Dopamine D1-Like Receptor-Mediated Insurmountable Blockade of the Reinforcing Effects of Cocaine in Rats

Takato Hiranita; Paul L Soto; Jonathan L Katz

doi:10.1124/jpet.124.002362

. 2024 Dec;391(3):415–429. doi: 10.1124/jpet.124.002362

Dopamine D₁-Like Receptor-Mediated Insurmountable Blockade of the Reinforcing Effects of Cocaine in Rats

Takato Hiranita ^1,^✉, Paul L Soto ¹, Jonathan L Katz ¹

PMCID: PMC11585313 PMID: 39443142

Abstract

Previous studies indicated differing effects of dopamine D₁-like and D₂-like receptor (D₁R and D₂R, respectively) agonists on cocaine self-administration. Leftward shifts by D₂R agonists in the cocaine self-administration dose-effect function contrast with decreases by D₁R agonists in maximal cocaine self-administration without rightward or leftward displacement. Whether the effects of the D₁R agonists are due to actions at D₁Rs has not been determined, possibly due to the difficulty in separating the blockade by a D₁R antagonist of the effects of the D₁R agonists and those of cocaine. In the present study, pretreatment with the D₁R agonists R(+)-SKF-81297 (0.1–1.0 mg/kg) and (±)-SKF-82958 (0.032–0.32 mg/kg) dose-dependently decreased maximal cocaine self-administration at doses below those affecting food-reinforced responding. In contrast, pretreatment with the D₂R agonists R(−)-NPA (0.001–0.01 mg/kg) and (−)-quinpirole (0.01–0.1 mg/kg) dose-dependently left-shifted the cocaine self-administration dose-effect function. The decreases by D₁R agonists in maximal cocaine self-administration were dose-dependently antagonized by the D₁R antagonist SCH-39166 at doses that alone had no effects on cocaine self-administration. Doses of SCH-39166 that blocked the effects of the D₁R agonists on cocaine self-administration were like those that shifted self-administration of D₁R agonists to the right but had no effects on self-administration of D₂R agonists. Self-administration of the D₂R agonists was dose-dependently shifted to the right by the preferential D₂R antagonist L-741,626 but not by SCH-39166. These results demonstrate that the decreases by the D₁R agonists in cocaine self-administration are selectively D₁R-mediated and support findings suggesting fundamentally distinct roles of the D₁Rs and D₂Rs in cocaine reinforcement.

SIGNIFICANCE STATEMENT

Dopamine D₁-like (D₁R) agonists decrease maximal cocaine self-administration, whereas D₂-like (D₂R) agonists shift the cocaine self-administration dose-effect function leftward, with mechanisms for those different effects unclear. The present study demonstrates blockade by the selective D₁R antagonist SCH-39166 of D1R-mediated decreases in maximal cocaine self-administration at doses that blocked other D₁R-mediated effects but not effects of cocaine, suggesting fundamentally distinct roles of the dopamine D₁-like and D₂-like receptors in cocaine reinforcement and development of D₁R agonists as potential treatments for cocaine use disorder.

Introduction

Cocaine reinforcement, thought to be a basis for its widespread abuse (https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2022/202205.htm; SAMHSA, 2021; CDC, 2021), results primarily from dopamine-uptake inhibition mediated by the dopamine transporter (Ritz et al., 1987), thereby increasing dopamine availability for direct actions at dopamine D₁-like receptors (D₁ and D₅) and D₂-like (D₂, D₃, and D₄) receptors (hereafter referred to as D₁R and D₂R, respectively). Further, studies in rats (Hemby et al., 1996; Caine et al., 2002; Barrett et al., 2004; Hiranita et al., 2013) and nonhuman primates (Woolverton, 1986; Woolverton and Virus, 1989; Bergman et al., 1990; Wojnicki and Glowa, 1996) indicate that selective D₁R and D₂R antagonists dose-dependently shift the cocaine self-administration dose-effect function rightward. These findings suggest similar roles of both D₁R and D₂R in cocaine reinforcement.

Pretreatments with direct D₁R or D₂R agonists, however, affect cocaine self-administration differently. Full D₂R agonists dose-dependently shifted the cocaine self-administration dose-effect function leftward in rats (Barrett et al., 2004). In contrast, full D₁R agonists dose-dependently decreased maximal rates of responding maintained by cocaine in rodents (Caine et al., 1999) and nonhuman primates (Platt et al., 2001). In humans, the D₁R agonist (−)-trans-9,10-acetoxy-2-propyl-4,5,5a,6,7,11-b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride (ABT-431) decreased several subjective effects accompanying cocaine administration, though it failed to appreciably alter the choice of smoked cocaine over a monetary voucher (Haney et al., 1999). Caine et al. (1999) argued that decreases in cocaine self-administration were a D₁R-mediated effect as food-maintained behavior was insensitive to D₁R agonist doses that decreased cocaine self-administration. However, Platt et al. (2001) found a similar potency of D₁R agonists for decreasing cocaine- and food-maintained responding.

Genetic studies have further suggested distinct roles of dopamine receptor subtypes in cocaine self-administration. For example, doses of cocaine that were sufficient for the acquisition of cocaine self-administration in drug-naïve wild-type mice were inactive in mice lacking the D₁ receptor gene (dopamine D₁ receptor knockout mice) (Caine et al., 2007; Thomsen et al., 2009a,b). Additionally, cocaine did not maintain self-administration when substituted for food in D₁ receptor knockout mice that had previously acquired food-reinforced responding, indicating that the D₁ receptor deletion altered cocaine self-administration rather than generally affecting behavioral acquisition (Caine et al., 2007). In contrast, dopamine D₂ receptor deletion did not alter cocaine self-administration at low doses but increased self-administration at higher doses (Caine et al., 2002).

The effects of genetic modification of other dopamine receptor subtypes on cocaine self-administration have been at best subtle. Dopamine D₃ receptor knockout mice acquired cocaine self-administration less rapidly than their wild-type controls, but not significantly so, at an intermediate but not a higher dose of cocaine (Caine et al., 2012). Further, cocaine self-administration, once acquired, did not differ among the D₃ genotypes (Caine et al., 2012). Acquisition of cocaine-reinforced responding did not differ between wild-type and dopamine D₄ receptor knockout mice (Thanos et al., 2010). Thus, genetic studies of dopamine receptors produce varied changes in the cocaine self-administration, with the most compelling impact coming from D₁ receptor deletion.

A decrease in maximal cocaine self-administration (insurmountable blockade) produced by D₁R agonists, if translatable to clinical outcome, suggests a therapeutic advantage compared with a blockade possibly surmounted by increasing cocaine intake. Thus, D₁R agonists might have the potential to treat stimulant use disorder in addition to other targets (e.g., schizophrenia, Martel and Gatti McArthur, 2020; Parkinsonism, Bezard et al., 2024). In the present study, decreases by D₁R agonists in maximal cocaine self-administration (Caine et al., 1999; Barrett et al., 2004) were replicated with a present focus on the full agonists as partial agonists have been reported to decrease cocaine self-administration by shifting its dose-effect function rightward (Katz and Witkin, 1992; Caine et al., 1999), suggesting antagonist actions. A primary objective of the present study was to assess the blockade by the D₁R antagonist (6aS-trans)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H-benzo[d]naphth[2,1-b]azepin-12-ol hydrobromide (SCH-39166) of the effects of D₁R agonists on cocaine self-administration to determine if the decreases in maximal cocaine self-administration were mediated through D₁Rs. A second objective was to characterize the blockade of self-administration of D₁R and D₂R agonists by SCH-39166 and the selective D₂R antagonist (±)-3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (L-741,626), with the selectivity of those effects determined by comparison with effects of the antagonists on behavior maintained by other reinforcers. In previous studies, the D₁R antagonists SCH-23390 (Self et al., 1996) or SCH-39166 (Weed et al., 1993) either increased or decreased self-administration of the D₁R agonists (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide ((±)-SKF-82958) or R(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (R(+)-SKF-81297), respectively. These differences could be due to the antagonist studied, the agonist self-administered, or its dose. The potencies of SCH-39166 in blocking self-administration of cocaine or D₁R agonists or a decrease by D₁R agonists in cocaine self-administration were compared.

Materials and Methods

Subjects.

Twenty-four male Sprague-Dawley rats (weighing approximately 300 g at the start of the study), obtained from Taconic Farms (Germantown, New York), served as subjects after at least one week of acclimation to the vivarium. Tap water and food (Rat Food Diet 8604, Harlan Teklad, Indianapolis, IN) were available in their home cages. After acclimation, weights of rats were maintained at approximately 320 g by adjusting their daily food ration. The animal housing room was humidity and temperature controlled and maintained on a 12:12-hour dark:light cycle, with lights on at 07:00 hours. The care of the animals was in accordance with the guidelines of the National Institutes of Health and the National Institute on Drug Abuse Intramural Research Program Animal Care and Use Program, which is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International.

Compounds.

The compounds used in the present study and their salt and enantiomeric forms were as follows: (−)-cocaine hydrochloride (cocaine, Sigma-Aldrich, St. Louis, MO), (R(+)-SKF-81297 Sigma-Aldrich), (±)-SKF-82958 (Sigma-Aldrich), R(−)-10,11-dihydroxy-N-n-propylnoraporphine hydrochloride [R(−)-NPA; Sigma-Aldrich], (−)-quinpirole (Tocris, Ballwin, MO), remifentanil hydrochloride (Ultiva, Hospira Inc., Lake Forest, IL), SCH-39166 (Tocris), and L-741,626 (Sigma-Aldrich). All drug solutions were prepared fresh daily in 0.9% saline (Hospira Inc.), except for L-741,626 [initially dissolved in ethanol (Sigma-Aldrich) and diluted to <25% polyethylene glycol (v/v, Sigma-Aldrich) and <6% ethanol (v/v) in sterile water (Hospira Inc.)]. Self-administered compounds were delivered intravenously, whereas those delivered as pretreatments were injected into the peritoneal cavity. All compound pretreatments were administered 5 minutes before the start of experimental sessions except for SCH-39166, which was administered 15 minutes before sessions. All doses of compounds used in the present study were expressed as their salt forms. Pretreatment doses and times of compounds used in the present study were chosen based on published (Caine et al., 1999, 2002; Barrett et al., 2004; Hiranita et al., 2013, 2017) or preliminary data obtained in this laboratory.

Apparatus.

Experimental sessions were conducted daily as described previously (Hiranita et al., 2017). Operant-conditioning chambers (modified ENV-203, Med Associates, St. Albans, VT) were enclosed within sound-attenuating cubicles equipped with a fan for ventilation and white noise to mask extraneous sounds. A downward displacement of a lever always produced an audible “feedback” click. Three light-emitting diodes (LEDs) were positioned in a row 4.5 cm above each lever. A receptacle for the delivery of 20-mg food pellets (Bio-Serv) via a pellet dispenser (Model ENV-203-20, Med Associates) was mounted behind a 5.0 × 5.0-cm opening in the front wall midline between the two levers and 2.0 cm above the floor. A syringe driver (Model 22, Harvard Apparatus, Holliston, MA) placed above a sound-attenuating cubicle delivered injections of specified volumes from a 10-mL syringe. The syringe was connected by Tygon tubing to a single-channel fluid swivel (375 Series Single Channel Swivels, Plymouth Meeting, PA). Tygon tubing from the swivel to the subject’s catheter was protected by a surrounding metal spring and completed the connection to the subject.

Response Acquisition and Intravenous Catheter Implantation.

Subjects were placed in chambers during experimental sessions that were conducted daily, 7 days per week, as described previously (Hiranita et al., 2017). During sessions, subjects were trained with food reinforcement to press the right lever under a fixed-ratio (FR)-1 schedule of reinforcement (each response produced a food pellet) and subsequently an FR-5 schedule of reinforcement (each fifth response produced a food pellet). Food delivery was followed by a 20-second time-out (TO) period during which all lights were off, and responses had no scheduled consequences other than the feedback click. During this training, sessions lasted for 20 minutes or until 30 food pellets were delivered.

After three consecutive sessions in which 30 food pellets were delivered, subjects were divided into two groups. One group (six rats) continued with food reinforcement, whereas subjects in the other group (18) were surgically implanted in the right or left external jugular vein with a chronic indwelling catheter that exited dorsally at the midscapular region under anesthesia (60.0 mg/kg ketamine, i.p., and 12.0 mg/kg xylazine, i.p.) as described previously (Hiranita et al., 2017). Catheters were maintained as described previously (Hiranita et al., 2017). All animals were allowed to recover from surgery for approximately 7 days before cocaine self-administration studies were initiated.

Self-Administration Procedures.

Experimental sessions started with the illumination of the LEDs above each lever and initially lasted for 120 minutes as described previously (Hiranita et al., 2017). Each response on the right lever turned off the LEDs, produced an audible click, and activated the infusion pump for 10 seconds (FR-1 schedule of reinforcement) followed by a 20-second TO period during which LEDs were off and responding had no scheduled consequences except the audible click. The concentration of cocaine in the syringe was adjusted for each subject based on its weight so that each infusion delivered 1.0 mg/kg cocaine. After the TO, the LEDs were illuminated and responding again produced an infusion. Responses on the left lever were recorded but had no scheduled consequences. The training lasted until responding was consistent from one session to the next as evidenced by the absence of visually apparent changes in rates of responding.

The self-administration procedure was then modified to facilitate pharmacological assessments as described previously (Hiranita et al., 2017). The session was divided into five 20-minute components, each preceded by a 2-minute TO period. This arrangement allowed the assessment of a range of self-administered doses in a single session (Hiranita et al., 2009). By adjusting infusion volumes and durations, the drug dose per injection was incremented in the sequential components as follows: no injection [also referred to as extinction (EXT) because responses had no scheduled consequences] or 0.03, 0.10, 0.32, or 1.00 mg/kg per injection for cocaine. Infusions were accompanied by LED stimulus illumination and were 0 seconds, with no LED stimulus (for 0 μL), 0.32 seconds (5.6 μL), 1.0 seconds (18.0 μL), 3.2 seconds (56.0 μL), and 10.0 seconds (180 μL) based on a body weight of 0.32 kg. A “sample” response-independent injection of cocaine at the corresponding unit dose and the illumination of stimulus LEDs occurred independently of responding at the beginning of each component except the first component, during which there were neither injections of cocaine nor illumination of stimulus LEDs. An injection of saline (1.0 mL/kg, i.p.) was given approximately 5 minutes prior to daily sessions as a control for drug pretreatment injections. Training continued until stable responding (less than 20% variation in response rates) was maintained across three consecutive sessions in individual subjects.

Once performances were stable, various compounds were substituted for cocaine to assess their reinforcing effects as described previously (Hiranita et al., 2017). The compounds substituted in half-log unit dose [in milligrams per kilogram per injection intravenously] increments were: R(+)-SKF-81297 (0.00032–0.01), (±)-SKF-82958 (0.00032–0.01), R(−)-NPA (0.0001–0.0032), (−)-quinpirole (0.0032–0.1), remifentanil (0.0001–0.0032), SCH-39166 (0.001–0.032), L-741,626 (0.01–0.32), and saline. Due to high rates of remifentanil self-administration, its infusion durations were reduced to 0, 0.24, 0.75, 2.40, and 7.50 seconds to avoid excessive fluid intake and emptying of the syringe.

Effects of pretreatment with dopamine receptor agonists and antagonists were subsequently assessed on self-administration of cocaine as described previously (Hiranita et al., 2017). Because, as expected, pretreatment with the D₁R agonists produced an insurmountable blockade of cocaine self-administration, antagonism of that blockade was assessed with coadministration of SCH-39166. Subsequently, substitution for cocaine of selective dopamine receptor agonists and remifentanil were conducted to assess whether self-administration of these agonists was sensitive to antagonist (SCH-39166 and L-741,626) pretreatments.

The schedule of food reinforcement was also modified to be comparable to that for cocaine self-administration. Five sequential 20-minute components, each preceded by a 2-minute TO, were scheduled within a single session. The first of the five components was EXT (no food available), with an FR-5 response schedule of food delivery in effect in the subsequent four components. The number of pellets delivered was increased in each component, from zero (EXT) to four pellets. Subjects were given their daily (∼35 g) ration of food (Rat Food Diet 8604, Harlan Teklad) 150 minutes before sessions so that their response rates approximated those maintained by cocaine.

Once performances were stable across successive sessions, the selectivity of the drug interactions with cocaine self-administration was assessed by conducting similar pretreatment studies on responding maintained by food presentation. Each test session with cocaine self-administration or food reinforcement was separated by a minimum of 72 hours and conducted only if performances met the training criteria. All tests were conducted with a mixed order of drugs and doses.

Data Analysis.

Response rates on the active (i.e., right) lever were determined by dividing the number of responses on the active lever by appropriate elapsed times (excluding TOs, and 0.32-10 seconds for each drug injection or food presentation). Average values across six subjects (with S.E.M.) are presented. Responses on the inactive (i.e., left) lever during TO periods only occurred infrequently if at all, and these data are not presented. The statistical significance of measures of responding on the active lever was assessed by analyses of variance with post hoc Bonferroni t tests using SigmaPlot 13.0 (Systat Software, Inc., San Jose, CA). For all analyses, the criterion for statistical significance was set at P < 0.05. One- or two-way repeated-measures ANOVAs were used as appropriate to assess the effects of the various conditions. The maximal rates of responding maintained by self-administered compounds and food pellets (i.e., fourth component for both compounds and food pellets) were compared as a function of dose of pretreated compounds by use of ANOVAs and linear regression techniques (Snedecor and Cochran, 1967) with GraphPad Prism version 9 for Windows (GraphPad Software, La Jolla, CA). A minimum effective dose (MED) of each pretreatment was defined as the lowest dose that significantly decreased maximal rates of responding (in the fourth component) relative to saline pretreatment and used to compare the potency of pretreated compounds.

Results

Self-Administration of Cocaine and Substitution of Saline and the Various Compounds.

The dose-effect function for self-administration of cocaine was biphasic as reported previously (Pickens and Thompson, 1968; Woods and Schuster, 1968; Goldberg, 1973) with dose-related increases in mean rates of responding across components from 0.061 (S.E.M., 0.008) responses/s during the extinction component to the maximum of 0.278 (0.043) responses/s obtained at a unit dose of 0.32 mg/kg per injection (Fig. 1A, ●). The rates of responding maintained were significantly greater than those maintained by saline, which were uniformly low across components (Fig. 1, ○; Table 1). ANOVA indicated significant effects of treatment (cocaine vs. saline), cocaine dose, and their interactions on response rate (Table 1). Post hoc analyses indicated significant effects of the 0.10- and 0.32-mg/kg per injection unit doses of cocaine on response rate (Table 1, see Δ values).

TABLE 1.

Statistical analyses of dose-effect functions for cocaine or substitution with various compounds compared with saline availability as shown in Fig. 1

Comparisons were made in rates of responding on the active lever maintained during each corresponding component using a two-way repeated-measures ANOVA followed by post hoc Bonferroni t tests, with those results shown only if effects were statistically significant. The Δ values in responses per second were calculated as a subtraction of response rates maintained by drug injections from those maintained by saline injections during a corresponding component.

Treatment	Drug (vs. Saline)	Dose (Component)	Interaction	Significant Post Hoc Test Results (P < 0.05)
Cocaine vs. saline substitution (Fig. 1A, N = 18)	F_1,68 = 39.3; P < 0.05	F_4,68 = 33.5; P < 0.05	F_4,68 = 33.1; P < 0.05	0.10 mg/kg per injection (t = 7.60, Δ = 0.166), 0.32 mg/kg per injection (t = 10.9, Δ = 0.237)
Cocaine vs. saline substitution (Fig. 1A, N = 6)	F_1,20 = 13.0; P < 0.05	F_4,20 = 12.2; P < 0.05	F_4,20 = 11.6; P < 0.05	0.10 mg/kg per injection (t = 4.71, Δ = 0.184), 0.32 mg/kg per injection (t = 6.17, Δ = 0.241)
R(+)-SKF-81297 vs. saline substitution (Fig. 1A, N = 12)	F_1,44 = 20.5; P < 0.05	F_4,44 = 16.3; P < 0.05	F_4,44 = 16.5; P < 0.05	0.001 mg/kg per injection (t = 5.00, Δ = 0.123), 0.0032 mg/kg per injection (t = 8.05, Δ = 0.198)
(±)-SKF-82958 vs. saline substitution (Fig. 1A, N = 12)	F_1,44 = 34.8; P < 0.05	F_4,44 = 28.3; P < 0.05	F_4,44 = 27.9; P < 0.05	0.001 mg/kg per injection (t = 7.06, Δ = 0.157), 0.0032 mg/kg per injection (t = 10.1, Δ = 0.224)
R(−)-NPA vs. saline substitution (Fig. 1A, N = 6)	F_1,20 = 40.6; P < 0.05	F_4,20 = 33.4; P < 0.05	F_4,20 = 33.0; P < 0.05	0.00032 mg/kg per injection (t = 7.26, Δ = 0.129), 0.001 mg/kg per injection (t = 11.2, Δ = 0.199)
(−)-Quinpirole vs. saline substitution (Fig. 1A, N = 12)	F_1,44 = 25.1; P < 0.05	F_4,44 = 17.8; P < 0.05	F_4,44 = 17.4; P < 0.05	0.010 mg/kg per injection (t = 4.83, Δ = 0.174), 0.032 mg/kg per injection (t = 8.19, Δ = 0.295), 0.10 mg/kg per injection (t = 4.08, Δ = 0.147)
Remifentanil vs. saline substitution (Fig. 1A, N = 12)	F_1,44 = 16.3; p P < 0.05	F_4,44 = 12.4; P < 0.05	F_4,44 = 12.2; P < 0.05	0.00032 mg/kg per injection (t = 5.41, Δ = 0.425), 0.001 mg/kg per injection (t = 6.08, Δ = 0.478), 0.0032 mg/kg per injection (t = 2.19, Δ = 0.172)
SCH-39166 vs. saline substitution (Fig. 1A, N = 6)	F_1,20 = 8.60; P < 0.05	F_4,20 = 0.760; P = 0.564	F_4,20 = 0.695; P = 0.604	Extinction (t = 3.15, Δ = 0.0285), 0.001 mg/kg per injection (t = 2.57, Δ = 0.0233), 0.0032 mg/kg per injection (t = 3.03, Δ = 0.0274), 0.032 mg/kg per injection (t = 2.51, Δ = 0.0227)
L-741,626 vs. saline substitution (Fig. 1A, N= 6)	F_1,20 = 8.83; P < 0.05	F_4,20 = 11.0; P < 0.05	F_4,20 = 5.42; P < 0.05	0.1 mg/kg per injection (t = 3.23, Δ = 0.0318), 0.32 mg/kg per injection (t = 4.02, Δ = 0.0396)

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Fig. 1. — Substitution of various compounds in rats trained to self-administer cocaine (0.032–1.0 mg/kg per injection, i.v.) under an FR-5 response schedule of reinforcement. Ordinates: responses per second. Abscissae: compound unit dose (mg/kg per injection, i.v.), log scale, or sequential component of the session (saline substitution for cocaine). Each point represents the mean ± 1 S.E.M. of responding on the right (active) lever in 6–18 rats. The dose-effect function of cocaine (0.032–1.0 mg/kg per injection, filled circles) was shown as an average of 22–37 assessments (N = 18). (A) Substitutions of saline vehicle, the direct dopamine [R(+)-SKF-81297, (±)-SKF-82958, R(−)-NPA, and (−)-quinpirole], and the μ-opioid (remifentanil) agonists for cocaine. Substitutions include saline injections (1–5 components; N = 18), R(+)-SKF-81297 (0.00032–0.01 mg/kg per injection; N = 12), (±)-SKF-82958 (0.00032–0.01 mg/kg per injection; N = 12), R(−)-NPA (0.0001–0.0032 mg/kg per injection; N = 6), (−)-quinpirole (0.0032–0.1 mg/kg per injection; N = 12), and remifentanil (0.0001–0.0032 mg/kg per injection; N = 12). (B) Substitutions of saline vehicle and dopamine receptor antagonists (SCH-39166 and L-741,626) for cocaine (N = 6). Substitutions include saline injections (1–5 components), SCH-39166 (0.001–0.032 mg/kg per injection), and L-741,626 (0.01–0.32 mg/kg per injection). The effects of substitution for cocaine were determined only once. The statistical analyses of dose-effect functions for cocaine or substitution with test compounds compared with saline availability are shown in Table 1.

Figure 2A shows characteristic performance of a representative subject under the FR schedule of cocaine injection with progressive increases in unit dose/injection. In the first component, responses had no scheduled consequences (EXT) and response rates were relatively low. In the second component, cocaine (0.032 mg/kg per injection) was delivered following completion of each FR-5, with response rates comparable to those obtained during EXT. During the next two components, active unit doses of cocaine (0.1 and 0.32 mg/kg per injection) followed completion of the FR-5 with high rates of responding maintained and characterized by a brief pause and an abrupt transition to five sequential responses emitted at a high constant rate. At the highest unit dose of cocaine (1.0 mg/kg per injection) delivered after completion of each FR-5 in the fifth component, overall response rates were lower, primarily due to a greater duration of pausing after each injection.

Fig. 2. — Representative cumulative records of performances maintained by intravenous cocaine under the FR-5 response schedule and those obtained when different drugs were administered before sessions. Ordinates, cumulative responses. Abscissae, time. Each experimental session started with a 2-minute TO period during which all lights were off, and responses had no schedule consequences (lower event line up). After the TO (lower event line down), lights above the levers were illuminated, although responses had no scheduled consequences (extinction, EXT) for 20 minutes, followed by another 2-minute TO. When the lights were again illuminated, each fifth response turned off the LEDs and activated the infusion pump for 0.2 seconds (diagonal marks on the cumulative record). A 20-second TO period during which lights were off and responding had no scheduled consequences followed each injection, after which the LEDs were again illuminated, and responding had scheduled consequences. During each 20-minute period of drug availability, the injection volumes were adjusted to deliver unit doses, as indicated on the figure, in an ascending order. The cumulative curve resets to the baseline at the end of each 20-minute component. Note that the D₁R agonist [0.32 mg/kg (±)-SKF-82958] attenuated responding maintained by cocaine (compare A with B) and that 0.032 mg/kg SCH-39166 restored rates and patterns of responding to those obtained without treatment (compare panels A with C). Finally, the D₂R agonist (−)-quinpirole (0.1 mg/kg) decreased response rates maintained by the maximally effective unit dose of cocaine but increased response rates at lower unit doses of cocaine (compare panels A with D).

As with cocaine, the dose-effect functions for self-administration of the dopamine receptor direct agonists [R(+)-SKF-81297, ▵; (±)-SKF-82958, ▽; R(−)-NPA, ◊; and (−)-quinpirole, □] when substituted for cocaine were also biphasic, with dose-related increases in mean response rates across low-to-intermediate unit doses and decreases from the maximum at the highest unit doses studied (Fig. 1A). Patterns of responding (not shown) resembled those obtained with cocaine self-administration. For each dopamine receptor direct agonist, unit dose self-administered (intravenous), treatment (drug vs. saline), and their interactions were significant (Table 1), with maximal rates of responding maintained comparable to those maintained by cocaine (Fig. 1A) and greater than the rates maintained by saline injections (Fig. 1, ○). The μ-opioid receptor agonist remifentanil (Fig. 1A, ⊗) also maintained 7high rates of self-administration with an inverted U-shaped dose-effect function (Panlilio and Schindler, 2000; Collins and Woods, 2007). Unit dose of remifentanil self-administered, treatment (remifentanil vs. saline), and their interactions were significant (Table 1).

In contrast to the agonists, neither dopamine receptor antagonist [SCH-39166 (Fig. 1B, ▵) or L-741,626 (Fig. 1B, ∇)] maintained rates of responding substantially greater than those obtained with saline injections (Fig. 1, ○). However, response rates obtained with substitution of the antagonists for cocaine were on occasion statistically significantly greater than those obtained with saline (Table 1), but the differences from saline in maximal response rates obtained were less than two-tenths of those obtained at the highest unit dose of cocaine (see Δ values in Table 1), and for SCH-39166, responding during the first component (extinction) was higher than during the same component when saline was the consequence, suggesting that the increases in responding were not due to reinforcing effects of SCH-39166. Finally, neither of the dose-effect functions obtained with the dopamine receptor antagonists had the inverted-U shape that is typical of self-administered drugs (Fig. 1B).

Effects of the Direct Dopamine Receptor Agonists on Self-Administration of Cocaine.

Presession treatments with the selective D₁R agonists R(+)-SKF-81297 and (±)-SKF-82958 dose-dependently decreased the maximal response rates maintained by cocaine (Fig. 3, A and C, respectively). For example, the effect of 0.32 mg/kg of (±)-SKF-82958 pretreatment on responding maintained by cocaine was to render performances previously maintained by progressive unit doses of cocaine to resemble those obtained during EXT or the lowest unit dose of cocaine (Fig. 2B). Similar effects were obtained with R(+)-SKF-81297 pretreatments. Statistical analyses indicated significant effects of pretreatment doses of R(+)-SKF-81297 and (±)-SKF-82958, cocaine unit dose, and their interaction (Table 2). Examining effects on responding maintained by cocaine at the 0.32-mg/kg per injection unit dose that maintained the maximum rates of responding (i.e., fourth component), (±)-SKF-82958 was approximately threefold more potent than R(+)-SKF-81297 in decreasing responding maintained by cocaine (MED values were 0.1 and 0.32 mg/kg, respectively; Table 3, column A).

TABLE 2.

Statistical analyses of the effects of dopamine receptor direct agonists on self-administration of cocaine in Fig. 3

Comparisons were made in rates of responding on the active lever maintained during each corresponding component in six subjects using a two-way repeated-measures ANOVA followed by post hoc Bonferroni t tests, with those results shown only if effects were statistically significant. The Δ values in responses per second were calculated as a subtraction of response rates maintained after saline pretreatment from those maintained after drug pretreatment during a corresponding component.

Treatment	Self-Administered Drug Unit Dose (Intravenous) (Component)	Pretreatment Dose (Intraperitoneal)	Interaction	Significant Post Hoc Test Results (P < 0.05)
R(+)-SKF-81297 (Fig. 3A)	F_4,60 = 40.3; P < 0.05	F_3,60 = 41.4; P < 0.05	F_12,60 = 21.3; P < 0.05	0.32 mg/kg (i.p.) at 0.1 mg/kg per injection (i.v.) (t = 7.12, Δ = −0.0974), 1.0 mg/kg (i.p.) at 0.1 mg/kg per injection (i.v.) (t = 7.61, Δ = −0.104), 0.1 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 4.47, Δ = −0.0612), 0.32 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 12.1, Δ = −0.166), 1.0 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 15.2, Δ = −0.208).
(±)-SKF-82958 (Fig. 3C)	F_4,60 = 10.5; P < 0.05	F_3,60 = 12.1; P < 0.05	F_12,60 = 10.4; P < 0.05	0.1 mg/kg (i.p.) at 0.1 mg/kg per injection (i.v.) (t = 4.06, Δ = −0.144), 0.32 mg/kg (i.p.) at 0.1 mg/kg per injection (i.v.) (t = 5.36, Δ = −0.150), 0.1 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 5.23, Δ = −0.147), 0.32 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 7.93, Δ = −0.222).
R(−)-NPA (Fig. 3E)	F_4,60 = 25.2; P < 0.05	F_3,60 = 19.6; P < 0.05	F_12,60 = 20.9; P < 0.05	0.01 mg/kg (i.p.) at extinction (t = 4.39, Δ = 0.110), 0.0032 mg/kg (i.p.) at 0.032 mg/kg per injection (i.v.) (t = 2.83, Δ = 0.0710), 0.01 mg/kg (i.p.) at 0.032 mg/kg per injection (i.v.) (t = 12.2, Δ = 0.306), 0.0032 mg/kg (i.p.) at 0.1 mg/kg per injection (i.v.) (t = 3.64, Δ = 0.0912), 0.0032 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 5.62, Δ= −0.141), 0.01 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 5.94, Δ= −0.149).
(−)-Quinpirole (Fig. 3G)	F_4,60 = 10.2; P < 0.05	F_3,60 = 5.80; P < 0.05	F_12,60 = 8.97; P < 0.05	0.1 mg/kg (i.p.) at extinction (t = 3.02, Δ = 0.151), 0.032 mg/kg (i.p.) at 0.032 mg/kg per injection (i.v.) (t = 4.22, Δ = 0.212), 0.1 mg/kg (i.p.) at 0.032 mg/kg per injection (i.v.) (t = 7.23, Δ = 0.363), 0.032 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 2.75, Δ = −0.0651), 0.1 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 4.14, Δ = −0.289).

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TABLE 3.

MED values (in milligrams per kilogram) for various test compounds pretreated in decreasing the maximal rates of responding maintained by injections (mg/kg per injection) of cocaine (0.32), R(+)-SKF-81297 (0.0032), (+)-SKF-82958 (0.0032), R(−)-NPA (0.001), (−)-quinpirole (0.032), or remifentanil (0.001) or food presentations (three 20-mg pellets) in Figs. 3–5

Response rates were calculated as percentage of control response rates (sessions before drug tests) for the maximal rates of responding maintained by respective drug injections or food presentations (i.e., fourth component).

	A	B	C	D	E	F
Compound	Cocaine self-administration	Food-maintained responding	R(+)-SKF-81297 or (±)-SKF-82958 Self-Administration	R(–)-NPA or (–)-quinpirole self-administration	Antagonize R(+)-SKF-81297 or (±)-SKF-82958 induced decrease in cocaine self-administration	Remifentanil self-administration
R(+)-SKF-81297	0.32	3.2	N.T.	N.T.	N.T.	N.T.
(±)-SKF-82958	0.1	0.32	N.T.	N.T.	N.T.	N.T.
R(−)-NPA	0.0032	>0.032	N.T.	N.T.	N.T.	N.T.
(−)-Quinpirole	0.032	0.1	N.T.	N.T.	N.T.	N.T.
SCH-39166	0.1	1.0	0.01	Inactive	0.01	Inactive
L-741,626	1.0	10.0	Inactive	0.32	N.T.	10.0

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N.T., not tested.

Fig. 3. — Effects of presession treatments with the direct dopamine receptor agonists [R(+)-SKF-81297, (±)-SKF-82958, R(−)-NPA, and (−)-quinpirole] on self-administration of cocaine (upper panels) and potency comparisons of the direct dopamine receptor agonists to decrease responding maintained by injections of cocaine (0.32 mg/kg per injection) from upper panels or food presentations (from each fourth component; lower panels). Upper ordinates: responses per second. Lower ordinates: response rates as percentage of control response rates (sessions prior to drug tests), which averaged 0.278 (S.E.M., 0.0427; N = 18) and 0.542 (S.E.M., 0.108; N = 6) responses/s, respectively, for the maximal rates of responses maintained by injections of cocaine or food presentations. One-way ANOVA indicated no significant difference in group (see the legend of Fig. 6). Upper abscissae: cocaine unit dose (mg/kg per injection, i.v.), log scale. Lower abscissae: dose of test compounds administered intraperitoneally in milligrams per kilogram, log scale. Each point represents the mean ± 1 S.E.M. of responding on the active lever under a within-subjects design [N = 6 except filled circles above vehicle for cocaine in lower panels (N = 18)]. All the direct agonists were administered intraperitoneally at 5 minutes before sessions. (A) effects of R(+)-SKF-81297 (0.1, 0.32, and 1.0 mg/kg) on self-administration of cocaine. (B) Effects of R(+)-SKF-81297 (0.1, 0.32, 1.0, and 3.2 mg/kg) on responding maintained by cocaine or food. (C) Effects of (±)-SKF-82958 (0.032, 0.1, and 0.32 mg/kg) on self-administration of cocaine. (D) Effects of (±)-SKF-82958 (0.032, 0.1, 0.32, and 1.0 mg/kg) on responding maintained by cocaine or food. (E) Effects of R(−)-NPA (0.001, 0.0032, and 0.01 mg/kg) on self-administration of cocaine. (F) Effects of R(−)-NPA (0.001, 0.0032, 0.01, and 0.032 mg/kg) on responding maintained by cocaine or food. (G) Effects of (−)-quinpirole (0.01, 0.032, and 0.1 mg/kg) on self-administration of cocaine. (H) Effects of (−)-quinpirole (0.01, 0.032, 0.1, and 0.178 mg/kg) on responding maintained by cocaine or food. Statistical analyses are shown in Tables 2 and 3.

Presession treatments with the selective D₂R full agonists R(−)-NPA and (−)-quinpirole produced dose-dependent shifts to the left in the dose-effect function for cocaine self-administration (Fig. 3, E and G, respectively). R(−)-NPA was approximately 10-fold more potent than (−)-quinpirole when examining effects on maximal rates of responding maintained by cocaine (at 0.32 mg/kg per injection, i.e., fourth component). Additionally, the highest doses of R(−)-NPA and (−)-quinpirole increased responding during the extinction component (Fig. 3, E and G, respectively; Table 2). These effects also include an increase in the maximum rates of responding maintained by unit doses lower than 0.32 mg/kg per injection cocaine.

The effect of 0.1 mg/kg quinpirole pretreatment on responding maintained by cocaine was to decrease rates of responding at the 0.32-mg/kg per injection unit dose of cocaine (i.e., fourth component) that previously maintained maximal response rates. However, rates of responding at lower unit doses of cocaine were increased such that patterns of response at these unit doses (0.032 and 0.1 mg/kg per injection) resembled those obtained with 0.32 mg/kg per injection of cocaine when studied alone (Fig. 2D).

The decreases in rates of responding maintained by cocaine or food produced by the direct dopamine receptor agonists at the unit dose of cocaine or amounts of food that maintained the highest rates of responding (i.e., fourth component) were compared to assess the selectivity of the effects. R(+)-SKF-81297, with an MED value of 0.32 mg/kg, was 10-fold more potent in decreasing the rates of responding maintained by cocaine than those maintained by food, with an MED value of 3.2 mg/kg (Fig. 3B; Table 3, compare columns A with B). Similarly, (±)-SKF-82958, with an MED value of 0.1 mg/kg, was threefold more potent in decreasing the rates of responding maintained by cocaine than those maintained by food, with an MED value of 0.32 mg/kg (Fig. 3D; Table 3, columns A with B). In contrast, the selective D₂R agonist R(−)-NPA decreased rates of responding maintained by the maximally effective unit dose of cocaine at R(−)-NPA doses that were without effects on responding maintained by food (Fig. 3F). Another selective D₂R full agonist, (−)-quinpirole, decreased rates of responding maintained by the maximally effective unit dose of cocaine and food at similar doses (Fig. 3H).

Effects of SCH-39166 on the D₁R Agonist–Induced Decreases in Cocaine Self-Administration.

The decreases in cocaine self-administration produced by the maximally effective doses of R(+)-SKF-81297 (Fig. 4A, ○) and (±)-SKF-82958 (Fig. 4B, ○) were dose-dependently reversed by coadministration of the selective D₁R antagonist SCH-39166, restoring the cocaine dose-effect functions with the highest doses of SCH-39166 (◇) to that obtained with cocaine alone (●). Statistical analyses indicated significant effects of SCH-39166 pretreatment dose, cocaine self-administration unit dose, and their interaction (Table 4). The MED value of SCH-39166 to reverse the effects of R(+)-SKF-81297 on self-administration of cocaine was 0.01 mg/kg and comparable to that to antagonize the effect of (±)-SKF-82958 on cocaine self-administration (Table 3, column E). Treatment with 0.032 mg/kg SCH-39166 prior to administration of 0.32 mg/kg of (±)-SKF-82958 restored performances to resemble those obtained with cocaine self-administration alone (Fig. 2C). Similar effects on patterns of responding were obtained with R(+)-SKF-81297 (data not shown).

TABLE 4.

Statistical analyses of the effects of SCH-39166 on the D₁R agonist–induced decreases in self-administration of cocaine as shown in Fig. 4

Comparisons were made in rates of responding on the active lever in six subjects using a two-way repeated-measures ANOVA followed by post hoc Bonferroni t tests, with those results shown only if effects were statistically significant. The Δ values in responses per second were calculated as a subtraction of response rates maintained by cocaine injections after pretreatment with SCH-39166 from those obtained after no pretreatment.

Treatment	Cocaine Dose (Component)	Pretreatment	Interaction	Significant Post Hoc Test Results (P < 0.05)
R(+)-SKF-81297 (1.0 mg/kg) + SCH-39166 (Fig. 4A)	F_4,80 = 23.6; P < 0.05	F_4,80 = 34.1; P < 0.05	F_16,80 = 23.1; P < 0.05	None (i.p.) at 0.1 mg/kg per injection (i.v.) (t = 7.71, Δ = −0.104), 0.0032 mg/kg (i.p.) at 0.1 mg/kg per injection (i.v.) (t = 6.91, Δ = −0.0933), 0.01 mg/kg (i.p.) at 0.1 mg/kg per injection (i.v.) (t = 4.10, Δ = −0.0554), None (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 15.4, Δ = −0.208), 0.0032 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 15.5, Δ = −0.209), 0.01 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 9.29, Δ = −0.126), 0.032 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 2.65, Δ = −0.0358)
(±)-SKF-82958 (0.32 mg/kg) + SCH-39166 (Fig. 4B)	F_4,80 = 11.5; P < 0.05	F_4,80 = 13.4; P < 0.05	F_16,80 = 13.3; P < 0.05	None (i.p.) at 0.1 mg/kg per injection (i.v.) (t = 6.41, Δ = −0.150), 0.0032 mg/kg (i.p.) at 0.1 mg/kg per injection (i.v.) (t = 5.83, Δ = −0.137), 0.01 mg/kg (i.p.) at 0.1 mg/kg per injection (i.v.) (t = 4.46, Δ = −0.104), None (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 9.48, Δ = −0.222), 0.0032 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 8.54, Δ = −0.200), 0.01 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 5.32, Δ = −0.125)

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Fig. 4. — Effects of presession treatments with SCH-39166 on the D₁R agonist–induced decreases in self-administration of cocaine. Ordinates: responses per second. Abscissae: cocaine injection unit dose in milligrams per kilogram (intravenous). Each point represents the mean ± 1 S.E.M. of response rates on the active lever in six subjects. R(+)-SKF-81297 (1.0 mg/kg, i.p.) and (±)-SKF-82958 (0.32 mg/kg, i.p.) were administered 5 minutes before sessions, whereas SCH-39166 (0.0032, 0.01, and 0.032 mg/kg, i.p.) was administered at 15 minutes before sessions. (A) Effects of SCH-39166 on R(+)-SKF-81297. (B) Effects of SCH-39166 on (±)-SKF-82958. The statistical analyses for the effects of SCH-39166 are shown in Table 4.

Effects of the Dopamine Receptor Antagonists on Self-Administration of Cocaine.

SCH-39166 dose-dependently shifted to the right the dose-effect function for self-administration of cocaine (Fig. 5A). The lowest dose of SCH-39166 (0.032 mg/kg) was without effects on rates of responding maintained by cocaine injections, whereas a higher dose (0.10 mg/kg) shifted the cocaine dose-effect function approximately threefold to the right. Further, the maximal rate of responding within the cocaine unit dose range tested was lower than that with vehicle pretreatments (Fig. 5A, compare ◇ with ●). At the highest dose of SCH-39166 (0.32 mg/kg), the cocaine dose-effect function was shifted approximately 10-fold to the right (Fig. 5A, compare □ with ●). Statistical analysis indicated significant effects of SCH-39166 pretreatment dose, cocaine self-administration unit dose, and their interaction (Table 5).

TABLE 5.

Statistical analyses of effects of the dopamine receptor antagonists on self-administration of cocaine, R(+)-SKF-81297, (±)-SKF-82958, R(−)-NPA, (−)-quinpirole, and remifentanil as shown in Fig. 5

Comparisons were made in rates of responses on the active lever in six subjects using a two-way repeated-measures ANOVA followed by post hoc Bonferroni t tests, with those results shown only if effects were statistically significant. The Δ values in responses per second were calculated as a subtraction of response rates maintained by drug injections after saline pretreatment from those obtained after pretreatment with SCH-39166 or L-741,626.

Treatment	Self-Administered Drug Unit Dose (Intravenous) (Component)	Pretreatment Dose (Intraperitoneal)	Interaction	Significant Post Hoc Test Results (P < 0.05)
	SCH-39166 pretreatments (intraperitoneal)
Cocaine (Fig. 5A)	F_4,60 = 54.1; P < 0.05	F_3,60 = 1.13; P = 0.368	F_12,60 = 9.30; P < 0.05	0.10 mg/kg (i.p.) at 0.10 mg/kg per injection (i.v.) (t = 3.36, Δ = 0.0830), 0.32 mg/kg (i.p.) at 0.10 mg/kg per injection (i.v.) (t = 3.74, Δ = −0.0983), 0.10 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 3.23, Δ = −0.124), 0.32 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 5.04, Δ = −0.196), 0.32 mg/kg (i.p.) at 1.0 mg/kg per injection (i.v.) (t = 2.52, Δ = 0.0809).
Remifentanil (Fig. 5C)	F_4,60 = 6.61; P < 0.05	F_3,60 = 8.99; P = 0.075	F_16,60 = 6.401; P < 0.05	0.032 mg/kg (i.p.) at 0.32 μg/kg per injection (i.v.) (t = 4.15, Δ = 0.0723), 0.032 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 3.32, Δ = 0.0578), 0.1 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 2.78, Δ = 0.0483)
R(+)-SKF-81297 (Fig. 5E)	F_4,60 = 22.3; P < 0.05	F_3,60 = 23.5; P < 0.05	F_12,60 = 22.6; P < 0.05	0.010 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 4.01, Δ= −0.0641), 0.032 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 3.89, Δ = −0.0622), 0.0032 mg/kg (i.p.) at 3.2 μg/kg per injection (i.v.) (t = 4.25, Δ = 0.678), 0.010 mg/kg (i.p.) at 3.2 μg/kg per injection (i.v.) (t = 4.35, Δ = −0.0695), 0.032 mg/kg (i.p.) at 3.2 μg/kg per injection (i.v.) (t = 9.35, Δ = −0.149), 0.010 mg/kg (i.p.) at 10 μg/kg per injection (i.v.) (t = 8.60, Δ = 0.137), 0.032 mg/kg (i.p.) at 10 μg/kg per injection (i.v.) (t = 4.52, Δ = 0.0722).
(±)-SKF-82958 (Fig. 5G)	F_4,60 = 29.2; P < 0.05	F_3,60 = 15.5; P < 0.05	F_12,60 = 23.8; P < 0.05	0.0032 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 2.64, Δ = −0.0459), 0.010 mg/kg (i.p.) 1.0 μg/kg per injection (i.v.) (t = 5.39, Δ = −0.0936), 0.032 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 4.65, Δ = −0.0808), 0.010 mg/kg (i.p.) at 3.2 μg/kg per injection (i.v.) (t = 6.35, Δ = −0.110), 0.032 mg/kg (i.p.) at 3.2 μg/kg per injection (i.v.) (t = 10.3, Δ = −0.179), 0.010 mg/kg (i.p.) at 10 μg/kg per injection (i.v.) (t = 7.61, Δ = 0.132), 0.032 mg/kg (i.p.) at 10 μg/kg per injection (i.v.) (t = 6.05, Δ = 0.105).
R(−)-NPA (Fig. 5J)	F_4,100 = 24.6; P < 0.05	F_5,100 = 9.78; P < 0.05	F_20,100 = 5.76; P < 0.05	0.01 mg/kg (i.p.) at 0.10 μg/kg per injection (i.v.) (t = 3.57, Δ = 0.00885), 0.032 mg/kg (i.p.) at 0.32 μg/kg per injection (i.v.) (t = 3.31, Δ = −0.0160), 0.1 mg/kg (i.p.) at 0.32 μg/kg per injection (i.v.) (t = 4.29, Δ = −0.0207), 0.32 mg/kg (i.p.) at 0.32 μg/kg per injection (i.v.) (t = 4.14, Δ = −0.0200), 0.0032 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 5.08, Δ = 0.0245), 0.01 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 4.53, Δ = 0.0219), 0.1 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 5.77, Δ = 0.0279), 0.01 mg/kg (i.p.) at 3.2 μg/kg per injection (i.v.) (t = 6.12, Δ = 0.0296)
(−)-Quinpirole (Fig. 5L)	F_4,100 = 21.4; P < 0.05	F_5,100 = 8.27; P < 0.05	F_20,100 = 6.40; P < 0.05	0.0032 mg/kg (i.p.) at 32 μg/kg per injection (i.v.) (t = 10.8, Δ = −0.0731), 0.010 mg/kg (i.p.) at 32 μg/kg per injection (i.v.) (t = 6.30, Δ = −0.0426), 0.032 mg/kg (i.p.) at 32 μg/kg per injection (i.v.) (t = 5.20, Δ = −0.0352), 0.10 mg/kg (i.p.) at 32 μg/kg per injection (i.v.) (t = 7.43, Δ = −0.0502),
				0.32 mg/kg (i.p.) at 32 μg/kg per injection (i.v.) (t = 6.89, Δ = −0.0466)
L-741,626 pretreatments (intraperitoneal)
Cocaine (Fig. 5B)	F_4,80 = 7.06; P < 0.05	F_4,80 = 10.0; P < 0.05	F_16,80 = 9.54; P < 0.05	1.0 mg/kg (i.p.) at 0.10 mg/kg per injection (i.v.) (t = 4.03, Δ = −0.125), 3.2 mg/kg (i.p.) at 0.10 mg/kg per injection (i.v.) (t = 3.86, Δ = −0.164), 10 mg/kg (i.p.) at 0.10 mg/kg per injection (i.v.) (t = 5.67, Δ = −0.206), 1.0 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 3.64, Δ = −0.198), 3.2 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 4.65, Δ = −0.226), 10 mg/kg (i.p.) at 0.32 mg/kg per injection (i.v.) (t = 6.60, Δ = −0.290), 1.0 mg/kg (i.p.) at 1.0 mg/kg per injection (i.v.) (t = 4.95, Δ = 0.161)
Remifentanil (Fig. 5D)	F_4,80 = 4.51; P < 0.05	F_4,80 = 7.02; P < 0.05	F_16,80 = 4.46; P < 0.05	10 mg/kg (i.p.) at 0.32 μg/kg per injection (i.v.) (t = 5.15, Δ = −0.491), 10 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 5.73, Δ = −0.540), 10 mg/kg (i.p.) at 3.2 μg/kg per injection (i.v.) (t = 2.90, Δ = −0.216)
R(+)-SKF-81297 (Fig. 5F)	F_4,80 = 6.04; P < 0.05	F_4,80 = 3.44; P < 0.05	F_16,80 = 3.62; P < 0.05	0.1 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 2.84, Δ = −0.0239), 1.0 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 4.12, Δ = 0.0166), 1.0 mg/kg (i.p.) at 3.2 μg/kg per injection (i.v.) (t = 3.65, Δ = −0.0193)
(±)-SKF-82958 (Fig. 5H)	F_4,80 = 11.5; P < 0.05	F_4,80 = 6.82; P = 0.001	F_16,80 = 3.33; P < 0.05	0.1 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 2.70, Δ = −0.0239), 0.1 mg/kg (i.p.) at 3.2 μg/kg per injection (i.v.) (t = 3.97, Δ = −0.0351), 3.2 mg/kg (i.p.) at 3.2 μg/kg per injection (i.v.) (t = 2.97, Δ = 0.0263)
R(−)-NPA (Fig. 5K)	F_4,60 = 29.4; P < 0.05	F_3,60 = 31.3; P < 0.05	F_12,60 = 21.9; P < 0.05	0.32 mg/kg (i.p.) at 0.32 μg/kg per injection (i.v.) (t = 4.59, Δ = −0.0442), 1.0 mg/kg (i.p.) at 0.32 μg/kg per injection (i.v.) (t = 4.07, Δ = −0.0153), 0.32 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 9.13, Δ = −0.191), 1.0 mg/kg (i.p.) at 1.0 μg/kg per injection (i.v.) (t = 11.4, Δ = −0.210), 0.32 mg/kg (i.p.) at 3.2 μg/kg per injection (i.v.) (t = 4.38, Δ = 0.0805), 1.0 mg/kg (i.p.) at 3.2 μg/kg per injection (i.v.) (t = 8.22, Δ = 0.165)
(−)-Quinpirole (Fig. 5M)	F_4,60 = 9.38; P < 0.05	F_3,60 = 7.10; P < 0.05	F_12,60 = 6.60; P < 0.05	0.32 mg/kg (i.p.) at 10 μg/kg per injection (i.v.) (t = 4.56, Δ = −0.186), 1.0 mg/kg (i.p.) at 10 μg/kg per injection (i.v.) (t = 4.34, Δ = −0.177), 0.32 mg/kg (i.p.) at 32 μg/kg per injection (i.v.) (t = 5.54, Δ = −0.226), 1.0 mg/kg (i.p.) at 32 μg/kg per injection (i.v.) (t = 6.97, Δ = −0.284)

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L-741,626 also dose-dependently shifted the cocaine self-administration dose-effect function to the right (Fig. 5B). The lowest dose of L-741,626 (0.32 mg/kg) was without effects on rates of responding maintained by injections of cocaine. However, doses of 1.0 and 3.2 mg/kg shifted the cocaine dose-effect function at least 10-fold to the right. Further, the maximal rates of responding at the 3.2 mg/kg dose of L-741,626 were less than those obtained with vehicle pretreatment over the range of cocaine unit doses examined (Fig. 5B, compare ◇ with ●). At the highest dose of L-741,626 (10 mg/kg), responding was virtually eliminated across the entire range of tested unit doses of cocaine (Fig. 5B, compare □ with ●). Statistical analyses indicated significant effects of L-741,626 pretreatment dose, cocaine self-administration unit dose, and their interaction (Table 5).

Selectivity of effects of the dopamine receptor antagonists on self-administration of cocaine was assessed by comparing those effects to effects on self-administration of the μ-opioid receptor agonist remifentanil (Fig. 5, C and D). In contrast to the effects on self-administration of cocaine, self-administration of remifentanil was generally insensitive to pretreatments with either dopamine receptor antagonist (Fig. 5, C and D). The exception was obtained at the highest dose of L-741,626, at which responding was virtually eliminated across the entire range of tested unit doses of remifentanil (Fig. 5D, compare □ with ●). Statistical analyses indicated significant effects of pretreatment doses of the antagonists, remifentanil unit dose, and their interactions (Table 5). However, post hoc tests indicated that statistically significant effects were found only with the highest dose of L-741,626 and with a few doses of SCH-39166, which insubstantially increased response rates (Table 5, see Δ values).

Effects of the Dopamine Receptor Antagonists on Self-Administration of the Dopamine Receptor Direct Agonists.

SCH-39166 dose-dependently shifted to the right the dose-effect functions for self-administration of the D₁R agonists R(+)-SKF-81297 and (±)-SKF-82958 (Fig. 5, E and G; Table 5). In contrast, no dose of SCH-39166 appreciably altered self-administration of the D₂R agonists R(−)-NPA or (−)-quinpirole (Fig. 5, I and K; Table 5). Conversely, L-741,626 dose-dependently shifted to the right the dose-effect functions for self-administration of the D₂R agonists (Fig. 5, J and L; Table 5) but did not appreciably alter self-administration of the D₁R agonists (Fig. 5, F and H; Table 5).

Relative Potency Comparisons.

SCH-39166 was approximately 10-fold more potent in decreasing rates of responding maintained by the D₁R agonists than it was in decreasing responding maintained by cocaine (Fig. 6A, compare ○ and ▵ with ●). The same 10-fold potency difference was reflected in the MED of SCH-39166 for decreasing rates of responding maintained by cocaine injections compared with that for decreasing rates of responding maintained by the D₁R agonists (Table 3, compare columns A with C). The potency of SCH-39166 for antagonizing the effects of the D₁R agonists on cocaine self-administration was similar to that for decreasing self-administration of the D₁R agonists and 10-fold greater than that for decreasing cocaine self-administration (Fig. 6A compare ⊗ and ☒ with ●; Table 3, compare columns A and C with E). Additionally, SCH-39166 was approximately 100-fold less potent in decreasing rates of responding maintained by food presentation than it was in decreasing self-administration of the D₁R agonists (Fig. 6A; Table 3, compare columns B with C).

Fig. 6. — Effects of presession treatments with the dopamine receptor antagonists (SCH-39166 and L-741,626) on responding maintained by injections (mg/kg per injection) of cocaine (0.32), R(+)-SKF-81297 (0.0032), (+)-SKF-82958 (0.0032), R(−)-NPA (0.001), (−)-quinpirole (0.032), or remifentanil (0.001) or food presentations (from each fourth component) from Figures 4 and 5. Ordinates: response rates as percentage of control response rates (sessions prior to drug tests), which averaged 0.278 (S.E.M., 0.0427; N = 18), 0.242 (S.E.M., 0.0509; N = 12), 0.267 (S.E.M., 0.0433; N = 12), 0.253 (S.E.M., 0.0468; N = 6), 0.340 (S.E.M., 0.0720; N = 12), 0.512 (S.E.M., 0.127; N = 12), and 0.542 (S.E.M., 0.108; N = 6) responses/s, respectively, for the maximal rates of responses maintained by injections of cocaine, R(+)-SKF-81297, (+)-SKF-82958, R(−)-NPA, (−)-quinpirole, or remifentanil or food presentations. For reversal by SCH-39166 of the effects of D₁R agonists, the values are percentages of the effects of the D₁R agonists alone on cocaine self-administration. One-way ANOVA indicated a significant difference in group (F_6,71 = 2.69; P = 0.021), whereas a post hoc Bonferroni t test indicated no significant difference in group (t values ≤ 2.85; P values ≥ 0.120). Abscissae: dose of test compounds administered intraperisoneally in milligrams per kilogram, log scale. Each point represents the mean ± 1 S.E.M. of response rates on the active lever (N = 6-18). SCH-39166 and L-741,626 were administered intraperitoneally at 15 and 5 minutes before sessions, respectively. (A) Effects of SCH-39166. (B) Effects of L-741,626. Values for MED of compounds to decrease the maximal rates of responses maintained by drug injections or food presentations are shown in Table 3. SA, self-administration.

L-741,626 was approximately threefold more potent in decreasing responding maintained by the D₂R agonists than it was in decreasing responding maintained by cocaine (Fig. 6B, compare ▽ and ◇ with ●). The MED of L-741,626 was 0.32 mg/kg for decreasing responding maintained by each D₂R agonist, whereas that for decreasing cocaine self-administration was 1.0 mg/kg (Table 3, compare columns A with D). In addition, doses of L-741,626 that decreased rates of responding maintained by food presentation (■) or remifentanil injections (□) were approximately 30-fold greater than the MED necessary to decrease D₂R agonist self-administration (Fig. 6B, compare ▽ and ◇ with ◊ and □; Table 3, compare columns D with B and F).

Discussion

A major focus of this study was the interaction between pretreatments with dopamine receptor direct agonists and cocaine self-administration. Leftward shifts produced by D₂R agonists were contrasted by the decreases in maximum self-administration produced by D₁R agonists. The decrease in the maximal self-administration, if clinically translated, suggests that treatments with D₁R agonists would be therapeutically advantageous compared with a blockade that can be surmounted by increasing cocaine dosage. The present technical challenge was to assess the capacity of the D₁R antagonist SCH-39166 to reverse the D₁R agonist–induced decrease in maximum cocaine self-administration as SCH-39166 also decreases cocaine self-administration. An additional focus was the pharmacological characterization of the self-administration of D₁R and D₂R agonists.

Self-Administration of Direct Dopamine Receptor Agonists.

Although previous findings have indicated both efficacy (Self and Stein, 1992; Weed et al., 1993; Weed and Woolverton, 1995) and a lack of efficacy (Grech et al., 1996; Weed et al., 1997; Caine et al., 1999) of D₁R agonists in self-administration, the full D₁R agonists (±)-SKF-82958 and R(+)-SKF-81297 were reliably self-administered in subjects with a cocaine self-administration history in this study. It has been suggested that positive findings are more consistent with full-efficacy agonists. However, Caine et al. (1999) reported that substitution of the full agonist SKF-82958 did not maintain responding above vehicle levels in rats trained to self-administer cocaine. In addition to differences in intrinsic activity, some inconsistencies among results with D₁R agonists may be related to differences in food restriction. Rats in this study were maintained at approximately 320 g, whereas those in the study by Caine et al. (1999) ranged from 400 to 600 g. Several other studies have indicated that food restriction can increase the effects of D₁R agonists (Carr et al., 2003; Haberny et al., 2004; Carr, 2020). At present, it appears that self-administration of D₁R agonists is influenced by both intrinsic efficacy and the level of food deprivation.

Although D₂R agonists have been reported more consistently than D₁R agonists to maintain self-administration above vehicle levels (Gill et al., 1978; Caine et al., 1999; Woolverton and Ranaldi, 2002; Collins and Woods, 2007), there are also qualifications to these results. For example, both the D₂R agonists 7-hydroxy-N, N-dipropyl-2-aminotetralin (7-OH-DPAT) and quinpirole maintained responding in subjects with a history of cocaine reinforcement but not in experimentally naïve subjects (Nader and Mach, 1996; Collins and Woods, 2007). Collins and Woods (2007) went further to find that exposure to cocaine administered independently of responding was insufficient to confer reinforcing effects of quinpirole. Influences of experimental history on whether a drug will be self-administered have been reported previously for N-methyl-D-aspartate receptor antagonists (Young and Woods, 1981; Hiranita et al., 2014) and σ₁-receptor agonists (Hiranita et al., 2013). Although there is much for further study, these results caution against overreliance on any one outcome for abuse liability assessments.

Effects of Subtype-Selective Dopamine Antagonists.

Both the presently studied D₁R and D₂R antagonists dose-dependently shifted cocaine dose-effect functions to the right. The selectivity of these effects is indicated by the finding that both antagonists were about 10-fold more potent in antagonizing cocaine self-administration than in decreasing food-reinforced behavior. Most importantly, SCH-39166 antagonized D₁R agonists and was inactive against D₂R agonist self-administration, with the converse true for L-471,626. Thus, it is likely that cocaine self-administration involves interactions between the dopamine receptor subtypes as previously reported for other behavioral effects (Braun and Chase, 1986; Walters et al., 1987; White, 1987).

The similarities in the effects of D₁R and D₂R antagonists on cocaine self-administration belie the differences obtained in studies of D₁ and D₂ receptor genetic deletions. The more dramatic effects on cocaine self-administration were obtained with D₁ receptor deletions (Caine et al., 2002, 2012; Thanos et al., 2010). These genetic findings are not fully reconciled with the acute blockade studies in this study as the former possibly reflect compensatory mechanisms during development.

Effects of D₂R Agonists on Cocaine Self-Administration.

The differences in the effects of genetic deletions of D₁ and D₂ dopamine receptors are, however, not inconsistent with differences between the effects of D₁R and D₂R agonist treatments. Whereas the D₂R agonists produced a leftward shift in the cocaine dose-effect function, the D₁R agonists decreased maximal self-administration of cocaine. The leftward shifts in the cocaine self-administration dose-effect function might suggest potentiation of cocaine reinforcement. However, previous studies have suggested that this shift may be simply due to a behavioral stimulant effect of the D₂R agonists (Rowlett et al., 2007). Other factors may also be involved. For example, several studies have documented a capacity of quinpirole to enhance rates of responding maintained by visual stimuli paired with cocaine injections (Hill, 1970; Collins and Woods, 2007, 2009). Thus, increases in the effectiveness of conditioned reinforcers accompanying cocaine injections may be involved with leftward shifts in cocaine dose-effect functions produced by D₂R agonists.

An increase in the effectiveness of conditioned reinforcers also may underly effects promoted as “reinstatement” (Shalev et al., 2002) as many of these procedures retain the stimuli previously associated with the drug injections when pretreatments are administered during “extinction.” The first of the five components used in this study was an extinction component in which there were neither injections of cocaine nor the stimulus change that previously accompanied those injections. Even without these stimulus changes the D₂R but not the D₁R agonists increased response rates during extinction. Skinner and Heron (1937) noted that the indirect dopamine agonist amphetamine increased response rates during extinction. Further studies of the environmental and behavioral determinants of the increases in response rates, with and without conditioned reinforcers, would provide a necessary empirical framework for reasonable behavioral and pharmacological mechanistic studies into phenomena involving the reinstatement of formerly reinforced behavior.

Effects of D₁R Agonists on Cocaine Self-Administration.

Both D₁R agonists dose-dependently and selectively decreased the maximal self-administration of cocaine, an effect antagonized by SCH-39166. Arguing for the selectivity of that effect is that both D₁R agonists were more potent in decreasing cocaine self-administration than in decreasing food-maintained responding (Caine et al., 1999; Barrett et al., 2004). Additionally, the temporal patterns of cocaine self-administration, disrupted by the D₁R agonists, were restored by coadministration of SCH-39166, further suggesting a selective antagonism (Vaillant, 1964). Because SCH-39166 also antagonized cocaine-self administration, there is potential ambiguity in the effects of SCH-39166 on the decrease in maximal cocaine self-administration produced by the D₁R agonists. Arguing in favor of blockades by SCH-39166 of the effects of the D₁R agonists rather than cocaine are the relative potencies: the blockade of the D₁R agonist effect on cocaine self-administration was obtained over a range of doses that were inactive against cocaine self-administration. Indeed, the dose that fully blocked the effects of the D₁R agonists was inactive alone on cocaine self-administration. Further, these dose-dependent effects of SCH-39166 were obtained across the range of doses that also blocked the self-administration of both D₁R agonists, indicating pharmacologically selective D₁R-mediated effects. Thus, this study demonstrated that the D₁R agonist–induced insurmountable blockade of cocaine self-administration is mediated by D₁Rs and is not an effect shared with D₂R agonists.

Summary and Conclusions.

This study demonstrated that full D₁R agonists dose-dependently produce an insurmountable blockade of cocaine self-administration that was mediated by D₁Rs as evidenced by similar potencies in the blockade of all of the effects of the D₁R agonists presently studied. Further, the present findings indicate distinct D₁R and D₂R mechanisms influencing cocaine self-administration. These findings suggest further study of D₁R agonists as treatments for cocaine use disorder, though with some caveats. In the single study of the D₁R agonist ABT-431 in cocaine users, there was a decrease in several cocaine-related subjective effects, though no attenuation of selections of smoked cocaine over a monetary reinforcer (Haney et al., 1999). However, as mentioned above, caution should be exercised in an overreliance on any one outcome in abuse liability assessments. Certainly, the present unique insurmountable blockade of cocaine self-administration suggests further study of the effects.

Another concern with the potential of translating the present results stems from reported tolerance to the effects of D₁R agonists. For example, the full D₁R agonist dihydrexidine evokes acetylcholine efflux in the hippocampus of freely moving rats, an effect that was diminished after daily injection (Wade and Nomikos, 2005). The reduction in that effect may have been due to receptor desensitization (Lewis et al., 1998). Although tolerance to the induction of contralateral rotations of the full D₁R agonist A-77636 developed rapidly, no tolerance developed to the effects of another full D₁R agonist A-81686 (Lin et al., 1996). Mutschler and Bergman (2002) reported little tolerance to the effects of the D₁R partial agonist SKF-77434 on cocaine self-administration in rhesus monkeys. Possibly critical to these outcomes is that prolonged D₁R occupancy accompanying the use of agonists as medications will require determination of the optimal parameter values for duration of action and D₁R occupancy. As mentioned above, caution should be exercised when any one outcome is relied upon in assessments of candidate medications. Nonetheless, the present insurmountable blockade of cocaine self-administration advocates for further evaluation of the effects of dopamine D₁R agonists in the treatment of cocaine use disorder.

Acknowledgments

The authors thank Patty Ballerstadt and Maryann Carrigan for administrative assistance.

Data Availability

The authors declare that all the data supporting the findings of this study are contained within the paper.

Abbreviations

(±)-SKF-82958: (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide
D₁R: dopamine D₁-like receptor
D₂R: dopamine D₂-like receptor
EXT: extinction
FR: fixed ratio
L-741,626: (±)-3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole
LED: light-emitting diode
MED: minimum effective dose
R(−)-NPA: R(−)-10,11-dihydroxy-N-n-propylnoraporphine hydrochloride
R(+)-SKF-81297: R(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide
SCH-39166: (6aS-trans)-11-chloro-6,6a,7,8,9,13bhexahydro-7-methyl-5H-benzo[d]naphth[2,1-b]azepin-12-ol hydrobromide
TO: time out

Authorship Contributions

Participated in research design: Hiranita, Soto, Katz.

Conducted experiments: Hiranita.

Performed data analysis: Hiranita, Soto, Katz.

Wrote or contributed to the writing of the manuscript: Hiranita, Soto, Katz.

Footnotes

This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (Z1A DA000103-26 to J.L.K.). T.H. was also supported by National Institutes of Health National Institute on Drug Abuse US Public Health Service [Grant R01DA058018].

No author has an actual or perceived conflict of interest with the contents of this article.

Portions of this manuscript were presented as follows: Hiranita T and Katz JL (2011) Contributions of dopamine D1-like and dopamine D2-like receptor to the self-administration of cocaine in rats. Annual Meeting of the Behavioral Pharmacology Society; 2011 Apr 7–8; Washington, DC.

dx.doi.org/10.1124/jpet.124.002362.

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PERMALINK

Dopamine D1-Like Receptor-Mediated Insurmountable Blockade of the Reinforcing Effects of Cocaine in Rats

Takato Hiranita

Paul L Soto

Jonathan L Katz

Abstract

SIGNIFICANCE STATEMENT

Introduction

Materials and Methods

Subjects.

Compounds.

Apparatus.

Response Acquisition and Intravenous Catheter Implantation.

Self-Administration Procedures.

Data Analysis.

Results

Self-Administration of Cocaine and Substitution of Saline and the Various Compounds.

TABLE 1.

Fig. 1.

Fig. 2.

Effects of the Direct Dopamine Receptor Agonists on Self-Administration of Cocaine.

TABLE 2.

TABLE 3.

Fig. 3.

Effects of SCH-39166 on the D1R Agonist–Induced Decreases in Cocaine Self-Administration.

TABLE 4.

Fig. 4.

Effects of the Dopamine Receptor Antagonists on Self-Administration of Cocaine.

TABLE 5.

Fig. 5.

Effects of the Dopamine Receptor Antagonists on Self-Administration of the Dopamine Receptor Direct Agonists.

Relative Potency Comparisons.

Fig. 6.

Discussion

Self-Administration of Direct Dopamine Receptor Agonists.

Effects of Subtype-Selective Dopamine Antagonists.

Effects of D2R Agonists on Cocaine Self-Administration.

Effects of D1R Agonists on Cocaine Self-Administration.

Summary and Conclusions.

Acknowledgments

Data Availability

Abbreviations

Authorship Contributions

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

Dopamine D₁-Like Receptor-Mediated Insurmountable Blockade of the Reinforcing Effects of Cocaine in Rats

Effects of SCH-39166 on the D₁R Agonist–Induced Decreases in Cocaine Self-Administration.

Effects of D₂R Agonists on Cocaine Self-Administration.

Effects of D₁R Agonists on Cocaine Self-Administration.