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Cocaine self-administration in monkeys: effects on the acquisition and performance of response sequences
Drug and Alcohol Dependence 59 (2000) 51 – 61 www.elsevier.com/locate/drugalcdep
Cocaine self-administration in monkeys: effects on the acquisition and performance of response sequences P.J. Winsauer *, K.R. Silvester, J.M. Moerschbaecher, C.P. France Department of Pharmacology and Experimental Therapeutics, Suite 7103, Louisiana State Uni6ersityMedical Center, 1901 Peridido Street, New Orleans, LA 70112 -1393, USA Received 1 August 1999; accepted 13 August 1999
Abstract A three-component multiple schedule of intravenous cocaine self-administration (0.01 – 0.3 mg/kg), repeated acquisition and performance was used to examine the effects of self-administered cocaine on learning in rhesus monkeys. A 0.03 mg/kg infusion of cocaine maintained reliable self-administration without markedly decreasing overall response rate or increasing the percentage of errors in the acquisition and performance components in which food was presented. When saline was substituted for 0.03 mg/kg of cocaine, there was little or no effect on responding in the acquisition or performance components while the number of infusions and response rate in the self-administration component decreased. These effects occurred to a greater extent under a FR 90 schedule (Experiment 2) as compared to a FR 30 schedule (Experiment 1) of cocaine self administration. Substitution of higher infusion doses of cocaine also decreased response rate and the number of infusions in the self-administration components, and substantially decreased responding in the acquisition components; decreases in overall accuracy of responding were evident when responding in this schedule component occurred. Taken together, these data indicate that learning is generally more sensitive than performance to the disruptive effects of self-administered cocaine. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cognitive processes; Reinforcers; Sequence
1. Introduction Cocaine, particularly in its smokable form (‘crack’), remains one of the most widely-used illicit substances in the United States, and in experimental animal models of drug self-administration is one of the most effective drug reinforcers (Balster, 1988; Mello and Negus, 1996). Cocaine can act as a positive reinforcer under a wide variety of conditions in both nonhuman and human subjects (Yokel, 1987; Johanson, 1988; Winsauer and Thompson, 1991). Despite the fact that there has been considerable research on this topic in many species, a number of important questions concerning the effects of self-administered cocaine remain unanswered; especially with regard to its effects on learning and other complex cognitive processes.
Abbre6iations: FR, fixed ratio. * Corresponding author. Tel.: +1-504-5684740; 5682361.
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When administered noncontingently, cocaine disrupts the acquisition of new behavior in experimental subjects responding under a variety of complex behavioral tasks (e.g. Schrot et al., 1978; Moerschbaecher et al., 1979; Thompson and Moerschbaecher, 1979). For example, in patas monkeys responding under a multiple schedule of repeated acquisition and performance of response sequences (Thompson and Moerschbaecher, 1979), increasing doses of cocaine dose-dependently disrupted both the rate and accuracy of responding in each behavioral component. However, responding in the performance component was generally less sensitive than responding in the learning component to the rate-decreasing and error-increasing effects of cocaine (i.e. the disruptive effects of cocaine were differentially modified by the degree of stimulus control in each behavioral component). This study and others clearly demonstrated the disruptive effects of cocaine on learning, and also demonstrated the importance of specific behavioral variables (e.g. stimulus control, task complexity) that could influence the effects of cocaine on complex behavioral processes such as learning.
0376-8716/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 6 - 8 7 1 6 ( 0 0 ) 0 0 1 0 5 - 2
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The present experiments used a multiple schedule with components of cocaine self administration, repeated acquisition and performance to compare the reinforcing effects of cocaine with its effects on learning. The repeated-acquisition technique, which was originally introduced by Boren (1963) and modified by Thompson (1973a) for the specific purpose of examining the effects of drugs on learning in individual subjects: (1) has been shown to have validity and generalizability in humans, non-human primates and rodents (Thompson, 1973a; Desjardins et al., 1982; Bickel et al., 1990; Winsauer et al., 1995, 1996 (2) can be used to assess both the quantity and quality of behavior (3) has been shown to be sensitive to numerous drugs from various pharmacologic classes (Moerschbaecher and Thompson, 1983; Thompson and Winsauer, 1986; Thompson et al., 1987); (4) has the capability to detect the effects of drugs that are administered either chronically or subchronically (Thompson, 1974; Moerschbaecher et al., 1979; Cohn and MacPhail, 1997); and (5) can be used to assess neurotoxicity (Cohn et al., 1993; Winsauer and Mele, 1993; Winsauer et al., 1995) and the effects of neurotoxicity on specific neurotransmitter systems (Cohn and CorySlechta, 1993, 1994). Therefore, unlike other procedures that have been used to examine the effects of cocaine on learning, this multiple schedule was used to directly assess the effects of self-administered cocaine on learning over time. An important feature of this procedure is that it may more closely resemble the human situation, where drug self administration occurs over extended periods of time (i.e. chronically or subchronically) and occurs in the context of other behavioral responses and reinforcers. A second study (Experiment 2) was conducted with this three-component multiple schedule in order to further demonstrate that cocaine was a primary reinforcer under these conditions and to identify specific schedule parameters that might influence the disruptive effects of cocaine on learning. Because the schedule under which a drug is self administered has been shown to affect responding for that drug (Goldberg et al., 1971; Comer et al., 1995) as well as choice between positive reinforcers (Nader and Woolverton, 1992), an initial manipulation to the three-component multiple schedule involved increasing the FR value in the selfadministration component from 30 to 90. As indicated previously (Goldberg et al., 1971), limiting drug access to short periods of each day and using small infusion doses facilitates the development of stable, day-to-day, self-administration behavior without complications resulting from severe toxicity or, in some cases, dependence. Attaining stable responding for cocaine over relatively short periods of time was also important in the present experiments because it allowed for better experimental control of deprivation level, a variable
that has been shown to affect responding maintained by the self administration of cocaine and other reinforcers (Carroll et al., 1981; de la Garza et al., 1981; Comer et al., 1995).
2. Method
2.1. Subjects Three adult male rhesus monkeys, Macaca mulatta, served as subjects in both Experiments 1 and 2. Monkeys were housed individually in stainless-steel cages and were moderately food restricted (approx. 95% of their free-feeding weight). The mean weight was 8.1 kg for monkey M, 9.3 kg for monkey S and 9.7 kg for monkey W and their diet consisted of banana-flavored food pellets (P.J. Noyes Co., Inc., Lancaster, NH), monkey chow, fresh fruit and vitamins. Water was available ad libitum in the home cage. For behavioral testing, each subject was removed from the colonyroom cage and transported via a macaque restrainer (Primate Products, Inc., Redwood City, CA) to experimental stations located in another room. Subjects had a history of responding under multiple schedules of repeated acquisition and performance, although they were naı¨ve to drug administration under these schedules and self-administration procedures. The colony room and the testing room were provided with 10 changes/h of 100% fresh air that was conditioned to 219 1°C with 509 10% relative humidity. The colony room was maintained on a 12 L: 12 D cycle (no twilight), which began at 06:00 h each day. These experiments were also approved by the Louisiana State University Institutional Animal Care and Use Committee, and conducted in accordance with the guidelines and principals of laboratory animal care (National Research Council, 1996).
2.2. Apparatus Three experimental stations were used to test the subjects. Each monkey was seated in a macaque restrainer for the duration of the experimental session and was secured in position at approximately armslength from a response panel that was mounted to the wall of each experimental station. Each aluminum response panel (measuring 54 cm×35.5 cm) contained three translucent response keys aligned horizontally (8 cm apart, center to center at eye level) and a single response lever located 7 cm above the center key. An in-line stimulus projector, mounted behind each key, projected colors and/or geometric forms onto the key. In addition to these stimuli, there was a single tricolored stimulus located 7 cm above the response lever and a single response key that could be illuminated
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with white light located above the food pellet aperture. Response keys required a minimum force of 0.15 N for activation and each correct response on the keys produced an audible click of a feedback relay. A response on the lever also produced a click of the feedback relay. Recessed florescent lights located in the ceiling of the testing room provided overhead lighting. All three experimental stations and their associated infusion pumps (Razel, model A; Stamford, CT) and cumulative recorders (Gerbrands Corp., Arlington, MA) were connected via an interface to a computer programmed in MED-PC/MEDSTATE NOTATION software (MED Associates, Inc. & Thomas A. Tatham, St. Albans, VT).
2.3. Beha6ioral procedure Prior to catheterization, subjects were trained to respond on a single response lever in the presence of a yellow stimulus under a simple FR 1 schedule of food presentation. When the subjects reliably responded under this schedule of reinforcement the FR value was gradually increased to 30. Once responding was stable under the FR-30 schedule of food presentation, a vascular port system was implanted in each subject as described below. After a brief recovery period (1–2 days), responding in the presence of the yellow stimulus was maintained by a 0.03 mg/kg infusion of cocaine. During cocaine infusions, the stimulus light above the lever changed from yellow to red and the infusion pump was activated. A 60-s timeout, during which the stimulus light above the lever remained off and responses had no programmed consequence, followed each cocaine infusion. When responding stabilized under the FR-30 schedule of cocaine presentation, this schedule of reinforcement was replaced with a threecomponent multiple schedule with components of cocaine self administration, repeated acquisition and performance. During the acquisition component, all three response keys were illuminated simultaneously with one of five geometric symbols, either squares, horizontal bars, triangles, vertical bars or circles. The task for each subject was to respond (key press) on the correct key in the presence of each sequentially illuminated set of geometric symbols (e.g. keys with squares, center correct; keys with horizontal bars, left correct; keys with triangles, center correct; keys with vertical bars, right correct; keys with circles, left correct). When the response sequence was completed, the keylights were turned off and the response key over the food pellet aperture was illuminated. A press on this key reset the sequence. The same sequence (in this case, center-left-center-right-left or CLCRL) was repeated throughout a given session and maintained by food presentation under a FR 4 schedule; that is, every fourth completion of the se-
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quence produced a 500 mg food pellet. When the subject pressed an incorrect key (in the example, the left or right key when the square symbols were presented), the incorrect response (error) was followed by a 5-s timeout. During timeouts, the keylights were off and responses had no programmed consequence. An incorrect response did not reset the five-response sequence; that is, the stimuli were the same before and after the timeout. To establish a steady state of repeated acquisition, the five-response sequence was changed from session to session. An example of a typical set of six sequences was as follows: LRCRC, CLRLR, LRLCL, RCRLC, CLCRL, RCLCR, with the order of the geometric symbols always squares, horizontal bars, triangles, vertical bars and circles. The sequences were carefully selected to be equivalent in several ways and there were restrictions on their ordering across sessions (Thompson, 1973b). Briefly, each sequence was scheduled with equal frequency and adjacent positions within a sequence for a given session were always different. During the performance components of the multiple schedule, the geometric symbols that identify each response in the five-response sequence were projected on a green background. Unlike the acquisition component, the five-response sequence in this component remained the same from session to session (i.e. LCLRL). In all other aspects (FR 4 schedule of food presentation, timeout duration of 5 s, etc.), the performance component was identical to the acquisition component. Each session began with a self-administration component and was followed immediately (i.e. no timeouts occurred between components) by a repeated-acquisition component and a performance component, respectively. Each self-administration and repeated-acquisition component was 10 min in duration, whereas each performance component was 5 min in duration. Sessions terminated after four complete cycles of the multiple schedule (i.e. 4 presentations of each component). Experimental sessions were conducted 7 days/week. For Experiment 2, the FR value in the self-administration component was increased from 30 to 90, whereas the contingencies for the acquisition and performance components remained the same as in Experiment 1.
2.4. Surgical procedure for catheter implantation Both the vascular access port system and the method used to surgically implant the catheters and ports have been described previously (Wojnicki et al., 1994). Briefly, in the present experiments, monkeys were instrumented under septic conditions with a subcutaneous vascular access port system (model c21-4562SIMS Deltec, Inc., St. Paul, MN) containing a polyurethane catheter (1.9 mm outside diameter× 1 mm inside di-
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ameter). Ketamine (10 – 18 mg/kg) was administered as a preanesthetic and anesthesia was maintained via inhalation of halothane (0.4 to 2%) and oxygen. Either the internal jugular vein, the external jugular vein or a femoral vein was catheterized during the course of these experiments. Following the surgery to implant a port system, monkeys received 30 mg/kg of chloramphenicol (b.i.d) intramuscularly for 5 days to minimize the risk of opportunistic bacterial infection.
2.5. Drug administrations Cocaine hydrochloride was purchased from Sigma (St. Louis, MO) and was dissolved in sterile saline (0.9%). The dose of cocaine (0.01 – 0.3 mg/kg) was adjusted by changing the concentration (mg/ml) and solutions of each dose were generally prepared fresh every day. The infusion rate was 2.385 ml/min. The administration volumes of cocaine for each monkey ranged from 0.4 to 0.5 ml/infusion and the substitution of different unit doses occurred in a mixed order across monkeys. In general, drug or saline treatment conditions in Experiments 1 and 2 were studied until the variation in the number of injections did not exceed9 20% for 3 or 4 consecutive daily sessions or for a maximum of 10 days. The training dose was also tested in each subject at various times during this testing period to ensure that the responding for this unit dose remained stable. Each change in the infusion dose of cocaine was followed by substitution of saline.
2.6. Data analyses The data for each session were analyzed in terms of: (1) the overall response rate (total responses/s, excluding timeouts) in each of the three components; (2) the number of infusions/session and infusions/component; and (3) the overall accuracy in the repeated-acquisition and performance components, expressed as the percentage of errors [(incorrect responses/total responses)× 100]. In general, individual subject data were analyzed by comparing drug sessions with sessions in which saline was substituted for cocaine. Percentage of errors for an individual subject was not included in the data analyses when response rate was less than 0.083 responses/s (i.e. 5 responses/min). In addition to these measures that are based on session totals, within-session changes in responding were monitored by a cumulative recorder and the computer. For example, acquisition of a response sequence was generally indicated by within-session error reduction (i.e. a decrease in the number of errors between food presentations as the session progressed).
3. Results Responding under the three-component multiple schedule stabilized quickly in all three subjects (i.e. 6–20 days). Responding was considered stable when overall rates in each of the three components did not differ from the respective mean rate by 9 20% and accuracy of responding or the percentage of errors (repeated acquisition and performance components) did not exceed the mean percentage error by more than 10% from session to session. In addition, acquisition in each monkey was characterized by stable within-session error reduction or learning, which was indicated by a decrease in the number of errors and an increase in errorless completions of the response sequence during the first cycle of the multiple schedule. Fig. 1 shows the mean effects of the last 3 or 4 days of each treatment condition on overall response rate (top panels), the percentage of errors (middle panels) and the number of infusions (bottom panels) in all three subjects. The symbols and ordinate on the righthand side of the bottom panels indicate the mean total dose obtained with each of the respective unit doses of cocaine. When compared with responding for the initial dose of cocaine (0.03 mg/kg), saline substitution (symbols and bars to the left of the dose-effect functions) decreased overall response rate and the number of infusions obtained in the self-administration component each session. These effects, although generally quite small, were most evident in subjects S and W, and least evident in subject M. In contrast, saline substitution had little or no effect on either measure of responding in the repeated-acquisition and performance components compared to the 0.03 mg/kg dose of cocaine. In contrast, increasing the unit dose of cocaine dosedependently decreased overall response rates in all three components of the multiple schedule, and increased the total amount of drug obtained per session (filled triangles in the bottom panels). In subjects M and W, increasing doses of cocaine also produced marked increases in the percentage of errors in the acquisition component, but not the performance component. Increases in the percentage of errors occurred at doses that also reduced response rates. In subject S, increasing unit doses of cocaine decreased rate of responding in the self-administration component while having little or no effect on rates of responding in the repeated-acquisition and performance components. The cumulative records for subject W in Fig. 2 depict the differential effects on the within-session patterns of responding in each component when either saline or increasing unit doses of cocaine were available in the self-administration component. The record in the second row of this figure represents the pattern of responding that occurred when the 0.03 mg/kg infusion dose was available in the self-administration compo-
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nent. Under these conditions, there was a consistent number of cocaine infusions (5 – 6) obtained in each self-administration component of the multiple schedule, and the overall response pattern was characteristic of responding under FR 30 schedules of reinforcement (i.e. pauses occurred prior to each ratio and responding during the ratio occurred at a high and constant rate). In the initial acquisition component (see inset labeled A), errors in responding occurred at the start of the component, and decreased to near zero after a short period of time (e.g. 2 – 5 min); indicating the point at which the subject acquired the correct sequence of responses for that session. Unlike the response pattern in acquisition, the pattern of responding in the performance component was characterized by nearly errorless responding at the start of the first component and throughout the session (see inset labeled P). Note that the pattern of responding in both the acquisition and performance components was comparable following acquisition of the response sequence. When saline was substituted for the 0.03 mg/kg dose of cocaine (record in the first row), responding during
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the self-administration component progressively decreased in each successive self-administration component, whereas responding in the repeated-acquisition and performance components was similar to that obtained with the 0.03 mg/kg dose. When the unit dose of cocaine was increased to 0.1 mg/kg, responding in the self-administration components remained unchanged or increased slightly compared to the 0.03 mg/kg dose, whereas responding during acquisition and performance decreased. The record in the last row of this figure reflects the within-session pattern of responding that occurred in this subject when the unit dose of cocaine was 0.3 mg/kg. As shown, the overall rates of responding were decreased in all three components and both the number of infusions and the number of pellets received in this session were decreased when compared with saline administration or administration of the 0.03 mg/kg dose. In acquisition, responding was eliminated during the first two cycles of the multiple schedule and acquisition of the response sequence was slowed when responding did occur. Also, note that fewer infusions were received when this unit dose of cocaine was avail-
Fig. 1. Effects of saline and varying unit doses of self-administered cocaine on overall response rate (top), percent errors (middle), and number of infusions per session (bottom) in three monkeys responding under a three-component multiple schedule of self-administration, repeated acquisition and performance. The symbols and bars with vertical lines represent the mean and standard error of the mean (SEM) of the last 3 or 4 days of each treatment condition in all three subjects. Data points without vertical lines indicate an instance in which the range is encompassed by the symbol. Note that the percentage of errors was not included in the data analyses when response rate was less than 5 responses/min (i.e. 0.083 responses/s). The right ordinate in the bottom panels (i.e. filled triangles) indicates the mean total dose obtained per session.
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Fig. 2. Cumulative records showing the within-session effects of the different unit doses of cocaine that were received by monkey W under the multiple schedule of self administration, repeated-acquisition and performance. The record in the top row represents responding obtained when saline was substituted for cocaine in the self-administration component. Each session began with a self-administration (SA) component and was followed by a repeated-acquisition (A) and performance (P) component, respectively. Each session terminated after four cycles of the multiple schedule.
able, and that the pattern of responding in the self-administration components was different than that observed when saline was available. The dose-effect data in Fig. 3 depict the effects on responding under the three-component multiple schedule when the final 3 or 4 days of each treatment condition in Experiment 2 were averaged. When compared with the mean data from Fig. 1, increasing the FR value in the self-administration component generally decreased the number of infusions obtained under both drug and saline treatment conditions, and decreased the total dose of cocaine that was obtained with
each unit dose of cocaine (compare the filled triangles in the bottom panels of Figs. 1 and 3). Self administration of unit doses larger than the 0.03 mg/kg dose of cocaine also tended to be less disruptive to responding in the acquisition and performance components. More specifically, under this FR schedule of cocaine presentation, there was little or no effect of cocaine on overall response rate in the performance component in each of the three monkeys (particularly at the 0.3 mg/kg dose) and the overall percentage of errors was increased above control levels in only one subject (monkey W). Additionally, when saline was substituted for cocaine
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Fig. 3. Mean effects of saline or varying unit doses of self-administered cocaine on overall response rate (top), percent errors (middle), and number of infusions per session (bottom) in three monkeys responding under the three-component multiple schedule when the FR value in the self-administration component was increased from 30 to 90. For additional details, see the legend for Fig. 1.
under the FR-90 schedule, the difference ratio of drug infusions to saline infusions increased in all three subjects by a factor of 4 or 5 in two of three subjects. The upper panels of Fig. 4 show the number of infusions obtained by each monkey during the four self-administration components of the multiple schedule used in Experiment 2. Similar to the mean dose-effect data in Fig. 3, these figures represent the mean data for the final 3 or 4 days of each treatment condition. As shown, the pattern of infusions across components varied among monkeys and treatments. This was particularly true for the 0.01 mg/kg dose of cocaine where the mean number of infusions increased (monkey M), remained consistent (monkey S), or decreased (monkey W) across components. However, the general pattern of infusions across components indicated that monkeys consistently obtained more infusions during administration of the 0.03 and 0.1 mg/kg doses of cocaine than during the administration of either saline or the 0.3 mg/kg dose of cocaine. Although both saline and the 0.3-mg/kg dose of cocaine substantially decreased the number of infusions obtained in each self-administration component, these decreases were also differentiated by two distinctive infusion patterns. When the 0.3 mg/kg dose of cocaine was available, all three monkeys self administered a small, but consistent, number of
infusions each component. When saline was substituted for cocaine, two of three monkeys (S and W) obtained the majority of their infusions during the first component and then took fewer with each successive component. The dose-effect functions for each monkey in the bottom panels of Fig. 4 show the effects of self-administering either cocaine or saline on the response rate and percentage of errors in each of the four repeatedacquisition components. As indicated by the filled symbols in this figure, saline infusions obtained in the self-administration component had little or no effect on either overall response rate or the percentage of errors in the repeated-acquisition components compared to the 0.03 mg/kg dose of cocaine. That is, response rates varied little across these components and the percentage of errors decreased for each monkey between the first and second components, indicating that acquisition had occurred. Note that the smallest dose of cocaine, which produced the smallest total dose, also produced the same pattern of infusions when it was available in the self-administration component. However, as the unit dose of cocaine increased, dose-dependent rate-decreasing and error-increasing effects occurred in all three subjects. Especially notable were the effects of the 0.03 mg/kg dose in monkeys M and W and the effects
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Fig. 4. The number of infusions obtained in each of the self-administration components and the effects on response rate and percentage of errors in each repeated acquisitioin component of the multiple schedule when either saline or varying doses of cocaine were available to all three monkeys. The symbols with vertical lines represent the mean and SEM of the last 3 or 4 days of each treatment condition in all three subjects. Data points without vertical lines indicate an instance in which the range is encompassed by the symbol.
of the 0.1 mg/kg in monkey S. These unit doses, which had little or no effect on response rate in each repeatedacquisition component, increased the percentage of errors. In addition, these infusion doses of cocaine produced the largest decreases in the accuracy of responding in the first component when subjects were acquiring the response sequence. Given the comparatively small effects of self-administered cocaine on response rate and the percentage of errors in each of the performance components of the multiple schedule, these data are not shown. As shown in Fig. 3, only the two largest doses of cocaine decreased response rate compared to self-administration of either saline or the 0.03-mg/kg dose, and none of the doses of cocaine produced an increase in the percentage of errors.
4. Discussion Both experiments in this study demonstrated that responding for cocaine could be maintained in monkeys responding under a three-component multiple schedule of self-administration, repeated acquisition and performance. More important, both experiments indicated that doses of cocaine that maintain self-administration
can also produce rate-decreasing and error-increasing effects on complex behavioral responses that are maintained by another positive reinforcer (food). This was demonstrated in Experiment 1 by virtue of the fact that infusion doses of cocaine larger than the 0.03 mg/kg dose, which decreased response rates in the self-administration components, also decreased response rates in the acquisition and performance components and selectively increased the percentage of errors in the acquisition component in two of three monkeys. In Experiment 2, the disruptive effects of cocaine self administration were evident in the component by component analyses, which indicated that small infusion doses of cocaine can produce marked decreases in accuracy of responding without producing decreases in the rate of responding during learning. An important experimental manipulation in both experiments in this study was to demonstrate a decrease in response rate and the number of infusions in the self-administration component when saline was substituted for cocaine. That is, in both experiments, saline substitution was conducted in order to demonstrate that the 0.03 mg/kg dose was maintaining responding in these components, thereby decreasing the likelihood that responding in the self-administration component was being maintained by events other than the presen-
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tation of cocaine. When experimental subjects are responding under complex multiple schedules such as the one used in this study, there can be difficulties identifying the variables that maintain responding. The context in which behavior occurs is known to be an important variable in the effects of drugs. In one study (McKearney and Barrett, 1975), for example, amphetamine was found to have different effects on punished responding in squirrel monkeys depending on whether an extinction component or a shock postponement (avoidance) schedule alternated with the punishment component. Additionally, there are studies indicating that the same drug may serve as a reinforcer or punisher depending on the environmental context (Woods et al., 1975), and that responding can be maintained in a multiple-schedule component even when no primary reinforcers are presented (e.g. Thomas, 1969). In the present study, therefore, there was the possibility that cocaine-maintained responding could have been superstitiously chained or maintained by the onset of the acquisition and performance components where responding was maintained by food presentation. However, this possibility seems unlikely (particularly in Experiment 2) because the rate of responding and the number of infusions were selectively reduced in the self-administration component when saline was substituted for cocaine, and saline substitution did not affect responding in the acquisition and performance components. Substituting different unit doses of cocaine for the 0.03 mg/kg dose also demonstrated the selective control this pharmacological variable had over responding. In Experiment 1, where the unit doses of cocaine were 0.03 mg/kg or larger, response rate and the mean number of infusions generally decreased as the unit dose (and total dose) increased. For example, 0.3 mg/kg of cocaine produced large decreases in overall response rate in all monkeys and decreased the number of infusions to levels below those obtained during saline substitution. In Experiment 2, where doses both smaller and larger than the 0.03 mg/kg dose were substituted, response rate and the number of infusions also changed with the unit dose of cocaine. Similar to Experiment 1, larger unit doses of cocaine generally increased the total dose of cocaine obtained, and decreased overall response rates and the mean number of infusions compared to levels obtained when the training dose was available. The one exception occurred in monkey W, where the 0.1 mg/kg dose of cocaine clearly increased overall response rate and the mean number of infusions to levels above those obtained with the training dose. Interestingly, this dose of cocaine also produced substantial disruptions in responding in the acquisition component in this monkey by decreasing overall response rate and increasing the percentage of errors. Thus, in individual animals, unit doses with the most reinforcing effectiveness may also be the ones most
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likely to disrupt responding in other contexts or disrupt responding maintained by other reinforcers. Despite some of the individual differences noted in the data, the effects observed after both saline substitution and substitution of varying unit doses of cocaine in the self administration component were similar to effects reported in other studies where monkeys self administered drugs under complex multiple schedules (Balster and Schuster, 1973; Herling, 1981; Woolverton and Virus, 1989; Glowa and Wojnicki, 1996). In one study involving monkeys, Herling (1981) compared food and codeine using a multiple schedule that had components with identical fixed-ratio (FR) 30 schedules of reinforcement. When the dose of codeine was increased, the rate of codeine-maintained responding either increased or decreased whereas the rate of food-maintained responding only decreased. Woolverton and Virus (1989) found similar effects on responding when the dose of cocaine was changed in a multiple FR FR schedule maintained by food and cocaine presentation. In their study, substituting saline for cocaine selectively decreased only responding in the cocainemaintained components, while substituting increasing doses of cocaine decreased responding in both the cocaine-maintained components and the food-maintained components. The findings from the present study represent an initial step in the development of a procedure that can examine the effects of self-administered drugs on the acquisition and performance of complex behaviors. Given the existing pharmacological literature involving the repeated-acquisition technique (Desjardins et al., 1982; Thompson, 1973a; Bickel et al., 1990; Winsauer et al., 1996), and the cross-species applicability and utility of this technique, this multiple-schedule procedure offers an established means for examining complex issues surrounding the effects of contingently-administered drugs on complex behaviors and on behaviors maintained by other reinforcers. This is a development in a relatively unexplored area of drug-abuse research, and one that may be extraordinarily valuable for testing potential pharmacotherapies for drug abuse. Clearly, the effectiveness of pharmacological interventions for drug abuse depends on the extent to which they selectively decrease drug-maintained responding. That is, those pharmacotherapies that have been shown to alter drug-maintained responding as well as cognitive behaviors with equal potency would probably have little utility outside of the laboratory. In summary, the present studies demonstrate that the reinforcing effects of cocaine under the schedule parameters chosen, had similar potency to its disruptive effects on food-maintained responding in the acquisition and performance components. Unlike the self-administration of saline in Experiments 1 and 2, self administration of varying doses of cocaine modified
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responding in the self-administration component while producing both rate-decreasing and error-increasing effects on responding in the acquisition and performance components. Furthermore, in both experiments, responding in the acquisition components was more susceptible than responding in the performance components to the rate-decreasing and error-increasing effects of cocaine. This was particularly evident in Experiment 2 where a component by component analysis of the effects of cocaine self administration indicated that relatively small doses of self-administered cocaine decreased the accuracy of responding without affecting the overall rate of responding. These results with contingently-administered cocaine extend the generality of previous findings by Thompson (e.g. Thompson and Moerschbaecher, 1979) and others (Moerschbaecher et al., 1979; Moerschbaecher and Thompson, 1980) indicating that responding under weak stimulus control is more sensitive to disruption by cocaine than responding under strong stimulus control. Finally, the results obtained with Experiments 1 and 2 suggest that the schedule of self administration, which affected both the total dose of cocaine obtained and the maximum number of infusions per component, was important both as a controlling variable for responding in the self-administration component and as a contextual variable for responding in the acquisition and performance components of the multiple schedule.
Acknowledgements The authors would like to thank Merrill Frost and Dr Robert Quinn, D.V.M. for their expert assistance during the surgeries to implant the vascular access port systems. This work was supported, in part, by DA 04775 (J.M.M.) and K02 DA 00211 (C.P.F.).
References Balster, R.L., Schuster, C.R., 1973. Fixed-interval schedule of cocaine reinforcement: effect of dose and infusion duration. J. Exp. Anal. Behav. 20, 119 – 129. Balster, R.L., 1988. Pharmacological effects of cocaine relevant to its abuse. NIDA Res. Monogr. 88, 1–13. Bickel, W.K., Hughes, J.R., Higgins, S.T., 1990. Human behavioral pharmacology of benzodiazepines: Effects on repeated acquisition and performance of response chains. Drug Dev. Res. 20, 53 – 65. Boren, J.J., 1963. Repeated acquisition of new behavioral chains. Amer. Psychol. 17, 421. Carroll, M.E., France, C.P., Meisch, R.A., 1981. Intravenous self-administration of etonitazene, cocaine and phencyclidine in rats during food deprivation and satiation. J. Pharmacol. Exp. Ther. 217, 241 – 247. Cohn, J., Cory-Slechta, D.A., 1993. Subsensitivity of lead-exposed rats to the accuracy-impairing and rate- altering effects of MK801 on a multiple schedule of repeated learning and performance. Brain Res. 600, 208 –218.
Cohn, J., Cory-Slechta, D.A., 1994. Lead exposure potentiates the effects of NMDA on repeated learning. Neurotoxicol. Teratol. 16, 455 – 465. Cohn, J., MacPhail, R.C., 1997. Chlorpyrifos produces selective learning deficits in rats working under a schedule of repeated acquisition and performance. J. Pharmacol. Exp. Ther. 283, 312– 320. Cohn, J., Cox, C., Cory-Slechta, D.A., 1993. The effects of lead exposure on learning in a multiple repeated acquisition and performance schedule. Neurotoxicology 14, 329 – 346. Comer, S.D., Turner, D.M., Carroll, M.E., 1995. Effects of food deprivation on cocaine base smoking in rhesus monkeys. Psychopharmacology (Berl.) 119, 127 – 132. de la Garza, R., Bergman, J., Hartel, C.R., 1981. Food deprivation and cocaine self-administration. Pharmacol. Biochem. Behav. 15, 141 – 144. Desjardins, P.J., Moerschbaecher, J.M., Thompson, D.M., Thomas, J.R., 1982. Intravenous diazepam in humans: effects on acquisition and performance of response chains. Pharmacol. Biochem. Behav. 17, 1055 – 1059. Glowa, J.R., Wojnicki, F.H., 1996. Effects of drugs on food- and cocaine-maintained responding, III: dopaminergic antagonists. Psychopharmacology (Berl.) 128, 351 – 358. Goldberg, S.R., Hoffmeister, F., Schlichting, U.U., Wuttke, W., 1971. A comparison of pentobarbital and cocaine self-administration in rhesus monkeys: effects of dose and fixed-ratio parameter. J. Pharmacol. Exp. Ther. 179, 277 – 283. Herling, S., 1981. Naltrexone effects on food-and codeine-maintained responding in rhesus monkeys. Eur. J. Pharmacol. 73, 41–49. Johanson, C.E., 1988. Behavioral studies of the reinforcing properties of cocaine. NIDA Res. Monogr. 88, 107 – 124. McKearney, J.W., Barrett, J.E., 1975. Punished behavior: increases in responding after D-amphetamine. Psychopharmacologia 41, 23– 26. Mello, N.K., Negus, S.S., 1996. Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology 14, 375 – 424. Moerschbaecher, J.M., Thompson, D.M., 1980. Effects of d-amphetamine, cocaine, and phencyclidine on the acquisition of response sequences with and without stimulus fading. J. Exp. Anal. Behav. 33, 369 – 381. Moerschbaecher, J.M., Thompson, D.M., 1983. Differential effects of prototype opioid agonists on the acquisition of conditional discriminations in monkeys. J. Pharmacol. Exp. Ther. 226, 738–748. Moerschbaecher, J.M., Boren, J.J., Schrot, J., Fontes, J.C., 1979. Effects of cocaine and D-amphetamine on the repeated acquisition and performance of conditional discriminations. J. Exp. Anal. Behav. 31, 127 – 140. Nader, M.A., Woolverton, W.L., 1992. Effects of increasing response requirement on choice between cocaine and food in rhesus monkeys. Psychopharmacology (Berl.) 108, 295 – 300. National Research Council, 1996. Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, DC. Schrot, J., Boren, J.J., Moerschbaecher, J.M., Simoes, F.J., 1978. Effects of D-amphetamine and cocaine on repeated acquisition with timeout from avoidance. Pharmacol. Biochem. Behav. 9, 659 – 663. Thomas, J.R., 1969. Maintenance of behavior by conditioned reinforcement in the signaled absence of primary reinforcement. In: Hendry, D.P. (Ed.), Conditioned Reinforcement. The Dorsey Press, Homewood, NJ, pp. 11 – 90. Thompson, D.M., Moerschbaecher, J.M., 1979. An experimental analysis of the effects of D-amphetamine and cocaine on the acquisition and performance of response chains in monkeys. J. Exp. Anal. Behav. 32, 433 – 444.
P.J. Winsauer et al. / Drug and Alcohol Dependence 59 (2000) 51–61 Thompson, D.M., Winsauer, P.J., 1986. Nicotine can attenuate the disruptive effects of phencyclidine on repeated acquisition in monkeys. Pharmacol. Biochem. Behav. 25, 185–190. Thompson, D.M., Winsauer, P.J., Mastropaolo, J., 1987. Effects of phencyclidine, ketamine and MDMA on complex operant behavior in monkeys. Pharmacol. Biochem. Behav. 26, 401–405. Thompson, D.M., 1973a. Repeated acquisition as a behavioral base line for studying drug effects. J. Pharmacol. Exp. Ther. 184, 506 – 514. Thompson, D.M., 1973b. Repeated acquisition as a behavioral base line for studying drug effects. J. Pharmacol. Exp. Ther. 184, 506 – 514. Thompson, D.M., 1974. Repeated acquisition of behavioral chains under chronic drug conditions. J. Pharmacol. Exp. Ther. 188, 700 – 713. Winsauer, P.J., Mele, P.C., 1993. Effects of sublethal doses of ionizing radiation on repeated acquisition in rats. Pharmacol. Biochem. Behav. 44, 809–814. Winsauer, P.J., Thompson, D.M., 1991. Cocaine self-administration in pigeons. Pharmacol. Biochem. Behav. 40, 41–52.
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Winsauer, P.J., Bixler, M.A., Mele, P.C., 1995. Differential effects of ionizing radiation on the acquisition and performance of response sequences in rats. Neurotoxicology 16, 257 – 269. Winsauer, P.J., Bixler, M.A., Mele, P.C., 1996. Comparison of the effects of typical and atypical anxiolytics on learning in monkeys and rats. J. Pharmacol. Exp. Ther. 276, 1111 – 1127. Wojnicki, F.H.E., Bacher, J.D., Glowa, J.R., 1994. Use of subcutaneous vascular access ports in rhesus monkeys. Lab. Animal Sci. 44, 491 – 494. Woods, J.H., Downs, D.A., Carney, J., 1975. Behavioral functions of narcotic antagonists: response-drug contingencies. Fed. Proc. 34, 1777 – 1784. Woolverton, W.L., Virus, R.M., 1989. The effects of a D1 and a D2 dopamine antagonist on behavior maintained by cocaine or food. Pharmacol. Biochem. Behav. 32, 691 – 697. Yokel, R.A., 1987. Intravenous self-administration: response rates, the effects of pharmacological challenges, and drug preference. In: Bozarth, M.A. (Ed.), Methods of Assessing the Reinforcing Properties of Abused Drugs. Springer-Verlag, New York, NY, pp. 1 – 33.
Cocaine self-administration in monkeys: effects on the acquisition and performance of response sequences P.J. Winsauer *, K.R. Silvester, J.M. Moerschbaecher, C.P. France Department of Pharmacology and Experimental Therapeutics, Suite 7103, Louisiana State Uni6ersityMedical Center, 1901 Peridido Street, New Orleans, LA 70112 -1393, USA Received 1 August 1999; accepted 13 August 1999
Abstract A three-component multiple schedule of intravenous cocaine self-administration (0.01 – 0.3 mg/kg), repeated acquisition and performance was used to examine the effects of self-administered cocaine on learning in rhesus monkeys. A 0.03 mg/kg infusion of cocaine maintained reliable self-administration without markedly decreasing overall response rate or increasing the percentage of errors in the acquisition and performance components in which food was presented. When saline was substituted for 0.03 mg/kg of cocaine, there was little or no effect on responding in the acquisition or performance components while the number of infusions and response rate in the self-administration component decreased. These effects occurred to a greater extent under a FR 90 schedule (Experiment 2) as compared to a FR 30 schedule (Experiment 1) of cocaine self administration. Substitution of higher infusion doses of cocaine also decreased response rate and the number of infusions in the self-administration components, and substantially decreased responding in the acquisition components; decreases in overall accuracy of responding were evident when responding in this schedule component occurred. Taken together, these data indicate that learning is generally more sensitive than performance to the disruptive effects of self-administered cocaine. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cognitive processes; Reinforcers; Sequence
1. Introduction Cocaine, particularly in its smokable form (‘crack’), remains one of the most widely-used illicit substances in the United States, and in experimental animal models of drug self-administration is one of the most effective drug reinforcers (Balster, 1988; Mello and Negus, 1996). Cocaine can act as a positive reinforcer under a wide variety of conditions in both nonhuman and human subjects (Yokel, 1987; Johanson, 1988; Winsauer and Thompson, 1991). Despite the fact that there has been considerable research on this topic in many species, a number of important questions concerning the effects of self-administered cocaine remain unanswered; especially with regard to its effects on learning and other complex cognitive processes.
Abbre6iations: FR, fixed ratio. * Corresponding author. Tel.: +1-504-5684740; 5682361.
fax: + 1-504-
When administered noncontingently, cocaine disrupts the acquisition of new behavior in experimental subjects responding under a variety of complex behavioral tasks (e.g. Schrot et al., 1978; Moerschbaecher et al., 1979; Thompson and Moerschbaecher, 1979). For example, in patas monkeys responding under a multiple schedule of repeated acquisition and performance of response sequences (Thompson and Moerschbaecher, 1979), increasing doses of cocaine dose-dependently disrupted both the rate and accuracy of responding in each behavioral component. However, responding in the performance component was generally less sensitive than responding in the learning component to the rate-decreasing and error-increasing effects of cocaine (i.e. the disruptive effects of cocaine were differentially modified by the degree of stimulus control in each behavioral component). This study and others clearly demonstrated the disruptive effects of cocaine on learning, and also demonstrated the importance of specific behavioral variables (e.g. stimulus control, task complexity) that could influence the effects of cocaine on complex behavioral processes such as learning.
0376-8716/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 6 - 8 7 1 6 ( 0 0 ) 0 0 1 0 5 - 2
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The present experiments used a multiple schedule with components of cocaine self administration, repeated acquisition and performance to compare the reinforcing effects of cocaine with its effects on learning. The repeated-acquisition technique, which was originally introduced by Boren (1963) and modified by Thompson (1973a) for the specific purpose of examining the effects of drugs on learning in individual subjects: (1) has been shown to have validity and generalizability in humans, non-human primates and rodents (Thompson, 1973a; Desjardins et al., 1982; Bickel et al., 1990; Winsauer et al., 1995, 1996 (2) can be used to assess both the quantity and quality of behavior (3) has been shown to be sensitive to numerous drugs from various pharmacologic classes (Moerschbaecher and Thompson, 1983; Thompson and Winsauer, 1986; Thompson et al., 1987); (4) has the capability to detect the effects of drugs that are administered either chronically or subchronically (Thompson, 1974; Moerschbaecher et al., 1979; Cohn and MacPhail, 1997); and (5) can be used to assess neurotoxicity (Cohn et al., 1993; Winsauer and Mele, 1993; Winsauer et al., 1995) and the effects of neurotoxicity on specific neurotransmitter systems (Cohn and CorySlechta, 1993, 1994). Therefore, unlike other procedures that have been used to examine the effects of cocaine on learning, this multiple schedule was used to directly assess the effects of self-administered cocaine on learning over time. An important feature of this procedure is that it may more closely resemble the human situation, where drug self administration occurs over extended periods of time (i.e. chronically or subchronically) and occurs in the context of other behavioral responses and reinforcers. A second study (Experiment 2) was conducted with this three-component multiple schedule in order to further demonstrate that cocaine was a primary reinforcer under these conditions and to identify specific schedule parameters that might influence the disruptive effects of cocaine on learning. Because the schedule under which a drug is self administered has been shown to affect responding for that drug (Goldberg et al., 1971; Comer et al., 1995) as well as choice between positive reinforcers (Nader and Woolverton, 1992), an initial manipulation to the three-component multiple schedule involved increasing the FR value in the selfadministration component from 30 to 90. As indicated previously (Goldberg et al., 1971), limiting drug access to short periods of each day and using small infusion doses facilitates the development of stable, day-to-day, self-administration behavior without complications resulting from severe toxicity or, in some cases, dependence. Attaining stable responding for cocaine over relatively short periods of time was also important in the present experiments because it allowed for better experimental control of deprivation level, a variable
that has been shown to affect responding maintained by the self administration of cocaine and other reinforcers (Carroll et al., 1981; de la Garza et al., 1981; Comer et al., 1995).
2. Method
2.1. Subjects Three adult male rhesus monkeys, Macaca mulatta, served as subjects in both Experiments 1 and 2. Monkeys were housed individually in stainless-steel cages and were moderately food restricted (approx. 95% of their free-feeding weight). The mean weight was 8.1 kg for monkey M, 9.3 kg for monkey S and 9.7 kg for monkey W and their diet consisted of banana-flavored food pellets (P.J. Noyes Co., Inc., Lancaster, NH), monkey chow, fresh fruit and vitamins. Water was available ad libitum in the home cage. For behavioral testing, each subject was removed from the colonyroom cage and transported via a macaque restrainer (Primate Products, Inc., Redwood City, CA) to experimental stations located in another room. Subjects had a history of responding under multiple schedules of repeated acquisition and performance, although they were naı¨ve to drug administration under these schedules and self-administration procedures. The colony room and the testing room were provided with 10 changes/h of 100% fresh air that was conditioned to 219 1°C with 509 10% relative humidity. The colony room was maintained on a 12 L: 12 D cycle (no twilight), which began at 06:00 h each day. These experiments were also approved by the Louisiana State University Institutional Animal Care and Use Committee, and conducted in accordance with the guidelines and principals of laboratory animal care (National Research Council, 1996).
2.2. Apparatus Three experimental stations were used to test the subjects. Each monkey was seated in a macaque restrainer for the duration of the experimental session and was secured in position at approximately armslength from a response panel that was mounted to the wall of each experimental station. Each aluminum response panel (measuring 54 cm×35.5 cm) contained three translucent response keys aligned horizontally (8 cm apart, center to center at eye level) and a single response lever located 7 cm above the center key. An in-line stimulus projector, mounted behind each key, projected colors and/or geometric forms onto the key. In addition to these stimuli, there was a single tricolored stimulus located 7 cm above the response lever and a single response key that could be illuminated
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with white light located above the food pellet aperture. Response keys required a minimum force of 0.15 N for activation and each correct response on the keys produced an audible click of a feedback relay. A response on the lever also produced a click of the feedback relay. Recessed florescent lights located in the ceiling of the testing room provided overhead lighting. All three experimental stations and their associated infusion pumps (Razel, model A; Stamford, CT) and cumulative recorders (Gerbrands Corp., Arlington, MA) were connected via an interface to a computer programmed in MED-PC/MEDSTATE NOTATION software (MED Associates, Inc. & Thomas A. Tatham, St. Albans, VT).
2.3. Beha6ioral procedure Prior to catheterization, subjects were trained to respond on a single response lever in the presence of a yellow stimulus under a simple FR 1 schedule of food presentation. When the subjects reliably responded under this schedule of reinforcement the FR value was gradually increased to 30. Once responding was stable under the FR-30 schedule of food presentation, a vascular port system was implanted in each subject as described below. After a brief recovery period (1–2 days), responding in the presence of the yellow stimulus was maintained by a 0.03 mg/kg infusion of cocaine. During cocaine infusions, the stimulus light above the lever changed from yellow to red and the infusion pump was activated. A 60-s timeout, during which the stimulus light above the lever remained off and responses had no programmed consequence, followed each cocaine infusion. When responding stabilized under the FR-30 schedule of cocaine presentation, this schedule of reinforcement was replaced with a threecomponent multiple schedule with components of cocaine self administration, repeated acquisition and performance. During the acquisition component, all three response keys were illuminated simultaneously with one of five geometric symbols, either squares, horizontal bars, triangles, vertical bars or circles. The task for each subject was to respond (key press) on the correct key in the presence of each sequentially illuminated set of geometric symbols (e.g. keys with squares, center correct; keys with horizontal bars, left correct; keys with triangles, center correct; keys with vertical bars, right correct; keys with circles, left correct). When the response sequence was completed, the keylights were turned off and the response key over the food pellet aperture was illuminated. A press on this key reset the sequence. The same sequence (in this case, center-left-center-right-left or CLCRL) was repeated throughout a given session and maintained by food presentation under a FR 4 schedule; that is, every fourth completion of the se-
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quence produced a 500 mg food pellet. When the subject pressed an incorrect key (in the example, the left or right key when the square symbols were presented), the incorrect response (error) was followed by a 5-s timeout. During timeouts, the keylights were off and responses had no programmed consequence. An incorrect response did not reset the five-response sequence; that is, the stimuli were the same before and after the timeout. To establish a steady state of repeated acquisition, the five-response sequence was changed from session to session. An example of a typical set of six sequences was as follows: LRCRC, CLRLR, LRLCL, RCRLC, CLCRL, RCLCR, with the order of the geometric symbols always squares, horizontal bars, triangles, vertical bars and circles. The sequences were carefully selected to be equivalent in several ways and there were restrictions on their ordering across sessions (Thompson, 1973b). Briefly, each sequence was scheduled with equal frequency and adjacent positions within a sequence for a given session were always different. During the performance components of the multiple schedule, the geometric symbols that identify each response in the five-response sequence were projected on a green background. Unlike the acquisition component, the five-response sequence in this component remained the same from session to session (i.e. LCLRL). In all other aspects (FR 4 schedule of food presentation, timeout duration of 5 s, etc.), the performance component was identical to the acquisition component. Each session began with a self-administration component and was followed immediately (i.e. no timeouts occurred between components) by a repeated-acquisition component and a performance component, respectively. Each self-administration and repeated-acquisition component was 10 min in duration, whereas each performance component was 5 min in duration. Sessions terminated after four complete cycles of the multiple schedule (i.e. 4 presentations of each component). Experimental sessions were conducted 7 days/week. For Experiment 2, the FR value in the self-administration component was increased from 30 to 90, whereas the contingencies for the acquisition and performance components remained the same as in Experiment 1.
2.4. Surgical procedure for catheter implantation Both the vascular access port system and the method used to surgically implant the catheters and ports have been described previously (Wojnicki et al., 1994). Briefly, in the present experiments, monkeys were instrumented under septic conditions with a subcutaneous vascular access port system (model c21-4562SIMS Deltec, Inc., St. Paul, MN) containing a polyurethane catheter (1.9 mm outside diameter× 1 mm inside di-
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ameter). Ketamine (10 – 18 mg/kg) was administered as a preanesthetic and anesthesia was maintained via inhalation of halothane (0.4 to 2%) and oxygen. Either the internal jugular vein, the external jugular vein or a femoral vein was catheterized during the course of these experiments. Following the surgery to implant a port system, monkeys received 30 mg/kg of chloramphenicol (b.i.d) intramuscularly for 5 days to minimize the risk of opportunistic bacterial infection.
2.5. Drug administrations Cocaine hydrochloride was purchased from Sigma (St. Louis, MO) and was dissolved in sterile saline (0.9%). The dose of cocaine (0.01 – 0.3 mg/kg) was adjusted by changing the concentration (mg/ml) and solutions of each dose were generally prepared fresh every day. The infusion rate was 2.385 ml/min. The administration volumes of cocaine for each monkey ranged from 0.4 to 0.5 ml/infusion and the substitution of different unit doses occurred in a mixed order across monkeys. In general, drug or saline treatment conditions in Experiments 1 and 2 were studied until the variation in the number of injections did not exceed9 20% for 3 or 4 consecutive daily sessions or for a maximum of 10 days. The training dose was also tested in each subject at various times during this testing period to ensure that the responding for this unit dose remained stable. Each change in the infusion dose of cocaine was followed by substitution of saline.
2.6. Data analyses The data for each session were analyzed in terms of: (1) the overall response rate (total responses/s, excluding timeouts) in each of the three components; (2) the number of infusions/session and infusions/component; and (3) the overall accuracy in the repeated-acquisition and performance components, expressed as the percentage of errors [(incorrect responses/total responses)× 100]. In general, individual subject data were analyzed by comparing drug sessions with sessions in which saline was substituted for cocaine. Percentage of errors for an individual subject was not included in the data analyses when response rate was less than 0.083 responses/s (i.e. 5 responses/min). In addition to these measures that are based on session totals, within-session changes in responding were monitored by a cumulative recorder and the computer. For example, acquisition of a response sequence was generally indicated by within-session error reduction (i.e. a decrease in the number of errors between food presentations as the session progressed).
3. Results Responding under the three-component multiple schedule stabilized quickly in all three subjects (i.e. 6–20 days). Responding was considered stable when overall rates in each of the three components did not differ from the respective mean rate by 9 20% and accuracy of responding or the percentage of errors (repeated acquisition and performance components) did not exceed the mean percentage error by more than 10% from session to session. In addition, acquisition in each monkey was characterized by stable within-session error reduction or learning, which was indicated by a decrease in the number of errors and an increase in errorless completions of the response sequence during the first cycle of the multiple schedule. Fig. 1 shows the mean effects of the last 3 or 4 days of each treatment condition on overall response rate (top panels), the percentage of errors (middle panels) and the number of infusions (bottom panels) in all three subjects. The symbols and ordinate on the righthand side of the bottom panels indicate the mean total dose obtained with each of the respective unit doses of cocaine. When compared with responding for the initial dose of cocaine (0.03 mg/kg), saline substitution (symbols and bars to the left of the dose-effect functions) decreased overall response rate and the number of infusions obtained in the self-administration component each session. These effects, although generally quite small, were most evident in subjects S and W, and least evident in subject M. In contrast, saline substitution had little or no effect on either measure of responding in the repeated-acquisition and performance components compared to the 0.03 mg/kg dose of cocaine. In contrast, increasing the unit dose of cocaine dosedependently decreased overall response rates in all three components of the multiple schedule, and increased the total amount of drug obtained per session (filled triangles in the bottom panels). In subjects M and W, increasing doses of cocaine also produced marked increases in the percentage of errors in the acquisition component, but not the performance component. Increases in the percentage of errors occurred at doses that also reduced response rates. In subject S, increasing unit doses of cocaine decreased rate of responding in the self-administration component while having little or no effect on rates of responding in the repeated-acquisition and performance components. The cumulative records for subject W in Fig. 2 depict the differential effects on the within-session patterns of responding in each component when either saline or increasing unit doses of cocaine were available in the self-administration component. The record in the second row of this figure represents the pattern of responding that occurred when the 0.03 mg/kg infusion dose was available in the self-administration compo-
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nent. Under these conditions, there was a consistent number of cocaine infusions (5 – 6) obtained in each self-administration component of the multiple schedule, and the overall response pattern was characteristic of responding under FR 30 schedules of reinforcement (i.e. pauses occurred prior to each ratio and responding during the ratio occurred at a high and constant rate). In the initial acquisition component (see inset labeled A), errors in responding occurred at the start of the component, and decreased to near zero after a short period of time (e.g. 2 – 5 min); indicating the point at which the subject acquired the correct sequence of responses for that session. Unlike the response pattern in acquisition, the pattern of responding in the performance component was characterized by nearly errorless responding at the start of the first component and throughout the session (see inset labeled P). Note that the pattern of responding in both the acquisition and performance components was comparable following acquisition of the response sequence. When saline was substituted for the 0.03 mg/kg dose of cocaine (record in the first row), responding during
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the self-administration component progressively decreased in each successive self-administration component, whereas responding in the repeated-acquisition and performance components was similar to that obtained with the 0.03 mg/kg dose. When the unit dose of cocaine was increased to 0.1 mg/kg, responding in the self-administration components remained unchanged or increased slightly compared to the 0.03 mg/kg dose, whereas responding during acquisition and performance decreased. The record in the last row of this figure reflects the within-session pattern of responding that occurred in this subject when the unit dose of cocaine was 0.3 mg/kg. As shown, the overall rates of responding were decreased in all three components and both the number of infusions and the number of pellets received in this session were decreased when compared with saline administration or administration of the 0.03 mg/kg dose. In acquisition, responding was eliminated during the first two cycles of the multiple schedule and acquisition of the response sequence was slowed when responding did occur. Also, note that fewer infusions were received when this unit dose of cocaine was avail-
Fig. 1. Effects of saline and varying unit doses of self-administered cocaine on overall response rate (top), percent errors (middle), and number of infusions per session (bottom) in three monkeys responding under a three-component multiple schedule of self-administration, repeated acquisition and performance. The symbols and bars with vertical lines represent the mean and standard error of the mean (SEM) of the last 3 or 4 days of each treatment condition in all three subjects. Data points without vertical lines indicate an instance in which the range is encompassed by the symbol. Note that the percentage of errors was not included in the data analyses when response rate was less than 5 responses/min (i.e. 0.083 responses/s). The right ordinate in the bottom panels (i.e. filled triangles) indicates the mean total dose obtained per session.
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Fig. 2. Cumulative records showing the within-session effects of the different unit doses of cocaine that were received by monkey W under the multiple schedule of self administration, repeated-acquisition and performance. The record in the top row represents responding obtained when saline was substituted for cocaine in the self-administration component. Each session began with a self-administration (SA) component and was followed by a repeated-acquisition (A) and performance (P) component, respectively. Each session terminated after four cycles of the multiple schedule.
able, and that the pattern of responding in the self-administration components was different than that observed when saline was available. The dose-effect data in Fig. 3 depict the effects on responding under the three-component multiple schedule when the final 3 or 4 days of each treatment condition in Experiment 2 were averaged. When compared with the mean data from Fig. 1, increasing the FR value in the self-administration component generally decreased the number of infusions obtained under both drug and saline treatment conditions, and decreased the total dose of cocaine that was obtained with
each unit dose of cocaine (compare the filled triangles in the bottom panels of Figs. 1 and 3). Self administration of unit doses larger than the 0.03 mg/kg dose of cocaine also tended to be less disruptive to responding in the acquisition and performance components. More specifically, under this FR schedule of cocaine presentation, there was little or no effect of cocaine on overall response rate in the performance component in each of the three monkeys (particularly at the 0.3 mg/kg dose) and the overall percentage of errors was increased above control levels in only one subject (monkey W). Additionally, when saline was substituted for cocaine
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Fig. 3. Mean effects of saline or varying unit doses of self-administered cocaine on overall response rate (top), percent errors (middle), and number of infusions per session (bottom) in three monkeys responding under the three-component multiple schedule when the FR value in the self-administration component was increased from 30 to 90. For additional details, see the legend for Fig. 1.
under the FR-90 schedule, the difference ratio of drug infusions to saline infusions increased in all three subjects by a factor of 4 or 5 in two of three subjects. The upper panels of Fig. 4 show the number of infusions obtained by each monkey during the four self-administration components of the multiple schedule used in Experiment 2. Similar to the mean dose-effect data in Fig. 3, these figures represent the mean data for the final 3 or 4 days of each treatment condition. As shown, the pattern of infusions across components varied among monkeys and treatments. This was particularly true for the 0.01 mg/kg dose of cocaine where the mean number of infusions increased (monkey M), remained consistent (monkey S), or decreased (monkey W) across components. However, the general pattern of infusions across components indicated that monkeys consistently obtained more infusions during administration of the 0.03 and 0.1 mg/kg doses of cocaine than during the administration of either saline or the 0.3 mg/kg dose of cocaine. Although both saline and the 0.3-mg/kg dose of cocaine substantially decreased the number of infusions obtained in each self-administration component, these decreases were also differentiated by two distinctive infusion patterns. When the 0.3 mg/kg dose of cocaine was available, all three monkeys self administered a small, but consistent, number of
infusions each component. When saline was substituted for cocaine, two of three monkeys (S and W) obtained the majority of their infusions during the first component and then took fewer with each successive component. The dose-effect functions for each monkey in the bottom panels of Fig. 4 show the effects of self-administering either cocaine or saline on the response rate and percentage of errors in each of the four repeatedacquisition components. As indicated by the filled symbols in this figure, saline infusions obtained in the self-administration component had little or no effect on either overall response rate or the percentage of errors in the repeated-acquisition components compared to the 0.03 mg/kg dose of cocaine. That is, response rates varied little across these components and the percentage of errors decreased for each monkey between the first and second components, indicating that acquisition had occurred. Note that the smallest dose of cocaine, which produced the smallest total dose, also produced the same pattern of infusions when it was available in the self-administration component. However, as the unit dose of cocaine increased, dose-dependent rate-decreasing and error-increasing effects occurred in all three subjects. Especially notable were the effects of the 0.03 mg/kg dose in monkeys M and W and the effects
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Fig. 4. The number of infusions obtained in each of the self-administration components and the effects on response rate and percentage of errors in each repeated acquisitioin component of the multiple schedule when either saline or varying doses of cocaine were available to all three monkeys. The symbols with vertical lines represent the mean and SEM of the last 3 or 4 days of each treatment condition in all three subjects. Data points without vertical lines indicate an instance in which the range is encompassed by the symbol.
of the 0.1 mg/kg in monkey S. These unit doses, which had little or no effect on response rate in each repeatedacquisition component, increased the percentage of errors. In addition, these infusion doses of cocaine produced the largest decreases in the accuracy of responding in the first component when subjects were acquiring the response sequence. Given the comparatively small effects of self-administered cocaine on response rate and the percentage of errors in each of the performance components of the multiple schedule, these data are not shown. As shown in Fig. 3, only the two largest doses of cocaine decreased response rate compared to self-administration of either saline or the 0.03-mg/kg dose, and none of the doses of cocaine produced an increase in the percentage of errors.
4. Discussion Both experiments in this study demonstrated that responding for cocaine could be maintained in monkeys responding under a three-component multiple schedule of self-administration, repeated acquisition and performance. More important, both experiments indicated that doses of cocaine that maintain self-administration
can also produce rate-decreasing and error-increasing effects on complex behavioral responses that are maintained by another positive reinforcer (food). This was demonstrated in Experiment 1 by virtue of the fact that infusion doses of cocaine larger than the 0.03 mg/kg dose, which decreased response rates in the self-administration components, also decreased response rates in the acquisition and performance components and selectively increased the percentage of errors in the acquisition component in two of three monkeys. In Experiment 2, the disruptive effects of cocaine self administration were evident in the component by component analyses, which indicated that small infusion doses of cocaine can produce marked decreases in accuracy of responding without producing decreases in the rate of responding during learning. An important experimental manipulation in both experiments in this study was to demonstrate a decrease in response rate and the number of infusions in the self-administration component when saline was substituted for cocaine. That is, in both experiments, saline substitution was conducted in order to demonstrate that the 0.03 mg/kg dose was maintaining responding in these components, thereby decreasing the likelihood that responding in the self-administration component was being maintained by events other than the presen-
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tation of cocaine. When experimental subjects are responding under complex multiple schedules such as the one used in this study, there can be difficulties identifying the variables that maintain responding. The context in which behavior occurs is known to be an important variable in the effects of drugs. In one study (McKearney and Barrett, 1975), for example, amphetamine was found to have different effects on punished responding in squirrel monkeys depending on whether an extinction component or a shock postponement (avoidance) schedule alternated with the punishment component. Additionally, there are studies indicating that the same drug may serve as a reinforcer or punisher depending on the environmental context (Woods et al., 1975), and that responding can be maintained in a multiple-schedule component even when no primary reinforcers are presented (e.g. Thomas, 1969). In the present study, therefore, there was the possibility that cocaine-maintained responding could have been superstitiously chained or maintained by the onset of the acquisition and performance components where responding was maintained by food presentation. However, this possibility seems unlikely (particularly in Experiment 2) because the rate of responding and the number of infusions were selectively reduced in the self-administration component when saline was substituted for cocaine, and saline substitution did not affect responding in the acquisition and performance components. Substituting different unit doses of cocaine for the 0.03 mg/kg dose also demonstrated the selective control this pharmacological variable had over responding. In Experiment 1, where the unit doses of cocaine were 0.03 mg/kg or larger, response rate and the mean number of infusions generally decreased as the unit dose (and total dose) increased. For example, 0.3 mg/kg of cocaine produced large decreases in overall response rate in all monkeys and decreased the number of infusions to levels below those obtained during saline substitution. In Experiment 2, where doses both smaller and larger than the 0.03 mg/kg dose were substituted, response rate and the number of infusions also changed with the unit dose of cocaine. Similar to Experiment 1, larger unit doses of cocaine generally increased the total dose of cocaine obtained, and decreased overall response rates and the mean number of infusions compared to levels obtained when the training dose was available. The one exception occurred in monkey W, where the 0.1 mg/kg dose of cocaine clearly increased overall response rate and the mean number of infusions to levels above those obtained with the training dose. Interestingly, this dose of cocaine also produced substantial disruptions in responding in the acquisition component in this monkey by decreasing overall response rate and increasing the percentage of errors. Thus, in individual animals, unit doses with the most reinforcing effectiveness may also be the ones most
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likely to disrupt responding in other contexts or disrupt responding maintained by other reinforcers. Despite some of the individual differences noted in the data, the effects observed after both saline substitution and substitution of varying unit doses of cocaine in the self administration component were similar to effects reported in other studies where monkeys self administered drugs under complex multiple schedules (Balster and Schuster, 1973; Herling, 1981; Woolverton and Virus, 1989; Glowa and Wojnicki, 1996). In one study involving monkeys, Herling (1981) compared food and codeine using a multiple schedule that had components with identical fixed-ratio (FR) 30 schedules of reinforcement. When the dose of codeine was increased, the rate of codeine-maintained responding either increased or decreased whereas the rate of food-maintained responding only decreased. Woolverton and Virus (1989) found similar effects on responding when the dose of cocaine was changed in a multiple FR FR schedule maintained by food and cocaine presentation. In their study, substituting saline for cocaine selectively decreased only responding in the cocainemaintained components, while substituting increasing doses of cocaine decreased responding in both the cocaine-maintained components and the food-maintained components. The findings from the present study represent an initial step in the development of a procedure that can examine the effects of self-administered drugs on the acquisition and performance of complex behaviors. Given the existing pharmacological literature involving the repeated-acquisition technique (Desjardins et al., 1982; Thompson, 1973a; Bickel et al., 1990; Winsauer et al., 1996), and the cross-species applicability and utility of this technique, this multiple-schedule procedure offers an established means for examining complex issues surrounding the effects of contingently-administered drugs on complex behaviors and on behaviors maintained by other reinforcers. This is a development in a relatively unexplored area of drug-abuse research, and one that may be extraordinarily valuable for testing potential pharmacotherapies for drug abuse. Clearly, the effectiveness of pharmacological interventions for drug abuse depends on the extent to which they selectively decrease drug-maintained responding. That is, those pharmacotherapies that have been shown to alter drug-maintained responding as well as cognitive behaviors with equal potency would probably have little utility outside of the laboratory. In summary, the present studies demonstrate that the reinforcing effects of cocaine under the schedule parameters chosen, had similar potency to its disruptive effects on food-maintained responding in the acquisition and performance components. Unlike the self-administration of saline in Experiments 1 and 2, self administration of varying doses of cocaine modified
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responding in the self-administration component while producing both rate-decreasing and error-increasing effects on responding in the acquisition and performance components. Furthermore, in both experiments, responding in the acquisition components was more susceptible than responding in the performance components to the rate-decreasing and error-increasing effects of cocaine. This was particularly evident in Experiment 2 where a component by component analysis of the effects of cocaine self administration indicated that relatively small doses of self-administered cocaine decreased the accuracy of responding without affecting the overall rate of responding. These results with contingently-administered cocaine extend the generality of previous findings by Thompson (e.g. Thompson and Moerschbaecher, 1979) and others (Moerschbaecher et al., 1979; Moerschbaecher and Thompson, 1980) indicating that responding under weak stimulus control is more sensitive to disruption by cocaine than responding under strong stimulus control. Finally, the results obtained with Experiments 1 and 2 suggest that the schedule of self administration, which affected both the total dose of cocaine obtained and the maximum number of infusions per component, was important both as a controlling variable for responding in the self-administration component and as a contextual variable for responding in the acquisition and performance components of the multiple schedule.
Acknowledgements The authors would like to thank Merrill Frost and Dr Robert Quinn, D.V.M. for their expert assistance during the surgeries to implant the vascular access port systems. This work was supported, in part, by DA 04775 (J.M.M.) and K02 DA 00211 (C.P.F.).
References Balster, R.L., Schuster, C.R., 1973. Fixed-interval schedule of cocaine reinforcement: effect of dose and infusion duration. J. Exp. Anal. Behav. 20, 119 – 129. Balster, R.L., 1988. Pharmacological effects of cocaine relevant to its abuse. NIDA Res. Monogr. 88, 1–13. Bickel, W.K., Hughes, J.R., Higgins, S.T., 1990. Human behavioral pharmacology of benzodiazepines: Effects on repeated acquisition and performance of response chains. Drug Dev. Res. 20, 53 – 65. Boren, J.J., 1963. Repeated acquisition of new behavioral chains. Amer. Psychol. 17, 421. Carroll, M.E., France, C.P., Meisch, R.A., 1981. Intravenous self-administration of etonitazene, cocaine and phencyclidine in rats during food deprivation and satiation. J. Pharmacol. Exp. Ther. 217, 241 – 247. Cohn, J., Cory-Slechta, D.A., 1993. Subsensitivity of lead-exposed rats to the accuracy-impairing and rate- altering effects of MK801 on a multiple schedule of repeated learning and performance. Brain Res. 600, 208 –218.
Cohn, J., Cory-Slechta, D.A., 1994. Lead exposure potentiates the effects of NMDA on repeated learning. Neurotoxicol. Teratol. 16, 455 – 465. Cohn, J., MacPhail, R.C., 1997. Chlorpyrifos produces selective learning deficits in rats working under a schedule of repeated acquisition and performance. J. Pharmacol. Exp. Ther. 283, 312– 320. Cohn, J., Cox, C., Cory-Slechta, D.A., 1993. The effects of lead exposure on learning in a multiple repeated acquisition and performance schedule. Neurotoxicology 14, 329 – 346. Comer, S.D., Turner, D.M., Carroll, M.E., 1995. Effects of food deprivation on cocaine base smoking in rhesus monkeys. Psychopharmacology (Berl.) 119, 127 – 132. de la Garza, R., Bergman, J., Hartel, C.R., 1981. Food deprivation and cocaine self-administration. Pharmacol. Biochem. Behav. 15, 141 – 144. Desjardins, P.J., Moerschbaecher, J.M., Thompson, D.M., Thomas, J.R., 1982. Intravenous diazepam in humans: effects on acquisition and performance of response chains. Pharmacol. Biochem. Behav. 17, 1055 – 1059. Glowa, J.R., Wojnicki, F.H., 1996. Effects of drugs on food- and cocaine-maintained responding, III: dopaminergic antagonists. Psychopharmacology (Berl.) 128, 351 – 358. Goldberg, S.R., Hoffmeister, F., Schlichting, U.U., Wuttke, W., 1971. A comparison of pentobarbital and cocaine self-administration in rhesus monkeys: effects of dose and fixed-ratio parameter. J. Pharmacol. Exp. Ther. 179, 277 – 283. Herling, S., 1981. Naltrexone effects on food-and codeine-maintained responding in rhesus monkeys. Eur. J. Pharmacol. 73, 41–49. Johanson, C.E., 1988. Behavioral studies of the reinforcing properties of cocaine. NIDA Res. Monogr. 88, 107 – 124. McKearney, J.W., Barrett, J.E., 1975. Punished behavior: increases in responding after D-amphetamine. Psychopharmacologia 41, 23– 26. Mello, N.K., Negus, S.S., 1996. Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology 14, 375 – 424. Moerschbaecher, J.M., Thompson, D.M., 1980. Effects of d-amphetamine, cocaine, and phencyclidine on the acquisition of response sequences with and without stimulus fading. J. Exp. Anal. Behav. 33, 369 – 381. Moerschbaecher, J.M., Thompson, D.M., 1983. Differential effects of prototype opioid agonists on the acquisition of conditional discriminations in monkeys. J. Pharmacol. Exp. Ther. 226, 738–748. Moerschbaecher, J.M., Boren, J.J., Schrot, J., Fontes, J.C., 1979. Effects of cocaine and D-amphetamine on the repeated acquisition and performance of conditional discriminations. J. Exp. Anal. Behav. 31, 127 – 140. Nader, M.A., Woolverton, W.L., 1992. Effects of increasing response requirement on choice between cocaine and food in rhesus monkeys. Psychopharmacology (Berl.) 108, 295 – 300. National Research Council, 1996. Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, DC. Schrot, J., Boren, J.J., Moerschbaecher, J.M., Simoes, F.J., 1978. Effects of D-amphetamine and cocaine on repeated acquisition with timeout from avoidance. Pharmacol. Biochem. Behav. 9, 659 – 663. Thomas, J.R., 1969. Maintenance of behavior by conditioned reinforcement in the signaled absence of primary reinforcement. In: Hendry, D.P. (Ed.), Conditioned Reinforcement. The Dorsey Press, Homewood, NJ, pp. 11 – 90. Thompson, D.M., Moerschbaecher, J.M., 1979. An experimental analysis of the effects of D-amphetamine and cocaine on the acquisition and performance of response chains in monkeys. J. Exp. Anal. Behav. 32, 433 – 444.
P.J. Winsauer et al. / Drug and Alcohol Dependence 59 (2000) 51–61 Thompson, D.M., Winsauer, P.J., 1986. Nicotine can attenuate the disruptive effects of phencyclidine on repeated acquisition in monkeys. Pharmacol. Biochem. Behav. 25, 185–190. Thompson, D.M., Winsauer, P.J., Mastropaolo, J., 1987. Effects of phencyclidine, ketamine and MDMA on complex operant behavior in monkeys. Pharmacol. Biochem. Behav. 26, 401–405. Thompson, D.M., 1973a. Repeated acquisition as a behavioral base line for studying drug effects. J. Pharmacol. Exp. Ther. 184, 506 – 514. Thompson, D.M., 1973b. Repeated acquisition as a behavioral base line for studying drug effects. J. Pharmacol. Exp. Ther. 184, 506 – 514. Thompson, D.M., 1974. Repeated acquisition of behavioral chains under chronic drug conditions. J. Pharmacol. Exp. Ther. 188, 700 – 713. Winsauer, P.J., Mele, P.C., 1993. Effects of sublethal doses of ionizing radiation on repeated acquisition in rats. Pharmacol. Biochem. Behav. 44, 809–814. Winsauer, P.J., Thompson, D.M., 1991. Cocaine self-administration in pigeons. Pharmacol. Biochem. Behav. 40, 41–52.
.
61
Winsauer, P.J., Bixler, M.A., Mele, P.C., 1995. Differential effects of ionizing radiation on the acquisition and performance of response sequences in rats. Neurotoxicology 16, 257 – 269. Winsauer, P.J., Bixler, M.A., Mele, P.C., 1996. Comparison of the effects of typical and atypical anxiolytics on learning in monkeys and rats. J. Pharmacol. Exp. Ther. 276, 1111 – 1127. Wojnicki, F.H.E., Bacher, J.D., Glowa, J.R., 1994. Use of subcutaneous vascular access ports in rhesus monkeys. Lab. Animal Sci. 44, 491 – 494. Woods, J.H., Downs, D.A., Carney, J., 1975. Behavioral functions of narcotic antagonists: response-drug contingencies. Fed. Proc. 34, 1777 – 1784. Woolverton, W.L., Virus, R.M., 1989. The effects of a D1 and a D2 dopamine antagonist on behavior maintained by cocaine or food. Pharmacol. Biochem. Behav. 32, 691 – 697. Yokel, R.A., 1987. Intravenous self-administration: response rates, the effects of pharmacological challenges, and drug preference. In: Bozarth, M.A. (Ed.), Methods of Assessing the Reinforcing Properties of Abused Drugs. Springer-Verlag, New York, NY, pp. 1 – 33.