Introduction

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Cocaine abuse continues to be a serious public health problem, and there are currently no uniformly effective medications for its treatment (Mendelson and Mello, 1996). The utility of oral methadone as a substitution medication for the treatment of opioid dependence (Ball and Ross, 1991) suggests that a relatively slow-onset, long-acting cocaine-like medication may be useful in the treatment of cocaine abuse. Cocaine nonselectively blocks the reuptake of dopamine, norepinephrine and serotonin (Koe, 1976), and compelling evidence suggests that the effects of cocaine on dopaminergic systems are especially important in mediating its high abuse potential (Koob and Bloom, 1988). Consequently, selective dopamine reuptake inhibitors are currently being evaluated as one class of potential substitution medications for the treatment of cocaine abuse (Mansbach and Balster, 1993; Glowa et al., 1995a; Nader et al., 1997; Dworkin et al., 1998). However, the effects of cocaine on norepinephrine and serotonin reuptake may also contribute to cocaine's abuse-related effects (Terry et al., 1994; Callahan and Cunningham, 1995; Spealman, 1995). As a result, it may also be instructive to assess the utility of nonselective monoamine reuptake inhibitors as potential substitution medications.

Indatraline (also known as Lu 19-005) is one such nonselective monoamine reuptake inhibitor (Bogeso et al., 1985; Hyttel and Larsen, 1985). In vitro, indatraline blocked the reuptake of dopamine, norepinephrine, and serotonin into rat brain synaptosomes with similar nanomolar potencies (Hyttel and Larsen, 1985). In vivo, indatraline produced behavioral effects suggestive of enhanced dopaminergic, noradrenergic, and serotonergic activity in mice, and these effects were all observed at similar indatraline doses (Arnt et al., 1985). Indatraline also substituted for a high dose of cocaine in rats trained to discriminate between a low and a high dose of cocaine, which demonstrates that indatraline produces cocaine-like discriminative stimulus effects (Kleven and Koek, 1998). In comparison with cocaine, however, indatraline has been reported to have a slow onset and long duration of action (Arnt et al., 1985; Rosenzweig-Lipson et al., 1992). In squirrel monkeys, for example, i.m. administration of either cocaine or indatraline produced a dose-dependent increase in response rates maintained under fixed interval schedules of operant responding. However, the effects of cocaine peaked after approximately 10 min and diminished after 1 h, whereas the effects of indatraline peaked after approximately 2 h and sometimes lasted for more than 24 h (Rosenzweig-Lipson et al., 1992). Overall, then, indatraline appears to produce cocaine-like behavioral effects with a slower onset and a much longer duration of action than cocaine. This pharmacological profile suggests that indatraline may be an ideal compound for evaluation of the clinical utility of nonselective monoamine reuptake inhibitors for the treatment of cocaine abuse.

Accordingly, the main goal of this study was to examine the effects of indatraline on cocaine discrimination and cocaine self-administration in rhesus monkeys. These behavioral assays have been used extensively to evaluate candidate treatment medications (e.g., Negus et al., 1995, 1996, 1997; Mello and Negus, 1996). First, the potency and time course of the cocaine-like behavioral effects produced by acute indatraline administration were determined in a cocaine discrimination procedure. Specifically, indatraline (0.1-1.0 mg/kg) was administered either alone or as a pretreatment to cocaine in rhesus monkeys trained to discriminate 0.4 mg/kg cocaine from saline. Once the potency and time course of indatraline were established, the effects of indatraline were further examined in monkeys trained to respond for i.v. cocaine injections (0.032 mg/kg/injection) and 1-g food pellets during multiple daily sessions of cocaine and food availability. The reinforcing effects of indatraline and cocaine were compared by substituting different unit doses of cocaine (0.001-0.1 mg/kg/injection) or indatraline (0.0032-0.032 mg/kg/injection) for the maintenance dose of cocaine as the drug solution available for self-administration. To examine the effects of indatraline on cocaine self-administration and concurrent food-maintained responding, monkeys were treated repeatedly with noncontingent administration of either saline or indatraline (0.1-0.56 mg/kg/day) during availability of different cocaine doses (0.0032-0.1 mg/kg/injection). Each combination of a treatment dose of indatraline and a unit dose of cocaine was studied for 7 consecutive days. It became apparent during these drug self-administration studies that repeated administration of indatraline produced stereotypic behaviors in some monkeys. To evaluate potential toxic effects associated with chronic indatraline treatment, a final study examined the effects of repeated treatment with saline or indatraline (0.32-1.0 mg/kg/day for 7 days) on overt behavior, body weight, and indices of hematology and blood chemistry.

	Materials and Methods

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Subjects

A total of 12 rhesus monkeys (Macaca mulatta) were subjects in three studies designed to to characterize the behavioral pharmacology of indatraline. Four male rhesus monkeys were studied in the drug discrimination experiments, two female and three male rhesus monkeys were studied in the drug self-administration experiments, and one female and two male monkeys were studied in observational studies. All monkeys had an experimental history involving the evaluation of dopaminergic and/or opioid compounds in assays of drug discrimination, drug self-administration, or thermal nociception. Monkeys weighed 5.4 to 11.4 kg and were maintained on a diet of multiple vitamins, fresh fruit, and Lab Diet Jumbo Monkey biscuits (PMI Feeds, Inc., St. Louis, MO). In addition, monkeys in drug discrimination and drug self-administration studies could receive 1-g banana-flavored pellets (Precision Primate Pellets Formula L/I Banana Flavor; P. J. Noyes Co., Lancaster, NH) during daily operant sessions (see below). Water was continuously available. A 12 h light/dark cycle was in effect (lights on from 7:00 AM to 7:00 PM).

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 provided an opportunity for environmental manipulation and enrichment.

Drug Discrimination Procedures

Apparatus. Each monkey was housed individually in a well-ventilated, stainless steel chamber (56 × 71 × 69 cm). The home cages of all monkeys were modified to include an operant panel (28 × 28 cm) mounted on the front wall. Three square translucent response keys (6.4 × 6.4 cm) were arranged 2.54 cm apart in a horizontal row 3.2 cm from the top of the operant panel. Each key could be transilluminated by red or green stimulus lights (Superbright LEDs). 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 (Superbright L.E.D.s). The operant panel also supported an externally mounted pellet dispenser (Gerbrands, Model G5210) that delivered 1-g food pellets to a food receptacle mounted on the cage beneath the operant response panel. Operation of the operant panels and data collection were accomplished with microprocessors and software provided by Med Associates Inc. (Georgia, VT).

Discrimination Training. Drug discrimination procedures were identical with those used in our previous studies of the effects of opioids and dopamine antagonists on cocaine self-administration (e.g., Lamas et al., 1995; Negus et al., 1995, 1996). Discrimination sessions consisted of multiple cycles and were conducted 5 days/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 two of the four monkeys, the left key was illuminated green and the right key was illuminated red. For the other two 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.

Discrimination Testing. Once monkeys met criterion levels of cocaine discrimination, testing began. Test sessions were identical with training sessions except that responding on either key produced food, and cocaine or indatraline was administered as described below. Two series of experiments were conducted to characterize the effects of indatraline administered alone or as a pretreatment to cocaine.

Data Analysis. The percentage of cocaine-appropriate responding (for the entire response period) and response rates were plotted as a function of either the time after indatraline administration (for time-course studies) or the cumulative dose of cocaine (for indatraline pretreatment studies). A percentage of cocaine-appropriate responding for a given cycle was included in the analysis only if the monkey emitted at least 30 responses during the cycle (i.e., enough responses to result in the delivery of one reinforcer). ED₅₀ values were defined as the dose of indatraline or cocaine that produced 50% cocaine-appropriate responding, and were calculated by linear interpolation from individual subject dose-effect curves. For indatraline, ED₅₀ values were calculated from data obtained 100 min after indatraline administration (the approximate time of peak effect), whereas for cocaine, ED₅₀ values were calculated from cumulative dose-effect curves. Individual ED₅₀ values were converted to their log values for calculation of means and 95% CL, then converted back to linear values for presentation.

Drug Self-Administration

Apparatus. Each monkey was housed individually in a well-ventilated stainless steel chamber (64 × 64 × 79 cm). The home cages of all monkeys were modified to include an operant panel identical with that described above for drug discrimination studies. In addition, 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 i.v. catheters. Operation of the operant panels and data collection were accomplished with Apple IIGS computers located in a separate room.

Surgical Procedures. Double-lumen Silicone rubber catheters (i.d. 0.7 mm; o.d. 2.0 mm) were implanted in the jugular or femoral vein and exited in the midscapular region. All surgical procedures were performed under aseptic conditions. Monkeys were initially sedated with ketamine (5 mg/kg), and anesthesia was induced with sodium thiopental (10 mg/kg, i.v). In addition, monkeys were treated with 0.05 mg/kg atropine to reduce salivation. Following insertion of a tracheal tube, anesthesia was maintained with isoflurane (1-1.5% in oxygen). After surgery, aspirin or acetaminophen (80-160 mg/day, p.o.) was administered for 3 days. An antibiotic, procaine penicillin G (300,000 U/day, i.m.), was administered every day for 5 days. The i.v. 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). This flexible tether system permitted monkeys to move freely. Catheter patency was periodically evaluated by i.v. administration of a short-acting barbiturate, methohexital (3 mg/kg, i.v.). The catheter was considered to be patent if i.v. administration of methohexital produced a loss of muscle tone within 10 s.

Initial Training Procedures. Procedures for the evaluation of cocaine- and food-maintained responding were identical with those used in our previous studies of the effects of opioids and dopamine antagonists on cocaine self-administration (Negus et al., 1995, 1996, 1997). After initial shaping of key pressing behavior for food reinforcement, animals were maintained on a variable ratio (VR) schedule that was gradually increased to a VR of 16. After monkeys received at least 50 food pellets/day for 3 consecutive days under the VR 16 schedule, behavior was maintained on a second order schedule that consisted of two components, a VR and FR. After completion of a variable number of responses that averaged 16, a red light originally associated with food delivery was illuminated for 1 s below the center response key (VR [16:S]). The FR component was gradually increased to a terminal second order schedule response requirement of FR2 [VR 16:S] (one monkey) or FR4 [VR 16:S] (all other monkeys). Under this terminal schedule, monkeys had to complete two or four VR components, and an average of 32 (range 26-39) or 64 responses (range 53-78) was required for the delivery of each food pellet. Each experimental day began at 9:00 AM, and there were four food sessions during each experimental day beginning at 11:00 AM, 3:00 PM, 7:00 PM, and 6:00 AM the next morning. Each session lasted for 1 h or until a maximum of 25 food pellets had been delivered, whichever occurred first.

Drug Self-Administration Testing. Once monkeys met the criteria for high stable levels of cocaine and food self-administration, testing began. Three series of tests were conducted to assess the effects of indatraline. The first series of experiments examined the reinforcing effects of indatraline alone in a group of three monkeys. Each dose of indatraline (0.0032-0.32 mg/kg/injection) was substituted for the maintenance dose of cocaine (0.032 mg/kg/injection) for a period of 7 days. The maintenance dose of cocaine was reinstated after each substitution test 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. Indatraline doses were tested in an irregular order across monkeys.

Data Analysis. The total numbers of injections or food pellets delivered per day were determined. Data for the effects of indatraline on self-administration of 0.01 mg/kg/injection cocaine (i.e., the first series of experiments) are shown in their entirety and evaluated using a two-factor ANOVA, with indatraline dose and treatment day as the two factors. A significant ANOVA was followed by individual means comparison using the Duncan post hoc test (Winer, 1971). The criterion for significance was set at p < .05.

Observational Studies

Apparatus and Procedure. Informal observation of monkeys during the drug self-administration studies suggested that chronic indatraline treatment may have produced stereotypies and a decrease not only in operant food-maintained responding but also in consumption of daily food rations. To assess the effects of chronic indatraline treatment more systematically, a series of observational studies was conducted in a group of three monkeys. Monkeys remained in their home cages throughout the 4-week experiment and had free access to both food and water. Saline was administered i.m. at 10:00 AM each morning during the first week, and increasing doses of indatraline (0.32, 0.56, and 1.0 mg/kg/day, i.m.) were administered during the second, third, and fourth weeks, respectively. On the last day of each 7-day treatment, monkeys were videotaped for a 10-min period between 1:00 and 1:30 PM, approximately 3 h after the last injection. Monkeys were then weighed under mild ketamine sedation (3-5 mg/kg), and blood samples were collected from the saphenous vein for analysis of hematology and blood chemistry indices.

Data Analysis. A one-factor, repeated measures ANOVA was used to evaluate the effects of indatraline on behavioral signs, body weight, and indices of hematology and blood chemistry. A significant ANOVA was followed by individual means testing using the Duncan post hoc test (Winer, 1971). The level of significance was set a priori at p > .05.

Drugs

Cocaine HCl was obtained in crystalline form from the National Institute on Drug Abuse (National Institutes of Health, Bethesda, MD), and purity was certified to be greater than 98%. Indatraline HCl (also know as Lu 19-005) was purchased from Research Biochemicals International (Natick, MA). All drugs were dissolved in sterile saline, filter-sterilized using a 0.22-µm Millipore filter and stored in pyrogen-free vials. In the drug discrimination studies and behavioral observation studies, all drugs were administered i.m. in a volume of 0.1 to 2.0 ml. In the drug self-administration experiments, cocaine and indatraline were delivered i.v in a volume of 0.1 ml/injection.

	Results

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Cocaine-Like Discriminative Stimulus Effects of Indatraline. Indatraline administered alone produced a dose- and time-dependent substitution for the discriminative stimulus effects of cocaine in monkeys trained to discriminate 0.4 mg/kg cocaine from saline (Fig. 1, top left). The lowest dose of indatraline (0.1 mg/kg) produced primarily saline-appropriate responding throughout the observation period. A higher dose of indatraline (0.32 mg/kg) produced a maximum of approximately 50% cocaine-appropriate responding after 300 min, but monkeys responded almost exclusively on the saline-appropriate key after 24 h. A dose of 1.0 mg/kg indatraline substituted completely for cocaine in all four monkeys. These cocaine-like discriminative stimulus effects peaked after 30 min and lasted 24 h. Monkeys responded primarily on the saline-appropriate key after 48 h. The mean ED₅₀ value (95% CL) for indatraline in producing cocaine-appropriate responding was 0.24 mg/kg (0.084-0.67 mg/kg) at the 100-min time point. Indatraline had little effect on response rates (Fig. 1, bottom left) at the doses and times tested.

View larger version (32K): [in this window] [in a new window]   Fig. 1.   Effects of indatraline administered alone (left) or as a pretreatment to cocaine (right) in monkeys trained to discriminate 0.4 mg/kg cocaine from saline. Abscissae (left), time after indatraline administration in minutes (10-300) or hours (24-48). Abscissae (right), cumulative dose cocaine in mg/kg. Ordinates (top), percentage of cocaine-appropriate responding. Ordinates (bottom), response rate in responses per second. All points show mean data (±S.E.) from four monkeys except for "% Cocaine Responding" for the following points in the upper right: 1.3 mg/kg cocaine alone, n = 1; 0.32 mg/kg indatraline (100 min) + 0.4 mg/kg cocaine, n = 3; 0.32 mg/kg indatraline (100 min) + 1.3 mg/kg cocaine, n = 2; and 0.32 mg/kg indatraline (24 h) + 1.3 mg/kg cocaine, n = 3. The remaining monkeys did not respond under these conditions, and a "% Cocaine Responding" could not be determined.

Self-Administration of Cocaine and Indatraline. Figure 2 shows the effects of substituting saline, cocaine alone (0.001-0.1 mg/kg/injection), or indatraline alone (0.0032-0.032 mg/kg/injection) for the maintenance dose of 0.032 mg/kg/injection cocaine in monkeys trained to respond for i.v. cocaine injections and food. Saline substitution maintained an average of 23.9 (±9.7) injections/day during the 7-day test period, and monkeys earned an average of 95.4 (±1.4) food pellets/day. Cocaine substitution produced an inverted U-shaped dose-effect curve for drug self-administration. Doses of 0.0032 to 0.1 mg/kg/injection cocaine maintained more injections per day than saline (p < .05), and peak rates of self-administration were maintained by the maintenance dose of 0.032 mg/kg/injection cocaine (79.5 ± 0.3 injections/day). Cocaine self-administration across the dose range tested did not significantly alter the number of food pellets earned per day.

View larger version (14K): [in this window] [in a new window]   Fig. 2.   Self-administration of saline, cocaine (0.001-0.1 mg/kg/injection), or indatraline (0.0032-0.032 mg/kg/injection) and concurrent responding for food. Abscissae, unit dose cocaine or indatraline in mg/kg/injection. Points above "Sal" show the effects of saline substitution. Ordinate (left), average number of injections per day (maximum = 80). Ordinate (right), average number food pellets per day (maximum = 100). Each point shows mean data (±S.E.M.) for three monkeys during 7 consecutive days of treatment, except for the highest dose of indatraline (0.032 mg/kg/injection). Availability of 0.032 mg/kg/injection indatraline had to be terminated after 3 days in one monkey due to the emergence of oral stereotypies. Asterisks indicate effects significantly different from saline substitution (*p < .05; **p < .01).

Effects of Indatraline Treatment on Cocaine Self-Administration. Figure 3 shows the numbers of injections per day and pellets per day when a unit dose of 0.01 mg/kg/injection cocaine was available for self-administration and monkeys were treated with saline or indatraline (0.1-0.56 mg/kg/day) daily for 7 days. During saline treatment, monkeys earned nearly maximal numbers of injections and pellets per day. Indatraline produced a dose- and time-dependent decrease in both cocaine- and food-maintained responding. Treatment with 0.32 mg/kg/day indatraline significantly decreased the number of pellets per day (p < .05), and 0.56 mg/kg/day indatraline significantly decreased the numbers of both pellets and cocaine injections per day (p < .01). The effects of indatraline on cocaine self-administration increased significantly during the 7 days of treatment (p < .01), and cocaine self-administration was nearly eliminated after 7 days of treatment with 0.56 mg/kg/day indatraline. The effects of indatraline on food-maintained responding did not change significantly over time. However, there was a trend toward recovery of food-maintained responding during the least few days of treatment with 0.56 mg/kg/day indatraline, when cocaine self-administration was maximally decreased.

View larger version (26K): [in this window] [in a new window]   Fig. 3.   Effects of treatment with saline or indatraline (0.1-0.56 mg/kg/day) on responding maintained by cocaine (0.01 mg/kg/injection) and food. Abscissae, consecutive days of treatment. Ordinate (left), average number of 0.01 mg/kg/injection cocaine injections per day (maximum = 80). Ordinate (right), average number food pellets per day (maximum = 100). Each point shows mean data (±S.E.) for four monkeys.

View larger version (20K): [in this window] [in a new window]   Fig. 4.   Effects of treatment with saline or indatraline (0.32-0.56 mg/kg/day) on the cocaine self-administration dose-effect curve and concurrent responding for food. Abscissae, unit dose cocaine in milligrams per kilogram per injection. Points above "Sal" show data obtained during saline substitution. Ordinate (left), average number of cocaine injections per day (maximum = 80). Ordinate (right), average number food pellets per day (maximum = 100). Each point shows mean data (±S.E.) for three monkeys except data obtained during availability of 0.032 and 0.1 mg/kg/injection cocaine and treatment with 0.56 mg/kg/day indatraline (n = 2).

Other Effects of Chronic Indatraline Treatment. Table 1 shows the effects of chronic treatment with saline and increasing doses of indatraline (0.32-1.0 mg/kg/day) on overt behavior, body weight, and indices of hematology and blood chemistry. During saline treatment, visual checking, stereotypic grooming and buccal movements, and splayed legs were rarely observed. However, indatraline significantly increased the overall stereotypy score. Visual checking was observed primarily during treatment with 0.32 mg/kg indatraline, and this sign decreased in frequency during treatment with higher indatraline doses. After treatment with 1.0 mg/kg/day indatraline, all three monkeys showed continuous buccal and/or grooming stereotypies, and splayed legs was frequently observed in two of the three monkeys. Indatraline treatment also produced a dose-dependent decrease in body weight, blood hemoglobin, hematocrit, red blood cell count, and white blood cell count. The decrease in blood hemoglobin was statistically significant at the highest dose of indatraline (1.0 mg/kg/day), and changes in the other indices approached significance (p < .1; Table 1). Blood chemistry measures were not significantly affected by indatraline treatment.

	Discussion

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The present study examined the hypothesis that indatraline may produce cocaine-like behavioral effects and be useful as a substitution medication for the treatment of cocaine abuse. Our major findings were that indatraline produced cocaine-like discriminative stimulus effects with a slow onset and a long duration of action, and repeated treatment with indatraline produced a sustained decreases in cocaine self-administration across a broad range of cocaine doses. However, at doses that decreased cocaine self-administration, indatraline usually produced undesirable effects that could limit its clinical utility. Each of these major findings is discussed below.

Cocaine-Like Discriminative Stimulus Effects of Indatraline. Drug discrimination studies confirmed that indatraline produced a dose-dependent and complete substitution for cocaine in rhesus monkeys. The potencies of indatraline and cocaine in producing cocaine-like discriminative stimulus effects were similar, and neither compound substantially altered response rates at doses that produced complete substitution. However, indatraline had a slow onset and long duration of action relative to cocaine. For example, the effects of 1.0 mg/kg indatraline peaked after 30 min and lasted at least 24 h, whereas the effects of the training dose of cocaine (0.40 mg/kg) peaked after only 3 min and were nearly gone after 60 min (Lamas et al., 1995). These results extend previous reports that indatraline produced psychomotor stimulant effects in rats and squirrel monkeys with a potency similar to cocaine but with a slower onset and longer duration of action (Arnt et al., 1985; Rosenzweig-Lipson et al., 1992; Kleven and Koek, 1998). These behavioral findings are also consistent with in vitro studies demonstrating that indatraline binds to [³H]cocaine-labeled binding sites in monkey striatum (Madras et al. 1989) and, like cocaine, functions as a relatively nonselective monoamine reuptake inhibitor (Koe, 1976; Hyttel, 1982; Hyttel and Larsen, 1985). In addition to producing cocaine-like discriminative stimulus effects when administered alone, indatraline pretreatment also enhanced the discriminative stimulus effects of low doses of cocaine. These findings agree with a previous report that indatraline pretreatment enhanced the discriminative stimulus effects of a low cocaine dose in rats (Kleven and Koek, 1998).

Reinforcing Effects of Indatraline. Despite its ability to produce cocaine-like discriminative stimulus effects, indatraline maintained low rates of self-administration similar to those maintained by saline. It was shown previously that decreases in the rate at which a cocaine dose was infused produced corresponding decreases in the rate of cocaine self-administration (Balster and Schuster, 1973). These findings have been interpreted to suggest that rate of onset may be an important determinant of a drug's reinforcing effects. Thus, indatraline's slow onset may limit its ability to function as positive reinforcer.

Effects of Indatraline on Cocaine Self-Administration. We have argued previously that treatments that produce a sustained decrease in cocaine self-administration across a broad range of cocaine doses are more likely to be effective medications for the treatment of cocaine dependence than treatments that do not affect or that increase cocaine self-administration (Mello and Negus, 1996). Consistent with this profile of effects, indatraline produced a dose-dependent decrease in the self-administration of a dose of cocaine (0.01 mg/kg/injection) near the peak of the cocaine dose-effect curve. These decreases in cocaine self-administration were sustained throughout the 7-day treatment period, and treatment with 0.56 mg/kg/day indatraline eliminated cocaine self-administration by the end of the treatment period. Indatraline also produced sustained decreases in the self-administration of other unit doses of cocaine (0.0032-0.1 mg/kg/injection), which resulted in an overall downward shift in the cocaine self-administration dose-effect curve.

Other Effects of Indatraline. To provide one measure of behavioral selectivity in the present study, the effects of indatraline treatment on concurrent food-maintained responding were examined. In some cases, the effects of indatraline on cocaine self-administration were greater than the effects on food-maintained responding. For example, after 7 days of treatment with 0.56 mg/kg/day indatraline, responding for the 0.01 mg/kg/injection cocaine was eliminated, whereas responding for food was only partially suppressed and appeared to be recovering. Overall, however, doses of indatraline that decreased cocaine self-administration also usually decreased responding maintained by food. In addition, separate studies found that doses of indatraline that decreased cocaine self-administration also produced behavioral stereotypies, a trend toward weight loss, and changes in hematology suggestive of mild anemia. These effects are similar to those produced by chronic high-dose cocaine administration in animals or cocaine abuse in humans (Farfel et al., 1992; Burkett et al., 1994), and provide additional evidence to suggest that indatraline and cocaine produce a similar profile of behavioral effects. However, these findings also suggest that robust decreases in cocaine self-administration occur only at relatively high indatraline doses that may also produce other undesirable effects.