers certainly poses an obstacle to their use in the treatment of stimulant dependence. Second, the present study documented optimal effects with releasers selective for dopamine/norepinephrine versus serotonin release; however, the degree to which the dopaminergic and/or noradrenergic effects of these drugs contributes to their profiles of behavioral effects remains to be determined. Releasers with selectivity for dopamine versus both norepinephrine and serotonin would help address this issue. Last, the present study used food-maintained responding to provide a measure of potentially undesirable, nonselective effects of candidate medications, and dopamine/norepinephrine-selective releasers produced more selective reductions in cocaine- versus food-maintained responding than nonselective or serotonin-selective releasers. However, as discussed previously (Mello and Negus, 1996), a reduction in food-maintained responding may be acceptable if a medication produces few other undesirable effects. Further assessment of the concordance between preclinical and clinical results awaits results from clinical studies with monoamine releasers.
One final caveat to the present study is that differences in the pharmacokinetics and time courses of the drugs may have influenced measures of relative potency. In drug discrimination studies, for example, test drug effects were examined from 15 to 20 min after their administration in cumulative dosing experiments. If a drug did not produce peak effects at this time, then its relative potency may have been underestimated relative to other drugs that were at peak effect. Similarly, in the drug self-administration studies, all drugs were administered using the same chronic infusion regimen. Again, this may have influenced relative potency measures, because long-acting drugs may have accumulated to higher degrees and seemed more potent than drugs with shorter durations of action. However, the primary dependent measures in the present study were not relative potencies, but rather 1) maximal degree of cocaine-like discriminative stimulus effects and 2) selectivity to reduce cocaine- versus food-maintained responding. To address this focus on efficacy, drugs were studied in both drug discrimination and drug self-administration procedures from ineffective to maximally effective doses (except PAL-314 in drug self-administration studies, and in this case, PAL-314 was studied up to the highest dose possible given its limited solubility). Thus, all drugs displayed sufficiently rapid onsets and durations of action to produce robust behavioral effects that permitted an assessment of their cocaine-like discriminative stimulus effects and their selectivity to reduce cocaine- versus food-maintained responding. By this measure, dopamine/norepinephrine-selective releasers produced optimally selective reductions in cocaine- versus food-maintained responding.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: PAL-287, 1-naphthyl-2-propylamine hydrochloride; PAL-314, m-methylamphetamine, 1-(3-toluyl)-2-propylamine fumarate; and PAL-353, m-fluoroamphetamine, 1-(3-fluorophenyl)-2-propylamine fumarate; DA, dopamine; NE, norepinephrine; 5HT, 5-hydroxytryptaime (serotonin); FR, fixed ratio; VR, variable ratio.
Address correspondence to: Dr. S. Stevens Negus, Alcohol and Drug Abuse Research Center, McLean Hospital; Harvard Medical School, 115 Mill St., Belmont, MA 02478-9106. E-mail: negus{at}mclean.harvard.edu
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2% cocaine-appropriate responding up to doses that eliminated responding. Note that mean (range) ED50 values show results only in those monkeys in which an ED50 value could be calculated. The percentage of cocaine responding and percentage of control response rate show data obtained with the highest dose tested in each monkey. Control response rates in individual monkeys ranged from 1.47 to 3.43 responses/s.
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