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All animals were experimentally naive, housed in groups of two to five in a temperature-controlled room (21°C) with a 12 hr light/dark cycle, and given ad libitum access to Purina Laboratory Chow and tap water before the start of the experimental procedure. The animals used in this study were maintained in facilities fully accredited by the American Association for the Accreditation of Laboratory Animal Care. The studies were conducted in accordance with the Guide for Care and Use of Laboratory Animals provided by the National Institutes of Health.
The Journal of Neuroscience, 2002, 22:RC224:1-6
RAPID COMMUNICATION
Failure of Intravenous Morphine to Serve as an Effective Instrumental Reinforcer in Dopamine D2 Receptor Knock-Out MiceGreg I. Elmer1, Jeanne O. Pieper2, Marcelo Rubinstein3, Malcolm J. Low4, David K. Grandy5, and Roy A. Wise2 1 Neuroscience Program, Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland 21228, 2 Behavioral Neuroscience Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, 3 Ingebi, Conicet and Departamento de Ciencias Biologicas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina, 4 Vollum Institute and 5 Department of Physiology and Pharmacology, Oregon Health and Sciences University, Portland, Oregon 97201
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
The rewarding effects of opiates are thought to be mediated through dopaminergic mechanisms in the ventral tegmental area, dopamine-independent mechanisms in the nucleus accumbens, or both. The purpose of the present study was to explore the contribution of dopamine to opiate-reinforced behavior using D2 receptor knock-out mice. Wild-type, heterozygous, and D2 knock-out mice were first trained to lever press for water reinforcement and then implanted with intravenous catheters. The ability of intravenously delivered morphine to maintain lever pressing in these mice was studied under two schedules of reinforcement: a fixed ratio 4 (FR4) schedule (saline, 0.1, 0.3, or 1.0 mg/kg, per injection) and a progressive ratio (PR) schedule (1.0 mg/kg, per injection). In the wild-type and heterozygous mice, FR4 behavior maintained by morphine injections was significantly greater than behavior maintained by vehicle injections. Response rate was inversely related to injection dose and increased significantly in the wild-type and heterozygous mice when the animals were placed on the PR schedule. In contrast, the knock-out mice did not respond more for morphine than for saline and did not respond more when increased ratios were required by the PR schedule. Thus, morphine served as a positive reinforcer in the wild-type and heterozygous mice but failed to do so in the knock-out mice. Under this range of doses and response requirements, the rewarding effects of morphine appear to depend critically on an intact D2 receptor system.
Key words: self-administration; morphine; dopamine; D2 receptor; mice; knock-out
INTRODUCTION
The mesolimbic dopamine system has been implicated in the rewarding effects of both the opiates and the psychomotor stimulants (Wise, 1998
). Direct localized administration of opioids to the ventral tegmental area (VTA) and the nucleus accumbens (NAc) have reinforcing effects (Bozarth and Wise, 1981
Genetically engineered animals offer one of the more recently available techniques to be applied to neuropharmacological research. Although a substantive role for the µ-opiate receptor in intravenous opiate self-administration has been demonstrated using knock-out (Becker et al., 2000
The discrepancy between the two D2 knock-out studies and the unknown relationship between CPP and instrumental drug self-administration leaves open the question of the relative importance of dopamine-dependent and dopamine-independent mechanisms in the positive reinforcing effects of opiates. The purpose of the present study was to explore the consequences of D2 dopamine receptor elimination on intravenous morphine self-administration. The control of lever pressing behavior by intravenous morphine was assessed in D2 knock-out, wild-type, and heterozygous mice under two conditions: across three morphine doses in a fixed-ratio (FR) paradigm and at the highest of these doses in a progressive ratio (PR) paradigm.
MATERIALS AND METHODS
Animals
Adult (60-120 d old) male dopamine D2 receptor knock-out (n = 13), heterozygous (n = 16), and wild-type (n = 20) mice weighing ~21-30 gm at the start of the experiment were used. The homologous recombination techniques and genealogy are described in detail in previous reports (Kelly et al., 1997Operant morphine-reinforced behavior
Procedure overview. The following procedures were used to assess operant intravenous morphine self-administration behavior. First, all mice were trained on a modified progressive ratio schedule for water reinforcement. This procedure was used to confirm the ability of the knock-out mice to learn and perform a lever press operant for a non-drug reinforcer. The modified progressive ratio was used to assess the range of lever pressing rates that could be expected from the various genotypes. Second, some of the water-trained mice were surgically implanted with intravenous catheters and then allowed to respond on an FR4 schedule of reinforcement for 1.0, 0.3, 0.1, and then 0 mg/kg morphine. Data from these tests were used to determine whether morphine would maintain responding in a dose-dependent manner. The remaining water-trained mice were surgically implanted with intravenous catheters and then placed on a progressive ratio schedule of morphine reinforcement. Mice were randomly assigned to each schedule. Data from these experiments were used to make an initial determination of potential differences in the efficacy of our test dose of morphine as a reinforcer in the different genotypes. Apparatus. Ten mouse operant chambers were used. Each chamber was equipped with one lever, a liquid solenoid, and a 22 ga liquid swivel. The lever was a balanced rocker arm that broke an infrared photo beam when 0.5 gm of force was applied. Two stimulus lights were used: one was positioned to illuminate the translucent lever, and the other was positioned above the solenoid delivery spout. The lever light was illuminated during periods of drug availability; the second light was illuminated during drug delivery. During water training, lever pressing resulted in delivery of a drop (~5 µl) of water after completion of each fixed-ratio component. A Harvard 22 µl syringe pump was used to deliver vehicle or drug. The syringe pump and stimulus lights were controlled by an integrated Coulborn (Allentown, PA) environmental control system and MedAssociates interface (St. Albans, VT). System control and data acquisition and storage were accomplished using MedAssociates software. Water training. Naive subjects were water deprived for 24 hr and then placed in the operant chamber. Initially, a single lever press turned on stimulus lights above a spout (FR1); a solenoid delivery system delivered a small amount of liquid in response to each lever press. After completion of each 50 reinforcements, there was an increase in the fixed ratio requirement (FRX + 1). The experimental sessions were run 24 hr/d for 4 d with ad libitum access to food. Surgery. After completion of the water training, subjects were surgically prepared with a catheter implanted in the jugular vein. Surgical procedures were performed under ketamine (80 mg/kg, i.p.)- and xylazine (16 mg/kg, i.p.)-induced anesthesia. SILASTIC tubing (0.012 inch inner diameter) was implanted in the right jugular vein approximately to the level of the atrium. The catheter was passed subcutaneously and exited in the midscapular region. The catheter was connected to a tether/swivel system that was mounted to the skull of the mouse with dental cement. Subjects recovered full movement and eating and drinking habits 3-5 d after surgery. Catheter patency was checked at the end of the experimental protocols via acute dosing with pentobarbital. Only those animals with patent catheters were included in the analysis. Morphine self-administration behavior: fixed ratio 4 dose-effect curve. After recovery from surgery (3-5 d), subjects [n = 12, 10, and 7 for the D2 wild-type (D2wt), D2 heterozygous (D2het), and D2 knock-out (D2ko) mice, respectively] were placed in the operant chamber and given access to 1.0, 0.3, 0.1, and 0 mg/kg morphine per injection for 5, 3, 3, and 8 d, respectively. All subjects were run on an FR4 schedule of reinforcement. Completion of each FR resulted in the illumination of the overhead house light and stimulus lights above the spout. Injections of 5-8 µl (based on body weight) were given over a period of 15 sec. A 30 sec time-out period, during which house and stimulus lights were out, followed the completion of each injection. All subjects had access to morphine 23 hr/d and ad libitum access to food and water 24 hr/d. A 12 hr light/dark cycle was maintained (on 7 A.M., off 7 P.M.). A stimulus light illuminating the lever signaled morphine availability. Morphine self-administration behavior: progressive ratio performance. In the second group of mice (n = 8, 6 and 6 for the D2wt, D2het, and D2ko mice, respectively), subjects were placed in the operant chamber after surgery (3-5 d) and given access to 1.0 mg/kg morphine per injection for 7 d on an FR4 schedule of reinforcement. These subjects were then placed on a progressive ratio schedule. Completion of each ratio resulted in an increase in the ratio requirement to obtain the next reinforcement. The sequential ratio requirements were adapted from Roberts and Bennet (1993)
RESULTS
Water training
All genotypes were successfully trained to stable rates of lever pressing for water reinforcement (Fig. 1A), reaching stable water intake by the second day of responding and maintaining that intake despite increasing response requirements (Fig. 1B). Although each genotype reached stable response and intake rates, the D2 knock-out mice emitted fewer responses and consumed less water during the water-training period. There was a significant overall main effect of genotype for the fixed ratio obtained (F(Genotype)(2,27) = 8.98; p < 0.001) and number of reinforcements (F(Genotype)(2,27) = 5.29; p < 0.01). Additionally, a genotype by day interaction was found for reinforcements (F(Genotype × Day)(6,78) = 2.66 ; p < 0.02). Overall, D2ko mice consumed significantly less water when required to lever press to obtain water. When mice were given ad libitum access to water in their home cages, water consumption did not differ significantly across the three genotypes (6.0 ± 0.4, 5.0 ± 0.5, and 6.2 ± 0.4 ml for the D2wt, D2het, and D2ko mice, respectively). The D2ko animals were clearly capable of lever pressing at rates of at least 566 responses per day. This would prove to be ~15× the rate of responding sustained under morphine reinforcement.
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Figure 1. A and B represent the highest fixed ratio completed each day and the actual number of reinforcements obtained during the water-training period, respectively. At the start of the water-training protocol, a single lever press resulted in liquid delivery; thereafter, completion of each 50 reinforcements resulted in an increase of the fixed ratio requirement (FRX + 1). The FR requirement was set to the previous day's last FR on days 2, 3, and 4. Each point represents the condition mean (±SEM) of results from 12 D2wt, 10 D2het, and 7 D2ko mice.
Morphine self-administration behavior: fixed ratio 4 dose-effect curve
The response rates of the D2wt and D2het mice were higher for low doses of drug than for saline (Fig. 2A). Although response rates for the D2wt and D2het mice decreased with increasing doses of morphine per injection, the response rates of the D2ko mice were the same for morphine as for saline and did not vary as a function of morphine dose. In the D2wt mice, injections of morphine maintained significantly greater and lesser amounts of behavior than saline at the 0.1 (p < 0.0367) and 1.0 mg/kg dose (p < 0.0052), respectively. In the D2het mice, the overall main effect of dose was significant; however, behavior maintained by the 0.1 mg/kg dose was only marginally greater than behavior maintained by saline (p < 0.0936), whereas behavior maintained by the 1.0 mg/kg dose was significantly less (p < 0.0328). In the D2ko mice, there was no significant difference between lever pressing for saline and lever pressing for morphine; furthermore, there were no significant differences in the responding across the three morphine dose conditions (p < 0.63; NS). Morphine intake in the D2ko mice was predictable from the rate of responding under saline reinforcement; the animals made the same 35 or so responses per day regardless of morphine dose and passively received the amount of drug that accompanied that number of responses at each dose (Fig. 2B). The overall main effects of dose, genotype, and genotype × dose interaction were significant for the number of lever presses maintained by morphine injections: F(Dose) = 10.93, df = 3,78, p < 0.0001; F(Genotype) = 3.77, df = 2,78, p < 0.02; F(Genotype × Dose) = 2.37, df = 6,78, p < 0.036. There was a dose-related change in the amount of behavior maintained at each dose in the D2wt (F(Dose) = 9.30, df = 3,33, p < 0.0001) and D2het mice (F(Dose) = 5.37, df = 3,33, p < 0.005). There was a significant main effect of genotype and dose and a significant genotype × dose interaction on drug intake: F(Genotype) = 2.7, df = 2,23, p < 0.02; F(Dose) = 8.7, df = 2,23, p < 0.002; F(Genotype × Dose) = 7.8, df = 4,23, p < 0.03.
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Figure 2. Lever pressing behavior (A) and drug intake (B) as a function of increasing morphine dose per injection. Each point represents the condition mean (±SEM) of results from 12 D2wt, 10 D2het, and 7 D2ko mice over the last three sessions of each condition. # represents a significant difference from the saline control level of each genotype; p < 0.06 from saline control; * indicates a significant difference from wild type.
Morphine self-administration behavior: progressive ratio performance
Under progressive ratio conditions, the D2wt and D2het animals increased their response rates as response demands increased, whereas the D2ko animals responded no more on the progressive ratio schedule than they had responded for either saline or morphine on the FR schedule (Fig. 3). Lever pressing increased significantly in the D2wt and D2het mice but not in the D2ko mice (p < 0.02, p < 0.02, p = 0.24, respectively). The overall main effects of schedule and genotype as well as the genotype by schedule interaction for the number of injections received were significant: (F(Schedule)(1,17) = 16.9, p < 0.0008; F(Genotype)(2,17) = 5.77, p < 0.02; F(Genotype × Schedule)(1,17) = 3.3, df = 1,17, p < 0.05. Thus, in the D2ko animals, morphine again failed to sustain levels of responding greater than those sustained by saline. Under saline or morphine conditions (any dose or schedule), the D2ko animals responded at <1/10 the rates that had been sustained under water reinforcement.
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Figure 3. Number of lever presses (A) and reinforcements (B) obtained under a fixed-ratio 4 and progressive-ratio schedule of reinforcement. Each point represents the condition mean (±SEM) of results from eight D2wt, six D2het, and six D2ko mice over the last three sessions of each condition. Asterisk indicates a significant difference from D2wt and D2het mice; # represents a significant difference from FR4 values.
DISCUSSION
Intravenous morphine delivery did not serve as a positive reinforcer in dopamine D2 receptor knock-out mice under conditions that were effective in the wild-type and heterozygous mice. D2ko mice responded at the same low levels for intravenous saline and intravenous morphine and did not alter their rate of responding when morphine doses were altered. D2wt and D2het mice responded at increased rates for the low dose of morphine and at decreased rates for the high dose of morphine. Thus the behavior of the D2wt and D2het animals was under the pharmacological control of morphine, whereas the behavior of the D2ko animals was not. That the D2ko animals were capable of responding more than they did for morphine seems clear from their level of responding for water during the water-training period. That they were not incapacitated by the morphine itself was clear from the fact that the same low rate of responding seen with intravenous saline was also seen with intravenous morphine. Thus morphine served effectively as a reinforcer in D2wt and D2het mice, but served no more effectively than intravenous saline reinforcement, and much less effectively than oral water reinforcement, in D2ko mice. Across the normally effective dose range, intravenous morphine seems unable to serve as a normal reinforcer in D2ko mice. Under the conditions described in this report, the rewarding effects of morphine appear to depend on an intact or a partially intact D2 receptor system.
Previous dialysis and voltammetry studies have suggested involvement of dopamine in morphine-reinforced behavior (Di Chiara and Imperato, 1988
Conflicting conclusions have been reached using D2 receptor knock-out mice in CPP models (Maldonado et al., 1997
Genetically manipulated animal models provide a means to eliminate a receptor system with a high degree of specificity. However, embryonic gene manipulation is unlikely to affect a single behavior or a single receptor system. As an example of pleiotropic effects on behavior, D2 knock-out mice emitted fewer responses during the water-training period in addition to the instrumental morphine reinforced period. Water consumption in the home cage did not differ significantly across the three groups of mice. The selective effect on instrumental responding may be explained by the fact that dopamine antagonists disrupt instrumental behaviors at lower doses than are required to disrupt free consumption of the reward in question (Gramling and Fowler, 1985
FOOTNOTES Received Dec. 3, 2001; revised March 5, 2002; accepted March 18, 2002.
This work was supported in part by National Institute on Drug Abuse (NIDA) Grant DA11888 and the Intramural Research Center, NIDA, National Institutes of Health. We thank Jamey Levy for expert technical assistance.
Correspondence should be addressed to Dr. Greg Elmer, Neuroscience Program, Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, P.O. Box 21247, Maple and Locust Streets, Baltimore, MD 21228. E-mail: gelmer{at}mprc.umaryland.edu.
This article is published in The Journal of Neuroscience, Rapid Communications Section, which publishes brief, peer-reviewed papers online, not in print. Rapid Communications are posted online approximately one month earlier than they would appear if printed. They are listed in the Table of Contents of the next open issue of JNeurosci. Cite this article as: JNeurosci, 2002, 22:RC224 (1-6). The publication date is the date of posting online at www.jneurosci.org.
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