Effects of dopamine indirect agonists and selective D1-like and D2-like agonists and antagonists on cocaine self-administration and food maintained responding in rats

Neuropharmacology 47 (2004) 256–273 www.elsevier.com/locate/neuropharm

Effects of dopamine indirect agonists and selective D1-like and D2-like agonists and antagonists on cocaine self-administration and food maintained responding in rats Andrew C. Barrett, John R. Miller, Jennifer M. Dohrmann, S. Barak Caine
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA Received 3 May 2004; received in revised form 30 June 2004; accepted 12 July 2004

Abstract A procedure is described for comprehensive evaluation of the effects of acute drug pretreatments on the reinforcing effects of cocaine using the rat self-administration assay in combination with a novel control assay of liquid-food maintained responding. In sessions comprised of five 20-min components, either complete dose-effect functions for cocaine self-administration or complete concentration-effect functions for liquid-food maintained responding were evaluated. The schedule of reinforcement (FR 5 TO 20-s), drug pretreatment doses and time intervals (0–30 min), and duration of sessions (108 min) were identical for cocaine- and food-reinforced test sessions. Whereas acute pretreatment with indirect dopamine agonists (d-amphetamine, GBR 12909) and D2-like agonists (7-OH-DPAT, quinelorane) produced dose-dependent leftward shifts in dose-effect functions for cocaine selfadministration, D1-like agonists (SKF 82958, R-6-Br-APB) and dopamine antagonists (D1-like, SCH 39166; D2-like, eticlopride) shifted dose-effect functions for cocaine downward and rightward, respectively. Interestingly, with the indirect dopamine agonists but not the D2-like agonists, increased responding maintained by low cocaine doses was paralleled by increased responding maintained by low food concentrations. Moreover, three of the four direct agonists were moderately selective (5-fold more potent) in decreasing cocaine self-administration relative to food maintained responding. When data were analyzed according to alterations in total cocaine intake, all of the agonists uniformly decreased total cocaine intake, whereas both antagonists increased total cocaine intake. Overall, this procedure was sensitive to leftward, downward and rightward shifts in cocaine dose-effect functions and should be useful for evaluating the nature of pharmacological interactions between novel compounds and self-administered cocaine, as well as the potential for altering cocaine self-administration selectively with candidate treatments for cocaine abuse and dependence. # 2004 Elsevier Ltd. All rights reserved. Keywords: Cocaine; Self-administration; Animal model; Pharmacotherapy; Dopamine; Rat

1. Introduction Cocaine abuse remains a serious public health problem, but as of yet there are no generally effective pharmacotherapies for cocaine abuse and dependence. Drug self-administration procedures in laboratory animals have been used to investigate the neurobiological and pharmacological mechanisms underlying the reinforcing effects of cocaine and to evaluate candidate phar
Corresponding author. Tel.: +1-617-855-2258; fax: +1-617-8553865. E-mail address: [email protected] (S.B. Caine).

0028-3908/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2004.07.007

macotherapies (Koob, 1992; Mello and Negus, 1996). As the ability of cocaine to increase levels of synaptic dopamine most likely accounts for its reinforcing effects (Wise and Bozarth, 1987; Woolverton and Johnson, 1992), systematic evaluation of the effects of nonselective and selective dopaminergic agents on cocaine self-administration may extend information on the mechanisms underlying cocaine’s reinforcing effects. In addition, these data may provide a benchmark for comparing the effects of novel compounds, thus aiding in the interpretation of the effects of novel compounds and the potential implications for pharmacotherapy. Accordingly, general aims of the present study were to

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develop procedures for systematic evaluation of the effects of novel compounds on cocaine self-administration and to collect a standard set of data with dopaminergic compounds using those procedures. Indirect dopamine agonists other than cocaine have been useful for establishing the role of dopamine in the reinforcing effects of cocaine. These agents often functioned as positive reinforcers when substituted for cocaine, and their potency in that respect has generally been related to their binding to the dopamine transporter (Ritz et al., 1987; Bergman et al., 1989; Roberts, 1993; Wojnicki and Glowa, 1996; Tella et al., 1996; Birmingham et al., 1998; Roberts et al., 1999; Stafford et al., 2001; Woolverton et al., 2001; Lile et al., 2003). Additionally, numerous studies have demonstrated the ability of indirect dopamine agonists to decrease responding maintained by intermediate to high doses of cocaine, (Skjoldager et al., 1993; Glowa et al., 1995, 1996; Nader et al., 1997; Dworkin et al., 1998; Lynch et al., 1998; Howell et al., 2000; Stafford et al., 2000; Sizemore et al., 2004), and although several studies have examined the interactions of indirect dopamine agonists with a range of cocaine doses, the results have been inconsistent (Glowa et al., 1995; Negus et al., 1999; Schenk, 2002; Negus and Mello, 2003; Negus, 2003). In comparison to indirect dopamine agonists, direct dopamine agonists may provide additional information by selectively binding to D1-like (D1, D5) or D2-like (D2, D3, D4) receptors that have differing neurobiological profiles. For example, D2-like agonists maintained selfadministration behavior in animals previously trained to self-administer cocaine (Woolverton et al., 1984; Wise et al., 1990; Caine and Koob, 1993; Nader and Mach, 1996; Sinnott et al., 1999; Ranaldi et al., 2001). Moreover, when administered as a pretreatment in animals self-administering cocaine, D2-like agonists produced leftward shifts in cocaine dose-effect functions (Caine and Koob, 1995; Caine et al., 1999, 2000a), effects qualitatively different from those of D2-like partial agonists (Platt et al., 2003). That D2-like agonists augmented the ability of cocaine to reinstate responding after extinction further suggests that activation of D2-like receptors enhances the effects of cocaine (Self et al., 1996; Khroyan et al., 2000). D1-like agonists also have been shown to support self-administration behavior (Self and Stein, 1992; Weed and Woolverton, 1995), but these effects may occur under a relatively limited set of conditions (Grech et al., 1996; Caine et al., 1999). In animals self-administering cocaine, D1like agonists produced downward shifts in cocaine doseeffect functions (Caine et al., 1999; 2000a; Platt et al., 2001; Mutschler and Bergman, 2002) and under conditions in which D1-like partial agonists were tested, modest rightward shifts were observed in the descending limb of the dose-effect function (Mutschler and

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Bergman, 2002). Corroborating these findings are data demonstrating that D1-like agonists attenuated the effects of cocaine in reinstatement procedures (Self et al., 1996; Khroyan et al., 2000, 2003). Finally, numerous studies have demonstrated that dopamine D2-like and D1-like antagonists attenuated the reinforcing effects of cocaine under a variety of parameters and schedules of reinforcement (see Mello and Negus, 1996 for review). These compounds did not function as positive reinforcers on their own, and when they were administered in combination with a full range of cocaine doses, rightward shifts in dose-effect functions for self-administration were apparent, suggestive of surmountable antagonism of the reinforcing effects of cocaine (Bergman et al., 1990; Negus et al., 1996; Schenk et al., 1999) or mutual antagonism of the behavioral effects of the antagonists and cocaine (Herling and Woods, 1980). The specific profile of effects (e.g., leftward, downward or rightward shifts in cocaine dose-effect functions) produced by various dopaminergic compounds may have relevance for the development of pharmacotherapies for cocaine abuse and dependence. Of additional importance in evaluating candidate medications is their potential for altering behavior maintained by cocaine without altering behavior maintained by other reinforcers, for example, food (see Mello and Negus, 1996, for review). Selective effects on cocaine self-administration relative to food maintained responding suggest that the treatment drug altered the reinforcing effects of cocaine rather than producing general effects on operant performance, and may also provide some measure of potential side effects of candidate medications. Although such ‘‘control’’ assays of food maintained behavior have been commonly used, the range of conditions evaluated was generally limited (e.g., responding maintained by a food-pellet reinforcer under temporal conditions that differed from cocaine self-administration). Given the importance of determining the extent to which a novel compound selectively alters cocaine self-administration, the development of more sophisticated protocols along these lines may represent a significant advance. One specific aim of the present study was to develop a procedure for comprehensive evaluation of alterations in the shape and position of cocaine dose-effect functions produced by drug pretreatments. A second specific aim was to evaluate the extent to which drug pretreatments produced effects that were selective for cocaine self-administration relative to food maintained responding under a broad range of conditions. To this end, drug pretreatment effects on responding maintained by low, intermediate and high magnitude food reinforcers were evaluated for two reasons. On the one hand, responding maintained by intermediate food concentrations may be more sensitive to disruption

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than responding maintained by high food concentrations, providing a more sensitive procedure for detecting nonselective rate decreasing effects. On the other hand, low rates of responding maintained by low food concentrations provides a procedure sensitive to detecting nonselective rate-increasing effects. Importantly, temporal parameters (i.e., drug pretreatment intervals and session durations) and the schedule of reinforcement were identical for cocaine- and food-reinforced test sessions, allowing reasonable comparisons of the relative potencies of compounds for altering cocaine and food maintained behavior. A third specific aim was to establish a set of standard drug pretreatment data with well established compounds using our procedures. For this purpose, we selected two compounds each from four classes of dopaminergic compounds: the indirect dopamine agonists d-amphetamine and GBR 12909, the D2-like agonists 7-OH-DPAT and quinelorane, the D1-like agonists SKF 82958 and R-6-Br-APB, and the D2-like and D1-like antagonists eticlopride and SCH 39166, respectively. In follow-up studies, cocaine was also administered as a pretreatment to both cocaine- and food-reinforced test sessions for comparison to the other dopaminergic drugs, and some compounds were administered prior to the evaluation of food consumption in free feeding tests in home cages.

cubicles equipped with a house light and an exhaust fan. Each chamber contained three response levers (3.0 cm above the grid floor), with two situated on one wall of the chamber (1.5 cm from the side walls), and a third located at the center of the opposite wall. A stimulus light was located above each lever. A steel molded cup was situated between the two levers and 2.0 cm above the floor for delivery of food pellets (45 mg A/I Rodent Pellets; P. J. Noyes Co., Lancaster, NH) or liquid food (EnsureR protein drink diluted with water). An infusion pump (Med Associates, PHM-100) mounted above each chamber was equipped with a 3.3 RPM motor to allow for specified infusion durations and volumes of cocaine (i.v.) or liquid food (into the steel molded cup). Hardware and software were obtained from MED Associates Inc. (Georgia, VT). In each experimental chamber, a single channel fluid swivel (Lomir Biomedical, Malone, NY) was mounted on a balance arm above the chamber and attached to a steel spring sleeve over a length of tygon tubing (0:0200 ID  0:0600 OD). The other end of the swivel was connected via tygon tubing to a 10 cc syringe situated in the infusion pump. For studies of liquid food maintained responding, the liquid swivel and spring lead were bypassed completely, and the food syringe was connected via tygon tubing to the liquid food reservoir.

2. Methods

2.3. Initial behavioral training

2.1. Animals

In all rats, lever pressing was initially shaped during training sessions up to 12 h in duration in which 45 mg food pellets reinforced responding under a fixed-ratio (FR) 1 schedule of reinforcement. Illumination of a cue light above the center lever signaled that responding had scheduled consequences. In subsequent sessions, the ratio requirement was increased to 5, and food training continued until rats earned a minimum of 50 food pellets in a single session under the FR 5 schedule of reinforcement. Rats were then assigned to groups in which responding was maintained by either cocaine (i.v.) or liquid food.

Male Sprague–Dawley rats ðn ¼ 6 8 per groupÞ weighing approximately 350 g at the start of the study were purchased from Charles River Laboratories (Wilmington, MA). Rats were maintained in the range of 400–600 g with once-daily feedings of standard rat chow (approximately 17 grams of Rat Diet 5012; PMI Feeds, Inc., St. Louis, MO), and all rats gained weight steadily under this regimen. Bacon-flavored biscuits (Bio-Serve, Frenchtown, NJ) were also provided periodically for enrichment. Rats were housed individually with free access to water in a temperature- and humidity-controlled facility that was maintained on a 12-h light/dark cycle (lights on at 7:00 am). Behavioral tests were conducted between the hours of 10:00 am and 3:00 pm. All protocols were in accordance with the guidelines provided by the National Institutes of Health Committee on Laboratory Animal Resources and were approved by the Institutional Animal Care and Use Committee. 2.2. Apparatus Studies were conducted in experimental chambers (21  29:5  24:5 cm) placed within sound-attenuating

2.4. Procedures for evaluating cocaine selfadministration 2.4.1. Surgery Rats were anesthetized with an isofluorane/oxygen vapor mixture and prepared with chronic indwelling i.v. catheters as previously described (Caine et al., 1993; Thomsen and Caine, in press). Each catheter consisted of a 13-cm length of Silastic tubing fitted to a 22-gauge guide cannula that was bent at a right angle. The guide cannula was encased in dental cement anchored with a 0.5-in-diameter circular nylon mesh. The tubing was passed s.c. from the animal’s back to

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the right external jugular vein. After surgery, a prophylactic dose of ticarcillin (approximately 17 mg/kg, i.v.) dissolved in saline containing heparin (3 USP U/0.1 ml) was delivered once daily for 5 days to prevent infection and maintain catheter patency. Thereafter, catheters were flushed daily with sterile physiological saline containing heparin (3 USP U/0.1 ml). If blood could not be withdrawn through the catheter, then approximately once per week or whenever behavior deviated from baseline parameters, catheter patency was tested by administering a solution containing 30 mg/ml ketamine and 1.5 mg/ml midazolam (0.1–0.2 ml, i.v.). Animals with patent catheters exhibited prominent signs of sedation within 3 s after i.v. injection. Animals with faulty catheters were prepared with a new catheter in the left jugular vein. 2.5. Initial cocaine self-administration training and maintenance procedures Daily training sessions of up to 3 h per day began approximately 7 days after surgery. Rats were placed in the experimental chambers and received a noncontingent automated infusion to fill the catheter (17 ll) and to deliver one unit dose of cocaine (1.0 mg/kg). Thereafter, a cue light above the center lever was illuminated, and responding on that lever was maintained by i.v. cocaine injections under a FR 5 timeout (TO) 20-s schedule of reinforcement. Under this schedule, completion of the response requirement produced an i.v. infusion of the unit dose of cocaine and initiated a 20-s TO period (including the time for drug infusion) during which the cue light was turned off and responses had no scheduled consequences. Responses on other levers were recorded as inactive responses, and responses on the center lever when the cue light was off were recorded as timeout responses. Training continued until cocaine self-administration behavior stabilized for at least three consecutive sessions, as follows: (1) a minimum of 5.0 mg/kg of cocaine self-administered every hour, and (2) less than 20% variability in the total number of cocaine reinforcers earned per session. After these criteria were met, extinction training commenced in which either cocaine (1.0 mg/kg/injection) or saline (180 ll/kg) was alternately available during four successive sessions. During the final phase of self-administration training, maintenance sessions were introduced during which cocaine (0.32 mg/kg/injection) was available under a FR 5 TO 20-s schedule in five sequential 20 min components, with each component separated by 2-min intercomponent timeout periods. Criteria for stable drug self-administration behavior during maintenance sessions were: (1) a minimum of 5.0 mg/kg of cocaine intake during the maintenance session, and (2) less than 20% variability in the total number of cocaine injections

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compared with the previous maintenance session. These maintenance sessions were interspersed with test sessions in which within-session dose-effect functions for cocaine self-administration were determined. 2.5.1. Cocaine dose-effect determinations When drug self-administration behavior during maintenance sessions was stable, within-session determinations of cocaine dose-effect functions were conducted up to 3 days per week. During these sessions, cocaine was available in five sequential 20 min components, with each component separated by 2-min intercomponent timeout periods. Each component began with the noncontingent delivery of the unit dose of cocaine available under the FR schedule. The cocaine unit doses, volumes and infusion durations were adjusted to deliver cocaine injections in an ascending doseorder in the five sequential components as follows: 0, 0.03, 0.10, 0.32, 1.0 mg/kg/injection of cocaine. The cocaine solution in the syringe was 1.8 mg/ml and the unit doses were adjusted for accuracy (mg/kg) according to the body weight of each rat. For example, for a rat weighing 0.32 kg the infusion volumes and durations would be, respectively, 0, 5.6, 18.0, 56.0, 180 ll and 0, 0.32, 1.0, 3.2, 10.0 s. These sessions were interspersed with maintenance sessions, and were repeated until the within-session dose-effect function stabilized. Criteria for stabilization were: (1) peak levels of responding maintained by at least one dose of cocaine equaled or exceeded 10 reinforcers within a 20 min component, and (2) the dose of cocaine that maintained peak responding varied by no more than onehalf log unit over three consecutive within-session determinations. 2.6. Procedures for evaluating responding maintained by liquid food In rats not prepared with i.v. catheters, a complementary set of studies was conducted in which responding was reinforced with liquid food (100% EnsureR), water, or various concentrations of liquid food diluted in water. Training for these rats followed a protocol similar to that for rats with i.v. catheters, with the major difference being the reinforcer maintaining behavior. Specifically, in daily 2-h training sessions, responding on the center lever was maintained by liquid food presentation (75 ll of 100% EnsureR) under a FR 5 TO 20-s schedule of reinforcement. Criteria for initial training were: (1) a minimum of 50 liquid food reinforcers earned in three consecutive sessions, and (2) less than 20% variability in the total number of reinforcers earned in three consecutive sessions. Once initial training criteria were met, extinction training commenced in which either liquid food (100% EnsureR) or water was alternately available over four subsequent sessions. There-

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after, maintenance sessions with 32% liquid food reinforcement (2 h in duration) were interspersed with test sessions in which concentration-effect functions for food maintained responding were determined. 2.6.1. Liquid food concentration-effect determinations When food-maintained behavior during maintenance sessions was stable, within-session determinations of concentration-effect functions for liquid food were conducted up to 3 days per week. During these sessions, liquid food was available in five sequential 20 min components, with each component separated by 2-min inter-component timeout periods. Food concentrations (0%, 3%, 10%, 32% and 100%) were tested in an ascending order, and each reinforcer was delivered in a volume of 75 ll over approximately 4.2 s. As with other cocaine and food reinforced sessions, each component began with noncontingent delivery of the reinforcer available under the FR schedule. These sessions were interspersed with maintenance sessions until the within-session concentration-effect function stabilized. Criteria for stabilization were: (1) peak levels of responding maintained by at least one concentration of food equaled or exceeded 20 reinforcers within a 20 min component, and (2) the concentration of liquid food that maintained peak responding varied by no more than one-half log unit over three consecutive withinsession determinations. 2.6.2. Pretreatment test procedures After stabilization of within-session dose- and concentration-effect functions for cocaine and food, respectively, pretreatment tests commenced. The following drugs and doses were evaluated as pretreatments: d-amphetamine (0.1–3.2 mg/kg), GBR 12909 (1.8–18.0 mg/kg), 7-OH-DPAT (0.1–10.0 mg/kg), quinelorane (0.001–0.18 mg/kg), SKF 82958 (0.1–10.0 mg/kg), R-6-Br-APB (0.018–1.8 mg/kg), eticlopride (0.01–0.32 mg/kg), SCH 39166 (0.032–0.32 mg/kg) and cocaine (10.0 mg/kg). All pretreatments were administered i.p. (1 ml/kg), and pretreatment occurred immediately before the test session for all drugs with the following exceptions: GBR 12909, 30 min; eticlopride, 15 min; SCH 39166, 15 min. Pretreatment times for all drugs were determined on the basis of prior evaluations of time course of behavioral effects using locomotor and drug discrimination procedures (unpublished observations). To examine the effects of pretreatment with liquid food, tests were also conducted in which liquid food (2.0 ml) was deposited into the food reservoir prior to the start of the test session. In addition, the effects of 7-OH-DPAT (0.03–1.0 mg/kg) and quinelorane (0.003–0.1 mg/kg) on consumption of liquid food from standard sipper-tube bottles in the home cage were evaluated during 20 min tests. Doses of the D2-like and D1-like agonists and antagonists were

selected on the basis of prior studies (Caine and Koob, 1994, 1995; Caine et al., 1999). Doses of the indirect dopamine agonists d-amphetamine and GBR 12909 were selected on the basis of preliminary tests. Pretreatment test sessions were interspersed with maintenance sessions and within-session dose- or concentrationeffect determinations in which there was no pretreatment. Criteria for conducting a pretreatment test were: (1) a minimum of 48 h since the most recent administration of a test compound, (2) behavior met criteria for stabilization (see training, above). 2.7. Data analysis Data from multiple-component test sessions were expressed as the total number of reinforcers earned in each 20-min component. Vehicle and each dose of each pretreatment drug were tested either once or twice, and in the latter case, data were averaged. Group mean values for the effects of pretreatment drugs on cocaineand food-maintained responding were analyzed with two-way within-subjects ANOVA with pretreatment dose and cocaine dose or food concentration as factors. Significant main effects or interactions were followed by pair-wise comparisons (Newman-Keuls) with each pretreatment dose compared to vehicle. For effects that were previously established (Caine and Koob, 1994, 1995; Caine et al., 1999) but did not reach significance with Newman-Keuls comparisons, t-tests were conducted to further test for replication of previous results. A50 values were calculated by linear interpolation of a portion of the log dose-effect function for each rat. For cocaine self-administration data, A50 values were defined as the estimated dose of each pretreatment drug that decreased responding maintained by 0.32 mg/kg/injection cocaine to 50% of vehicle pretreatment values. For food self-administration data, the A50 values were defined as the estimated dose of each pretreatment drug that decreased responding maintained by 32% food to 50% of vehicle pretreatment values. This dose of cocaine (0.32 mg/kg/injection) and this concentration of liquid food (32%) were selected for calculation of A50 values for the following two reasons. First, these were the lowest magnitudes of each reinforcer that reliably maintained responding in every rat. Second, these reinforcer magnitudes for cocaine and food were presented at the same time in the multiplecomponent test sessions after administration of the pretreatment drugs. Group means and 95% confidence intervals were then calculated from the individual A50 values. Data from multiple-component test sessions were also evaluated as total cocaine (mg/kg) or food earned (g/kg) during test sessions. These latter data, as well as data from tests of liquid food consumption in the home cages were analyzed using one-way ANOVA with pretreatment dose as the factor.

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2.8. Drugs Cocaine was generously provided by the National Institute on Drug Abuse, NIH. d-amphetamine sulfate, ()-GBR 12909 HCl, ()-7-OH-DPAT HBr, ()-quinelorane 2HCl, ()-SKF 82958 HBr, R(+)-6-Br-APB HBr, and S( )-eticlopride HCl were obtained from Research Biomedicals International (Natick, MA). R(+)-SCH 39166 was a gift from Schering Plough, Inc. (Kenilworth, NJ). All drug doses refer to the weights of the salts. All drug vehicles were water or saline, and heat was often used to insure dissolution.

3. Results 3.1. Effects of pretreatment with indirect dopamine agonists on cocaine self-administration (Fig. 1, far left panels) In all groups of rats pretreated with vehicle injections, responding maintained by cocaine was dosedependent and reliable when increasing unit doses of

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cocaine were available in successive 20-min components. Across the dose range tested (0.03–1.0 mg/kg/ injection), cocaine produced an inverted U-shaped dose-effect function, with low levels of responding in the presence of the cocaine-associated cue light alone (0 mg/kg/injection) and peak responding maintained by an intermediate dose of cocaine (0.1 mg/kg). Compared to the 0.1 mg/kg unit dose, higher doses of cocaine (0.32 and 1.0 mg/kg/injection) maintained lower rates of responding on the descending limb of an inverted U-shaped dose-effect function that is characteristic for cocaine self-administration under these conditions. Pretreatment with the indirect DA agonists d-amphetamine and GBR 12909 produced alterations in the cocaine dose-effect function that depended on both the dose of cocaine and the dose of each pretreatment compound (d-amphetamine: main pretreatment-dose effect, F4;28 ¼ 9:5, p < 0:05; main cocaine-dose effect, F4;28 ¼ 11:2, p < 0:05; cocaine-dose  pretreatmentdose interaction, F16;112 ¼ 9:5, p < 0:05; GBR 12909: main cocaine-dose effect, F4;28 ¼ 18:4, p < 0:05, cocainedose  pretreatment dose interaction, F8;56 ¼ 5:8,

Fig. 1. Effects of dopamine indirect agonists and selective D1-like and D2-like agonists and antagonists on cocaine self-administration in rats. Abscissae: unit dose cocaine in mg/kg/injection (log scale). The point above ‘‘0’’ in the left of each panel shows responding maintained by the cocaine-associated cue light alone. Ordinates: total number of injections earned during a 20-min period of drug availability. Values shown are group means (SEM) calculated from seven or eight rats. Asterisks and daggers indicate significant differences from effects of vehicle injection by Neuman-Keul’s pairwise comparison and one-group t-test, respectively, following a significant main effect by repeated measures ANOVA (p < 0:05).

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p< 0:05). For example, whereas a low dose of damphetamine (0.32 mg/kg) produced no marked changes in the cocaine dose-effect function (data not shown, for clarity), an intermediate dose (1.8 mg/kg) increased responding in the presence of the cocaine-associated cue light alone and during availability of a low dose of cocaine (0.03 mg/kg/injection). Responding maintained by higher doses of cocaine (0.1–1.0 mg/kg/injection) was decreased, resulting in a leftward shift in the cocaine dose-effect function. A higher dose of damphetamine (3.2 mg/kg) markedly reduced responding maintained by all doses of cocaine. Pretreatment with GBR 12909 produced effects that were qualitatively similar to those produced by damphetamine. A relatively low dose of GBR 12909 (3.2 mg/kg) failed to alter the cocaine dose-effect function, and a higher dose (10 mg/kg) produced a leftward shift in the cocaine dose-effect function. Specifically, responding in the presence of the cocaine-associated cue light and during availability of a low dose of cocaine (0.03 mg/kg/injection) was increased following pretreatment with 10 mg/kg, whereas responding maintained by higher doses of cocaine (0.1 and 0.32 mg/kg/injection) was decreased. 3.2. Effects of pretreatment with D2-like agonists on cocaine self-administration (Fig. 1, left-center panels) Pretreatment with the D2-like agonist 7-OH-DPAT altered responding maintained by cocaine in a manner that depended on both the dose of cocaine and the pretreatment dose (main cocaine-dose effect, F 4;28 ¼ 13:5, p < 0:05; cocaine-dose  pretreatment-dose interaction, F12;84 ¼ 3:9, p < 0:05). A low dose of 7-OH-DPAT (0.32 mg/kg) increased responding maintained by only a low dose of cocaine (0.03 mg/kg/injection), with no significant effects observed at any other cocaine doses. However, a higher dose (1.0 mg/kg) increased responding in the presence of the cocaine-associated cue light alone and during availability of a low dose of cocaine (0.03 mg/kg/injection), and decreased responding maintained by higher doses of cocaine (0.32 and 1.0 mg/kg/injection), resulting in a leftward shift in the cocaine dose-effect function. Pretreatment with quinelorane produced effects that were qualitatively similar to those produced by 7-OHDPAT (main cocaine-dose effect, F 4;24 ¼ 19:2, p < 0:05; cocaine-dose  pretreatment-dose interaction, F8;48 ¼ 8:8, p < 0:05). At both doses of quinelorane (0.01 and 0.03 mg/kg) responding maintained by the cocaineassociated cue light alone (significant for 0.01 mg/kg dose only) and by a low dose of cocaine was generally increased. In addition, these pretreatment doses decreased responding maintained by higher doses of cocaine (0.1–1.0 mg/kg/injection), resulting in a leftward shift in the cocaine dose-effect function.

3.3. Effects of pretreatment with D1-like agonists on cocaine self-administration (Fig. 1, right-center-panels) Pretreatment with the D1-like agonists SKF 82958 and R-6-Br-APB produced alterations in the cocaine dose-effect function that depended on both the dose of cocaine and the dose of each pretreatment compound (SKF 82958: main pretreatment-dose effect, F2;14 ¼ 6:3, p < 0:05; main cocaine-dose effect, F4;28 ¼ 14:1, p < 0:05; cocaine-dose  pretreatment-dose interaction, F8;56 ¼ 3:6, p < 0:05; R-6-Br-APB: main pretreatmentdose effect, F2;12 ¼ 9:3, p < 0:05; main cocaine-dose effect, F4;28 ¼ 14:1, p < 0:05; cocaine-dose  pretreatment dose interaction, F8;56 ¼ 3:6, p < 0:05). Pretreatment doses of both SKF 82958 (0.32 and 1.0 mg/kg) and R-6Br-APB (0.1 and 0.32 mg/kg) decreased responding for doses of cocaine (0.1 and 0.32 mg/kg/injection) that maintained the highest rates of behavior. These D1-like agonists failed to alter responding maintained by either lower (0.03 mg/kg/injection) or higher (1.0 mg/kg/injection) doses of cocaine, thus resulting in overall downward shifts in the cocaine dose-effect function. 3.4. Effects of pretreatment with dopamine antagonists on cocaine self-administration (Fig. 1, far right panels) Pretreatment with the D1-like antagonist SCH 39166 or the D2-like antagonist eticlopride altered responding maintained by cocaine in a manner that was dependent on both the dose of cocaine and the dose of each pretreatment drug (SCH 39166: main pretreatment-dose effect, F4;24 ¼ 9:4, p < 0:05; main cocaine-dose effect, F4;24 ¼ 31:7, p < 0:05; cocaine-dose  pretreatment-dose interaction, F16;96 ¼ 8:4, p < 0:05; eticlopride: main pretreatment-dose effect, F4;24 ¼ 18:1, p < 0:05; main cocaine-dose effect, F4;24 ¼ 16:7, p < 0:05; cocainedose  pretreatment dose interaction, F16;96 ¼ 5:7, p < 0:05). For example, although a low dose of SCH 39166 failed to alter the cocaine dose-effect function (data not shown, for clarity), higher doses (0.1 and 0.32 mg/kg) nearly eliminated responding maintained by low doses of cocaine (0.03 and 0.1 mg/kg/injection) and generally increased responding maintained by higher doses of cocaine (0.3 and 1.0 mg/kg/injection), resulting in a rightward shift in the cocaine dose-effect function. Indeed, pretreatment with the highest dose of SCH 39166 (0.32 mg/kg) increased the dose of cocaine that maintained peak rates of responding by 1.0 log unit. Similar to SCH 39166, eticlopride dose-dependently decreased responding maintained by a low dose of cocaine (0.1 mg/kg/injection) and increased responding maintained by the highest dose of cocaine (1.0 mg/ kg/injection), resulting in a rightward shift in the cocaine dose-effect function. That pretreatment with 0.32 mg/kg eticlopride produced a 1.0 log unit increase

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in the dose of cocaine that maintained peak rates of responding is also indicative of a rightward shift in the cocaine dose-effect function. 3.5. Effects of pretreatment with indirect dopamine agonists on responding maintained by liquid food (Fig. 2, far left panels) In all groups of rats pretreated with vehicle injections, responding maintained by food generally increased as a monotonic function of food concentration when increasing concentrations were available in successive 20-min components. Concentrations of food from 0 to 3% food maintained relatively low rates of responding, and concentrations of food from 32% to 100% maintained peak rates of responding that were 2to 3-fold greater than peak rates of responding maintained by cocaine (0.1 mg/kg/injection). Pretreatment with the indirect DA agonists d-amphetamine and GBR 12909 altered responding maintained by food in a manner that depended on both the concentration of food and the pretreatment dose (damphetamine: main pretreatment-dose effect, F6;36 ¼ 25:1, p < 0:05; main food-concentration effect, F4;24 ¼ 107:4, p < 0:05; food-concentration  pretreatment-dose

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interaction, F24;144 ¼ 10:9, p < 0:05; GBR 12909: main pretreatment-dose effect, F5;30 ¼ 5:9, p < 0:05; main food-concentration effect, F4;24 ¼ 80:4, p < 0:05; foodconcentration  pretreatment dose interaction, F20;120 ¼ 11:5, p < 0:05). Relatively low doses of d-amphetamine (0.32 mg/kg) and GBR 12909 (3.2 mg/kg) tended to increase responding maintained by low concentrations of food (0–10%), and this effect reached statistical significance with d-amphetamine in combination with 3% food and with GBR 12909 in combination with 0– 10% food. In contrast, a higher dose of d-amphetamine (1.8 mg/kg) and GBR 12909 (10 mg/kg) tended to decrease responding maintained by high concentrations of food (32% and 100%), with near complete elimination of responding apparent at the highest doses tested (3.2 mg/kg d-amphetamine and 18 mg/kg GBR 12909). 3.6. Effects of pretreatment with D2-like agonists on responding maintained by liquid food (Fig. 2, left-center panels) Pretreatment with the D2-like agonists 7-OH-DPAT and quinelorane altered responding maintained by food in a manner that depended on both the concentration

Fig. 2. Effects of dopamine indirect agonists and selective D1-like and D2-like agonists and antagonists on responding maintained by liquid food in rats. Abscissae: concentration of liquid food (log scale). The point above ‘‘0’’ in the left of each panel shows responding maintained by water. Ordinates: total number of food presentations (75 ll) earned during a 20-min period of food availability. Values shown are group means (SEM) calculated from six to eight rats. Asterisks and daggers indicate significant differences from effects of vehicle injection by Neuman-Keul’s pairwise comparison and one group t-test, respectively, following a significant main effect by repeated measures ANOVA (p < 0:05).

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of food and the pretreatment dose (7-OH-DPAT: main pretreatment-dose effect, F7;49 ¼ 10:1, p < 0:05; main food-concentration effect, F4;28 ¼ 169:8, p < 0:05; foodconcentration  pretreatment-dose interaction, F 28;196 ¼ 6:5, p < 0:05; quinelorane: main pretreatment-dose effect, F6;42 ¼ 20:5, p < 0:05; main food-concentration effect, F4;28 ¼ 236:9, p < 0:05; food-concentration  pretreatment dose interaction, F24;168 ¼ 12:3, p < 0:05). Relatively low doses of 7-OH-DPAT (0.32 and 1.0 mg/ kg) produced no significant alterations in the concentration-effect function for food. However, a higher dose of 7-OH-DPAT (3.2 mg/kg) decreased responding maintained by high concentrations of food (32% and 100%). Quinelorane produced dose-dependent decreases in responding maintained by high concentrations of food (32% and 100%), with very low levels of behavior observed at the highest dose tested (0.1 mg/kg). In addition, all pretreatment doses of quinelorane produced small but significant decreases in responding maintained by water (0% food). 3.7. Effects of pretreatment with D1-like agonists on responding maintained by liquid food (Fig. 2, centerright panels) Pretreatment with the D1-like agonists SKF 82958 and R-6-Br-APB altered responding maintained by food in a manner that depended on both the concentration of food and the pretreatment dose (SKF 82958: main pretreatment-dose effect, F6;42 ¼ 17:2, p < 0:05; main food-concentration effect, F4;28 ¼ 152:9, p < 0:05; food-concentration  pretreatment-dose interaction, F24;168 ¼ 6:5, p < 0:05; R-6-Br-APB: main pretreatmentdose effect, F6;42 ¼ 12:1, p < 0:05; main food-concentration effect, F4;28 ¼ 216:3, p < 0:05; foodconcentration  pretreatment dose interaction, F24;168 ¼ 308:7, p < 0:05). Similar to the D2-like agonists, pretreatment with both D1-like agonists produced dose-dependent reductions in responding maintained by food. For example, although low doses of SKF 82958 (0.32 and 1.0 mg/kg) and R-6-Br-APB (0.1 and 0.32 mg/kg) produced no significant alterations in the concentration-effect function, pretreatment with higher doses of SKF 82958 (3.2 and 10 mg/kg) and R-6-Br-APB (1.0 and 1.8 mg/kg) generally decreased responding maintained by high concentrations of food (32% and 100%). The highest dose of each drug tested (10 mg/kg SKF 82958 and 1.8 mg/kg R-6-Br-APB) produced near complete elimination of responding at all food concentrations except 100%. 3.8. Effects of pretreatment with dopamine antagonists on responding maintained by liquid food (Fig. 2, far right panels) Pretreatment with the D1-like antagonist SCH 39166 or the D2-like antagonist eticlopride altered responding

maintained by food in a manner that was dependent on both the concentration of food and the dose of each pretreatment drug (SCH 39166: main pretreatment-dose effect, F4;20 ¼ 14:6, p < 0:05; main food-concentration effect, F4;20 ¼ 64:9, p < 0:05; food-concentration  pretreatment-dose interaction, F16;80 ¼ 7:1, p < 0:05; eticlopride: main pretreatment-dose effect, F5;25 ¼ 35:1, p < 0:05; main food-concentration effect, F4;20 ¼ 34:7, p < 0:05; food-concentration  pretreatment dose interaction, F20;100 ¼ 20:3, p < 0:05). For example, whereas pretreatment doses of SCH 39166 ranging from 0.03 to 1.0 mg/kg produced little or no change in the concentration-effect function for food, a higher dose (0.32 mg/ kg) decreased responding maintained by concentrations of food ranging from 10% to 100%. Pretreatment with eticlopride also produced dosedependent reductions in responding maintained by food. The lowest dose tested (0.01 mg/kg) decreased responding maintained by a low concentration of food (3%), and higher pretreatment doses (0.03 and 1.0 mg/ kg) decreased responding maintained by all concentrations of food (3%–100%). The highest dose of eticlopride produced near complete elimination of responding at all concentrations of food tested. 3.9. Effects of pretreatment with cocaine or presentation of liquid food on responding maintained by cocaine (Fig. 3, left panel) Pretreatment with cocaine (10.0 mg/kg IP) or presentation of liquid food (100% ensure, 2.0 ml) prior to test sessions altered cocaine self-administration in a manner that was dependent on both the pretreatment

Fig. 3. Effects of cocaine (10.0 mg/kg IP) or food presentation (2.0 ml) prior to the start of test sessions on cocaine self-administration and food maintained responding in rats. Abscissae: Left panel, unit dose of cocaine (mg/kg/injection); right panel, concentration of liquid food. The point above ‘‘0’’ in the left of each panel shows responding maintained by the cocaine associated cue light alone (left panel) or by water (right panel). Ordinates: total number of cocaine injections or food presentations (75 ll) earned during a 20-min period of availability. Values shown are group means (SEM) calculated from seven rats. Asterisks indicate significant differences from effects of vehicle injection by Neuman-Keul’s pairwise comparison following a significant main effect by repeated measures ANOVA (p < 0:05).

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type (cocaine or food) and the unit dose of cocaine (main pretreatment-type effect, F2;12 ¼ 3:30, p > 0:05; main unit dose-cocaine effect, F4;24 ¼ 4:12, p < 0:05; main pretreatment type  unit dose-cocaine interaction, F8;48 ¼ 3:88, p < 0:05). Specifically, pretreatment with cocaine increased responding in the presence of the cocaine-associated cue light alone. Presentation of liquid food prior to the session decreased self-administration of an intermediate cocaine dose (0.1 mg/kg/ injection). 3.10. Effects of pretreatment with cocaine or presentation of liquid food on responding maintained by liquid food (Fig. 3, right panel) Pretreatment with cocaine (10.0 mg/kg IP) or presentation with liquid food (100% ensure, 2.0 ml) prior to test sessions altered food maintained responding in a manner that was dependent on both the pretreatment type (cocaine or food) and the food concentration that maintained responding (main pretreatment-type effect, F2;12 ¼ 6:34, p < 0:05; main food concentration effect, F4;24 ¼ 75:6, p < 0:05; main pretreatment type  food concentration interaction, F8;48 ¼ 2:38, p < 0:05). Specifically, pretreatment with cocaine increased responding when 0% food was available and when an intermediate food concentration (10% food) was available. Presentation of liquid food prior to the session increased responding when 0% food was available. 3.11. Effects of pretreatment with D2-like agonists on consumption of liquid food in home cages (Fig. 4) Both D2-like agonists increased responding maintained by low magnitude cocaine, but not food, reinforcers. One potential explanation for these selective effects is that doses of D2-like agonists that increase cocaine-reinforced responding and that may have generalized rateincreasing effects may also produce selective ratedecreasing effects for food maintained responding. To further examine this hypothesis, tests were conducted in which these drugs were administered to rats that had free access to liquid food in their home cages. Pretreatment with 7-OH-DPAT and quinelorane dose-dependently decreased consumption of liquid food in home cages (mls of food consumed in 20 min) in a manner that was dependent on both the food concentration that was consumed and the pretreatment dose (7-OHDPAT: main food concentration effect, F2;18 ¼ 9:74, p < 0:05; main pretreatment dose-effect, F4;36 ¼ 23:95, p < 0:05; main food concentration  pretreatment dose interaction, F8;72 ¼ 3:36, p < 0:05; quinelorane: main food concentration effect, F2;18 ¼ 13:37, p < 0:05; main pretreatment dose-effect, F4;36 ¼ 25:45, p < 0:05; main food concentration  pretreatment dose interaction, F8;72 ¼ 3:58, p < 0:05). Specifically, pretreatment with

Fig. 4. Effects of dopamine D2-like agonists on consumption of liquid food in home cages. Abscissae: dose of pretreatment drug. The point above ‘‘S’’ in the left of each panel shows the effects of saline injection. Ordinates: total number of ml of liquid food consumed during a 20-min period of availability. Values shown are group means (SEM) calculated from ten rats. Asterisks indicate significant differences from effects of vehicle injection by Neuman-Keul’s pairwise comparison following a significant main effect by repeated measures ANOVA (p < 0:05).

7-OH-DPAT in the dose range of 0.32–1.0 mg/kg decreased consumption of 10% and 32% liquid food, but not 100% liquid food. The effects of pretreatment with quinelorane were qualitatively similar to those of 7-OH-DPAT, and quinelorane in the dose range of 0.01–0.1 mg/kg decreased consumption of 10% liquid food and/or 32% liquid food, but not 100% liquid food. 3.12. Potency of pretreatment drugs to alter responding maintained by cocaine and liquid food One strategy for assessing the ability of dopaminergic compounds to decrease cocaine self-administration selectively is to compare the potency of each compound to decrease responding during both cocaine and food reinforced sessions. Table 1 shows A50 values for each compound to decrease responding maintained by either 0.32 mg/kg/injection cocaine or 32% food. These reinforcer magnitudes of cocaine and food were selected because both were the lowest magnitude reinforcers that reliably maintained behavior in every rat tested, and both were available at the same time during test sessions after administration of pretreatment compounds. The A50 values for the indirect dopamine agonists damphetamine and GBR 12909 were very similar for both cocaine and food, differing by less than 1.4-fold, and with overlapping confidence intervals. In contrast, there were small but significant potency differences for one D2-like agonist (7-OH-DPAT) and for both D1-like agonists to alter responding maintained by cocaine ver-

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Table 1 A50 (mg/kg i.p.) values for dopaminergic compounds to reduce responding maintained by cocaine (0.32 mg/kg) or liquid food (32% in water). All values are the group means and 95% confidence intervals, calculated from the individual A50 values for each rat Drug

Cocaine (0.32 mg/kg i.v.)

Food (32% in water)

d-amphetamine GBR 12909 7-OH-DPAT Quinelorane SKF 82958 R-6-Br-APB SCH 39166 Eticlopride

1.2 (0.6–2.4) 7.4 (5.4–10.3) 0.6 (0.5–0.7)a 0.02 (0.01–0.02) 0.5 (0.4–0.7)a 0.19 (0.18–0.20)a 0.16 (0.11–0.25) 0.15 (0.09–0.23)

1.6 (1.0–2.5) 9.8 (7.4–12.4) 3.4 (1.9–5.9) 0.03 (0.01–0.05) 2.1 (1.2–3.7) 0.44 (0.28–0.68) 0.15 (0.11–0.23) 0.03 (0.02–0.04)b

a

Indicates higher potency for decreasing cocaine- than food-maintained responding. b Indicates higher potency for decreasing food- than cocainemaintained responding.

total cocaine intake and total food earned during test sessions. All of the dopamine agonists decreased both total cocaine intake and total food earned at some dose of the pretreatment drug, and no increases in cocaine intake or food earned were observed after pretreatment with dopamine agonists. In addition, all of the dopamine agonists decreased total cocaine intake more potently than they decreased total food intake. In contrast, the dopamine antagonists SCH 39166 and eticlopride did not significantly decrease cocaine intake across the range of pretreatment doses tested, whereas significant decreases in food earned were observed. Furthermore, both of the dopamine antagonists significantly increased cocaine intake but not food earned across the range of pretreatment doses tested.

4. Discussion sus food, as the confidence intervals for the A50 values did not overlap. 7-OH-DPAT was approximately 5.7fold more potent and SKF 82958 and R-6-Br-APB were approximately 4.2- and 2.3-fold more potent, respectively, in altering cocaine- versus food-maintained responding. Opposite effects were observed with the D2-like antagonist eticlopride that was 5-fold more potent in altering food- than cocaine-maintained responding. SCH 39166 was approximately equipotent in reducing cocaine and food maintained responding. 3.13. Effects of pretreatment drugs on total cocaine intake and total food earned during test sessions Another strategy for assessing the modification of cocaine self-administration by pretreatment drugs and the behavioral selectivity of these effects is to examine total cocaine intake and total food earned during test sessions. Table 2 shows the lowest dose of each dopaminergic compound that significantly (p < 0:05) altered Table 2 Lowest dose of dopaminergic compounds (mg/kg ip) that significantly altered total cocaine intake or total food earned per session Decreased Cocaine d-amphetamine GBR 12909 7-OH-DPAT Quinelorane SKF 82958 R-6-Br-APB SCH 39166 Eticlopride

1.8 10.0 0.56 0.01 1.0 0.32 NDa (>0.32) NDa (>0.32)

Increased Food 3.2 18.0 3.2 0.03 3.2 1.0 0.18 0.03

Cocaine b

NI NIb NIb NIb NIb NIb 0.032 0.1

Food NIb NIb NIb NIb NIb NIb NIb NIb

4.1. Summary In the present study, pretreatment with four classes of dopaminergic compounds produced four different profiles of effects on cocaine self-administration. The present results confirm results from many previous studies (see Mello and Negus, 1996 for review), and also extend those results with several novel findings. First, acute treatment with indirect dopamine agonists produced leftward shifts in dose-effect functions for cocaine self-administration, and moreover, increased responding with low cocaine doses was paralleled by increased responding with low food concentrations. Second, D2-like agonists shifted dose-effect functions for cocaine leftward, and in contrast to effects with indirect agonists, increased responding observed with low cocaine doses as well as decreased responding observed with high cocaine doses was somewhat selective for cocaine relative to food maintained responding. Third, D1-like agonists shifted dose-effect functions for cocaine downward, and both D1-like agonists were moderately but significantly more potent in decreasing cocaine selfadministration relative to food maintained responding. Finally, antagonists for both D2-like and D1-like receptors shifted cocaine dose-effect functions rightward in rats, and these antagonists were either equally potent or more potent in decreasing food maintained responding relative to cocaine self-administration. In addition, all of the agonists uniformly decreased total cocaine intake, whereas the antagonists increased total cocaine intake. 4.2. Effects of dopamine indirect agonists

a

No decreases observed at any dose tested; higher doses may decrease cocaine intake. b No increase observed at any dose tested; lower doses were ineffective and higher doses only decreased responding.

In the present study, the indirect agonists d-amphetamine and GBR 12909 produced leftward shifts in dose-effect functions for cocaine self-administration,

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suggestive of enhanced or additive effects in combination with cocaine. These results confirm and extend results from previous studies that evaluated the effects of dopamine indirect agonists on self-administration of doses on the descending limb of the inverted U-shaped cocaine dose-effect function (Skjoldager et al., 1993; Glowa et al., 1995, 1996; Nader et al., 1997; Dworkin et al., 1998; Lynch et al., 1998; Howell et al., 2000; Stafford et al., 2000; Sizemore et al., 2004). Fewer studies have examined the interactions of indirect dopamine agonists with doses comprising both the ascending and descending limbs of the cocaine doseeffect function, and the present results contrast with results from those previous studies (Glowa et al., 1995; Negus et al., 1999; Schenk, 2002; Negus and Mello, 2003; Negus, 2003). An important reason for the discrepancy between the present and some previous findings is that indirect agonists were administered acutely in the present study and chronically in several previous studies in which downward shifts (Negus et al., 1999; Negus and Mello, 2003) or rightward shifts in cocaine dose-effect functions were observed (Negus, 2003). This discrepancy highlights the importance of frequency and duration of treatment as a determinant of drug pretreatment effects on cocaine self-administration. Indeed, tolerance to the effects of experimenter-administered indirect agonists and cross-tolerance to the effects of cocaine was one explanation offered for effects observed in studies with chronic treatments (Negus and Mello, 2003; Negus, 2003). Thus, findings from the present study of leftward shifts in dose-effect functions for cocaine self-administration after acute pretreatment with indirect dopamine agonists are relatively novel (but see also Schenk, 2002). Furthermore, these findings demonstrate that acute pretreatment with drugs which are known to increase levels of synaptic dopamine and to produce cocaine-like discriminative stimulus effects (Kleven et al., 1990; Melia and Spealman, 1991) and reinforcing effects (Bergman et al., 1989; Howell and Byrd, 1991; Roberts, 1993; Wojnicki and Glowa, 1996; Ranaldi et al., 1999) shift the cocaine dose-effect function leftward under some conditions. 4.3. Effects of dopamine D2-like and D1-like agonists Similar to the indirect dopamine agonists, the D2-like agonists 7-OH-DPAT and quinelorane produced leftward shifts in the dose-effect function for cocaine. Previous reports have also documented leftward shifts in cocaine self-administration dose-effect functions after administration of high efficacy D2-like agonists (Caine and Koob, 1995; Caine et al., 1999; Caine et al., 2000a), and other reports have demonstrated the ability of D2-like agonists to maintain self-administration behavior (Woolverton et al., 1984; Wise et al., 1990; Caine

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and Koob, 1993; Nader and Mach, 1996; Sinnott et al., 1999; Ranaldi et al., 2001) and to engender cocaine-like discriminative stimulus effects (Barrett and Appel, 1989; Callahan et al., 1991; Witkin et al., 1991; Spealman et al., 1991; Spealman, 1996; Lamas et al., 1996; Caine et al., 2000b). Collectively, these findings suggest that activation of D2-like receptors and their consequent neurobiological effects mediate, at least in part, the abuse-related effects of cocaine. In contrast to direct D2-like dopamine agonists, the D1-like agonists produced uniform downward shifts in cocaine dose-effect functions, and these findings are generally consistent with previous studies in both rats and nonhuman primates (Caine et al., 1999, 2000a; Platt et al., 2001; Mutschler and Bergman, 2002). Although it can be difficult to interpret downward shifts in the cocaine dose-effect function as they relate to the pharmacology of cocaine, previous studies generally support the conclusion that D1-like agonists produce cocaine-like effects under a narrower range of conditions than D2-like agonists. For example, although positive reinforcing effects of D1-like agonists have been clearly demonstrated in both rats and primates (Self and Stein, 1992; Weed and Woolverton, 1995), D1-like agonists failed to maintain self-administration behavior under some conditions in which cocaine and D2-like agonists served effectively as reinforcers (Grech et al., 1996; Caine et al., 1999). Similarly, at least one study found that D2-like agonists engendered cocaine-like discriminative stimulus effects across a broader range of conditions than D1-like agonists (Caine et al., 2000b), and several studies found that D2-like agonists, and not D1-like agonists, enhanced the discriminative stimulus effects of cocaine (Callahan et al., 1991; Callahan and Cunningham, 1993; Caine et al., 2000b). Finally, results from studies of drug-induced reinstatement are in agreement with the present results that D2-like agonists generally enhanced or produced additive effects with cocaine, whereas D1-like agonists did not (Self et al., 1996; Khroyan et al., 2000, 2003). 4.4. Effects of dopamine D2-like and D1-like antagonists Prior studies in rats with selective D2-like and D1-like antagonists have demonstrated that they modify selfadministration of a single unit dose of cocaine in a manner consistent with pharmacological antagonism (Koob et al., 1987; Hubner and Moreton, 1991; Caine and Koob, 1994; Britton et al., 1991). The present findings of rightward shifts in complete cocaine dose-effect functions extend findings obtained in nonhuman primates with eticlopride, SCH 39166 and flupenthixol (Bergman et al., 1990; Negus et al., 1996) and with SCH 23390 and flupenthixol in rats (Caine and Koob, 1995; Schenk et al., 1999) to include comparable effects of eticlopride and SCH 39166 in rats. Such findings

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further emphasize that both D2-like and D1-like receptor mechanisms can be targeted to modify cocaine selfadministration and suggest agreement between results from studies of nonhuman primates and rats. These effects of dopamine antagonists are consistent with surmountable antagonism of cocaine’s reinforcing effects or mutual antagonism of the behavioral effects of cocaine and dopamine antagonists (Mello and Negus, 1996; Herling and Woods, 1980). In addition to analyzing shifts in cocaine dose-effect functions, data were also analyzed according to total cocaine intake. All of the agonists dose-dependently and uniformly decreased the total amount of cocaine self-administered. For the indirect dopamine agonists and D2-like agonists, this was a consequence of increased responding maintained by low unit doses of cocaine that contributed little to total cocaine intake, with concomitant decreased responding maintained by high unit doses of cocaine that contributed significantly to total cocaine intake. The D1-like agonists decreased responding maintained by both low and high doses of cocaine. In marked contrast to the effects of the agonists, the dopamine antagonists increased total cocaine intake. 4.4.1. Effects of dopaminergic compounds on food maintained responding: comparison to cocaine maintained responding To assess the extent to which dopaminergic compounds produced effects that were selective for cocaine as a reinforcer, the effects of these drugs on food maintained responding were determined. The use of a range of food concentrations that maintained both low and high rates of behavior afforded a novel approach with as least two advantages. First, responding maintained by low- to intermediate-magnitude food reinforcers may be more sensitive to disruption than with high magnitude food reinforcers, providing a more sensitive control for observing nonselective rate decreasing effects. Second, because both low and high rates of responding were obtained using a range of food concentrations, both increases and decreases in food maintained responding could be evaluated. For example, damphetamine and GBR 12909, at selected doses, increased responding maintained by relatively low food concentrations (see below). In addition, responding maintained by relatively high food concentrations was dose-dependently decreased by some dose of each dopaminergic compound. Because plasma levels of pretreatment drugs as well as the cocaine unit dose and food concentration varied over the course of the session, the relative potency of each compound to decrease responding maintained by cocaine (0.32 mg/ kg/injection) and food (32% food) during the fourth component of the sessions were directly compared. Whereas the indirect dopamine agonists d-ampheta-

mine and GBR 12909 were approximately equipotent in decreasing cocaine- and food maintained responding in the present study (but see Glowa et al., 1995), the D2-like agonist 7-OH-DPAT produced moderately selective effects, with 5-fold higher potency in decreasing cocaine- relative to food-maintained responding. Both D1-like agonists also produced effects that were moderately selective for cocaine, as evidenced by the 2- to 4fold greater potency in decreasing cocaine maintained behavior, consistent with results from a few previous studies (Katz and Witkin, 1992; Mutschler and Bergman, 2002; but see Platt et al., 2001). When these data were examined as the lowest dose of each compound that significantly decreased total cocaine or food intake, all of the agonists were slightly more potent in decreasing total cocaine intake relative to total food earned during test sessions. In contrast to the effects of all of the dopamine agonists, the dopamine antagonists displayed a greater potency in decreasing food- relative to cocaine intake. 4.4.2. Interpretation of leftward shifts in dose-effect functions for cocaine self-administration: rate-altering effects, discriminative stimulus effects and reinforcing effects Although leftward shifts in the cocaine dose-effect function have been interpreted as enhanced reinforcing effects of cocaine (Caine and Koob, 1995; Mello and Negus, 1996), that both d-amphetamine and GBR 12909 also produced increases in responding maintained by low magnitude food reinforcers suggests that nonselective rate-increasing effects on schedule controlled responding (McKearney, 1974, 1982) may at least in part account for increased self-administration on the ascending limb of the cocaine dose-effect function. Nevertheless, it is worth noting that cocaine administered as a pretreatment also nonselectively increased responding maintained by both low magnitude cocaine and food reinforcers. To the extent that mechanisms common to cocaine and other indirect dopamine agonists probably account for both rateincreasing and reinforcing effects of these drugs (Bergman et al., 1989; Spealman et al., 1989), the nonselective rate-increasing effects of the dopamine indirect agonists d-amphetamine and GBR 12909 are indicative of cocaine-like behavioral effects. Additionally, that responding was increased in the first component of the test sessions when cocaine was not yet available for self-administration suggests that the pretreatment drugs produced effects independently of self-administered cocaine. Thus, alterations in the shape and position of cocaine dose-effect functions after pretreatment with indirect dopamine agonists may also be described as upward and leftward shifts, acknowledging effects of the pretreatment drug alone as well as effects in combination with cocaine.

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In contrast to the indirect dopamine agonists, pretreatment with D2-like agonists selectively increased responding maintained by low cocaine doses relative to low food concentrations. This dissociation may suggest that D2-like agonists are less efficacious compounds for producing generalized rate-increasing effects than are indirect dopamine agonists, and thus rate-increasing effects were observed under some conditions in the present study (cocaine-reinforced test sessions) and not others (food-reinforced test sessions). A similar and more compelling explanation may be invoked for the lack of leftward shifts in cocaine dose-effect functions after pretreatment with D1-like agonists, in that the latter compounds are relatively ineffective in producing rate-increasing effects on schedule-controlled responding (Bergman et al., 1995). However, with regard to D2-like agonists, some evidence suggests that these compounds are comparably effective to indirect dopamine agonists in producing rate-increasing effects (Bergman et al., 1989; Bergman et al., 1995). Alternatively, it is possible that doses of D2-like agonists that increase responding maintained by cocaine and that may occasion generalized rate-increasing effects also interfere with the reinforcing effects of food. In support of the latter hypothesis, the same doses of D2-like agonists that increased behavior maintained by low doses of cocaine also decreased consumption of liquid food in the rats’ home cages. This result highlights the importance of considering effects of pretreatment drugs that may be selective for food when using food-reinforced responding as a control for evaluating effects on cocaine self-administration. An alternative, but not mutually exclusive explanation for leftward shifts in cocaine dose-effect functions relates to the ability of pretreatment compounds to engender a cocaine-like discriminative stimulus. In other words, the pretreatment may have provided an interoceptive cue that signaled cocaine availability even in the absence of cocaine and when ineffective cocaine doses were available for self-administration. This hypothesis may be worthy of special consideration under the present conditions, given that self-administration components in this study were always initiated with a noncontingent infusion of the dose of cocaine available for self-administration. In comparison with cocaine self-administration sessions, components of food-reinforced test sessions also were initiated with a noncontingent presentation of the food concentration available. In this regard, it seems relevant that noncontingent presentation of food prior to test sessions increased responding only in food-reinforced test sessions and not in cocaine self-administration test sessions. This dissociation suggests that stimuli that increase responding maintained by low magnitude reinforcers may do so at least in part by virtue of overlap in the nature of the pretreatment and reinforcing stim-

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uli. In support of the hypothesis that leftward shifts observed in this study were related to the ability of pretreatment drugs to elicit cocaine-like discriminative stimuli, in the present study dopamine indirect and D2like agonists produced leftward shifts but D1-like agonists did not. Similarly, in some previous studies dopamine indirect and D2-like agonists produced cocaine-like discriminative stimulus effects under a broader range of conditions than D1-like agonists (see above). A third possible explanation is that pretreatment with dopamine indirect and D2-like agonists enhanced the reinforcing effects of cocaine and/or the cocaineassociated cues. This explanation also is consistent with observations from previous studies that dopamine indirect and D2-like agonists produced positive reinforcing effects under a broader range of conditions than D1-like agonists (see above). In studies with conditioned reinforcement, dopamine indirect and dopamine D2-like and D1-like agonists all enhanced conditioned reinforcing effects of a cue light associated with water presentation in water-deprived rats (Robbins and Everitt, 1992). In those studies, a dopamine indirect agonist was more effective than direct dopamine D2-like and D1like agonists. This latter result bears concordance with results of the present study in which dopamine indirect agonists were the most effective pretreatment drugs for increasing rates of responding during the first component of test sessions when cues were available in the absence of either cocaine or food reinforcers. In summary, rate-altering effects, discriminative stimulus effects, and reinforcing effects may all have contributed to leftward shifts in cocaine dose-effect functions produced by pretreatment compounds in the present study. Regardless of the explanation, it is clear from this series of experiments that increased responding maintained by both low cocaine doses and low food concentrations and overall leftward shifts in cocaine dose-effect functions are indicative of overlapping behavioral effects with cocaine. Moreover, pretreatment drugs that shifted cocaine dose-effect functions leftward also produced effects during the first component of test sessions independently of self-administered cocaine. Accordingly, overlap with the behavioral effects of cocaine were most evident for the indirect agonists d-amphetamine and GBR 12909, less so for the D2-like agonists 7-OH-DPAT and quinelorane and least for the D1-like agonists SKF 82958 and R6-Br-APB. 4.4.3. Implications for dopaminergic drugs as pharmacotherapies Regarding the different profiles of dopaminergic drugs observed in the present study, it is unclear as to which type of effect (i.e., leftward or downward shift) is most predictive of clinical efficacy. However, it is likely that different profiles of effects will prove efficacious for

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different subsets of the treatment population. Insofar as dopamine indirect agonists exhibited the greatest degree of overlap with cocaine in the present and previous studies, these compounds may offer the highest efficacy as ‘‘replacement’’ pharmacotherapies for cocaine abuse and dependence. However, these compounds were relatively nonselective for altering cocaine versus food maintained behavior, and this may be predictive of undesirable side-effects. Recent studies in nonhuman primates suggest that undesirable effects of indirect dopamine agonists may diminish with chronic treatment, whereas therapeutic effects may be preserved (Negus and Mello, 2003). An additional and perhaps unprecedented advantage of dopamine indirect agonists is that promising clinical data with these compounds have already emerged (Fleming and Roberts, 1994; Charnaud and Griffiths, 1998; White, 2000; Grabowski et al., 2001; Shearer et al., 2001). In the present study, one D2-like agonist and both D1like agonists were moderately selective in decreasing cocaine- versus food-maintained responding. Although the magnitude of behavioral selectivity was relatively small (<5-fold more potent for altering cocaine versus food maintained responding), these results imply that agonist activity at D2-like and/or D1-like receptors, or targeting their downstream neurobiological mechanisms, may have potential for the development of pharmacotherapies. Additionally, D1-like agonists conferred effects that only partially overlapped with those of cocaine, and to the extent that such findings are predictive of decreased abuse liability, these compounds may provide another useful strategy in the development of candidate medications. In contrast to the indirect and direct dopamine agonists, antagonists of D2-like and/or D1-like receptors may offer less potential as candidate pharmacotherapies. In this regard, both antagonists increased total cocaine intake and potently reduced food maintained responding. Importantly, this profile of effects bears significant similarity to profiles observed in clinical studies (Evans et al., 2001; Grabowski et al., 2000; Haney et al., 2001), and does not appear favorable for pharmacotherapy for cocaine abuse and dependence. 4.4.4. Implications for evaluating novel compounds using these procedures Results of the present study suggest that the procedures used here impart several advantages for screening novel compounds for their ability to modify cocaine’s abuse related effects and their potential for pharmacotherapy development. First, determination of leftward, downward or rightward shifts in complete doseeffect curves for cocaine self-administration provides a basis for meaningful interpretations regarding pharmacological interactions between novel compounds and cocaine. Second, our novel procedure for evaluating

food maintained responding confers several advantages. This procedure allows comparison of effects on cocaine self-administration and food maintained responding under identical schedule and temporal parameters after pretreatment drug administration. Comparison of treatment effects on responding maintained by various doses of cocaine to responding maintained by various concentrations of food may also be important because behavior maintained by low magnitude reinforcers may be more easily affected than behavior maintained by high magnitude reinforcers. In addition, responding maintained by both low and high concentrations of food was sensitive to both increases and decreases in response rates. Notably, results with the indirect dopamine agonists in the present study suggest that rate-altering effects of drugs remain a potential confound, particularly in the case of leftward shifts in cocaine dose-effect functions. Although the present procedure is useful for determining whether rate-altering effects are selective for cocaine maintained responding, clearly other procedures aimed at evaluating the modification of cocaine’s abuse related effects independent of rate-altering effects are warranted (e.g., Griffiths et al., 1976; Woolverton and Balster, 1981; Negus, 2003). Third, although dopaminergic compounds exhibited limited selectivity in modifying cocaine self-administration relative to food maintained responding, we propose that as a preclinical screening tool, the present procedures would successfully identify a novel treatment that is highly effective in modifying cocaine’s reinforcing effects with profound selectivity, should such a compound ever exist. Of course, such a result would be only a first step, and would help to justify efforts in evaluating the effects of chronic treatments, effects in nonhuman primates and ultimately, effects in clinical trials. 4.4.5. Other ongoing studies in our research program Comprehensive evaluation of drugs for their effects on cocaine self-administration and food maintained responding in rats offers one avenue toward a better understanding of pharmacological interactions between novel compounds and self-administered cocaine, and the potential implications for the development of safe and effective pharmacotherapies for cocaine abuse and dependence. In addition, other procedures are currently being developed in our laboratory including a choice procedure in rats based on similar procedures that have been developed using nonhuman primates (Negus, 2003). We are currently employing these various assays of cocaine self-administration in rats to study novel dopaminergic compounds (including selective dopamine D3 receptor ligands and novel dopamine transporter ligands), as well as compounds that influence neurotransmitter systems that interact with dopaminergic systems, including glutamate (mGluR5), glycine

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(GlyT1), GABA (GABA-A and GABA-B), serotonin (5-HT transporter), muscarinic cholinergic (M5) and cannabinoid (CB1) systems. Incorporating genetic technologies also is an important goal of our research program. Ongoing projects include comprehensive evaluation of cocaine selfadministration and food maintained responding in ‘‘knockout’’ mice with targeted genetic mutations in genes encoding receptors and transporters mentioned above. Importantly, some features of pharmacological studies in rats are in agreement with our genetic studies in mice. For example, just as pharmacological blockade of dopamine receptors increased self-administration of high cocaine doses and total cocaine intake in rats the present study, knockout of the dopamine D2 receptor produced similar effects in mutant mice (Caine et al., 2002a). In addition, just as pharmacological blockade of dopamine receptors decreased self-administration of low cocaine doses in rats in the present study, knockout of the dopamine D1 receptor produced similar effects in mutant mice (Caine et al., 2002b; in preparation). Comparisons of drug treatments in rats to genetic modifications in mutant mice are important first steps for understanding the relative advantages and disadvantages of these two general approaches (Caine and Ralph-Williams, 2002). Such comparisons may be especially important when highly selective pharmacological tools are lacking or remain controversial, as in the case of the dopamine D3 receptor (Koob and Caine, 1999). Ultimately, we hope to use genetic technologies to identify genes that were previously unexplored for their potential roles in cocaine’s abuse related effects. We are currently studying inbred strains of mice that exhibit profound differences in their unconditioned responses to cocaine, and we are assessing the extent to which differences in cocaine induced hyperactivity predict differences in the reinforcing effects of cocaine. These results may have implications for our collaborative studies in screening large numbers of mice with random genetic mutations using a ‘‘forward genetics’’ approach, thus employing a relatively unbiased strategy for identifying genes involved in cocaine abuse and dependence. Collectively, our aim is to provide rigorous behavioral pharmacology assays for preclinical evaluation of candidate medications and also for genetic studies in rodents that may point to novel biological targets for the development of pharmacotherapies for cocaine abuse and dependence.

Acknowledgements This work was supported in part by United States Public Health Service Grants DA-12142, DA-07252, DA-11949 and DA-14528 from the National Institute

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on Drug Abuse, National Institutes of Health. Support from the Zaffaroni Foundation is also gratefully acknowledged. The authors thank Nancy K. Mello, Ph.D. at the Alcohol and Drug Abuse Research Center, and David McCann, Ph.D., Jane B. Acri, Ph.D. and Carol Hubner, Ph.D. of the Cocaine Treatment Discovery Program, Division of Treatment Research and Development, NIDA for valuable discussions that influenced the experimental design of these studies. The authors are grateful to S. Stevens Negus, Ph.D. for assistance with experimental design and for comments on an early version of this manuscript. The authors thank Cynde Harmon, Justin Hamilton and Patricia Pimentel for outstanding technical assistance. References Barrett, R.L., Appel, J.B., 1989. Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine. Psychopharmacology (Berl) 99, 13–16. Bergman, J., Madras, B.K., Johnson, S.E., Spealman, R.D., 1989. Effects of cocaine and related drugs in nonhuman primates. III. Self-administration by squirrel monkeys. J. Pharmacol. Exp. Ther. 251, 150–155. Bergman, J., Kamien, J.B., Spealman, R.D., 1990. Antagonism of cocaine self-administration by selective dopamine D(1) and D(2) antagonists. Behav. Pharmacol. 1, 355–363. Bergman, J., Rosenzweig-Lipson, S., Spealman, R.D., 1995. Differential effects of dopamine D1 and D2 receptor agonists on schedulecontrolled behavior of squirrel monkeys. J. Pharmacol. Exp. Ther. 273, 40–48. Birmingham, A.M., Nader, S.H., Grant, K.A., Davies, H.M., Nader, M.A., 1998. Further evaluation of the reinforcing effects of the novel cocaine analog 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) in rhesus monkeys. Psychopharmacology (Berl) 136, 139– 147. Britton, D.R., Curzon, P., Mackenzie, R.G., Kebabian, J.W., Williams, J.E., Kerkman, D., 1991. Evidence for involvement of both D1 and D2 receptors in maintaining cocaine self-administration. Pharmacol. Biochem. Behav. 39, 911–915. Caine, S.B., Koob, G.F., 1993. Modulation of cocaine self-administration in the rat through D-3 dopamine receptors. Science 260, 1814–1816. Caine, S.B., Koob, G.F., 1994. Effects of dopamine D-1 and D-2 antagonists on cocaine self-administration under different schedules of reinforcement in the rat. J. Pharmacol. Exp. Ther. 270, 209–218. Caine, S.B., Koob, G.F., 1995. Pretreatment with the dopamine agonist 7-OH-DPAT shifts the cocaine self-administration dose-effect function to the left under different schedules in the rat. Behav. Pharmacol. 6, 333–347. Caine, S.B., Ralph-Williams, R.J., 2002. Behavioral pharmacologists, don’t just say ‘‘no’’ to knockout mice. Commentary on Stephens et al. ‘Studying the neurobiology of stimulant and alcohol abuse and dependence in genetically manipulated mice’. Behav. Pharmacol. 13, 349–352. Caine, S.B., Lintz, R., Koob, G.F., 1993. Intravenous drug selfadministration techniques in animals. In: Sahgal, A., (Ed.), Behavioral Neuroscience: a practical approach. IRL Press at Oxford University Press, Oxford, pp. 117–143. Caine, S.B., Negus, S.S., Mello, N.K., Bergman, J., 1999. Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine. J. Pharmacol. Exp. Ther. 291, 353–360.

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