Psychopharmacologia (Berl.) 43, 207-213 (1975) - 9 by Springer-Verlag 1975
Original Investigations Self-Administration of CNS Stimulants by Dog MARC E. RISNER and B. E. JONES National Institute on Drug Abuse, Division of Research, Addiction Research Center, Lexington, Kentucky and U. S. Department of Health, Education and Welfare, Public Health Service, Alcohol, Drug Abuse and Mental Health Administration Received September 24, 1974; Final Version May 13, 1975 Abstract. Drug-naive dogs were trained to respond for intra-
venous infusions of either d-amphetamine, phenmetrazine, or methylphenidate until a stable response rate per 4-hr daily session was achieved. The magnitude of reinforcement (i.e., 'mg/kg/infusion) was then varied systematically across a wide range for each drug. An inverse relationship between unit dose and number of self-administered infusions per session was seen. Thus, total drug intake per session remained relatively constant and was independent of unit dose. Using a parallel line bioassay design, the relative potencies of d-
amphetamine, phenmetrazine, and methylphenidate to maintain self-administration were estimated. By comparing the unit doses of d-amphetamine which yielded the same rate of self-administration it was found that 1 mg of phenmetrazine is equivalent to 0.1 mg of d-amphetamine. It was also determined that 1 mg of methylphenidate is equivalent to 0.75 mg of d-amphetamine. These data indicate the dog can be used to assess the reinforcing properties of psychomotor stimulants.
Key words. Self-Administration - Dog - d-Amphetamine - Phenmetrazine - Methylphenidate - Parallel Line Bioassay.
Introduction
Several investigators (Schuster and Thompson, 1969; Thompson and Pickens, 1971) have shown that opioids, barbiturates, and psychomotor stimulants can serve as positive reinforcers when intravenously selfadministered on a response-contingent basis by either the rat or the monkey. The purpose of the present study was to determine if the dog is a suitable animal for assessing the reinforcing properties of psychoactive agents, particularly the CNS stimulants. Information about the parameters of drug self-administration by the dog will complement and enlarge an existing body of data describing the pharmacodynamics of several drugs in this species. Additional reasons make the dog, instead of the rat or monkey, a desirable subject for self-administration research. First, since rats have a relatively short life span and present some special technical problems, they are not particularly useful for longterm studies of this type. Second, a shortage of primates for research purposes is expected to occur soon due to recent cutbacks (up to 40 ~o) in Rhesus monkey exportation from foreign countries into the United States (National Society for Medical Research, 1974). Jones and Prada (1973) have previously demonstrated that the dog is capable of performing an operant reinforced by intravenous infusions of morphine. To a limited extent they als0 examined the
ability of d-amphetamine to maintain responding. The 2 experiments described below were designed to expand this latter finding and attempt to establish an animal model for assessing the reinforcing properties of the stimulants. The quantitative aspects of intravenous self-administration were determined for d-amphetamine, phenmetrazine, and methylphenidate, all known to be abused by humans (Russo, 1968 ; Angrist and Gershon, 1969). Preliminary studies in our laboratory have shown that drug-naive dogs will initiate and maintain responding for intravenous infusions of these three drugs. The behavioral characteristics were similar to those reported for humans. A regular cycle of drug intake (1 - 3 days), interspersed with voluntary abstinence ( 1 - 3 days) was observed in all cases. During the drug self-administration phases there was a marked increase in locomotor behavior and stereotypy along with a decrease in body weight; the abstinence periods were characterized by minimal activity.
Method
In general the surgical methods and mechanical equipment were adaptations of those developed by Headlee et al. (1955), Weeks (1962), and Yanagita et al. (1963) as described by Jones and Prada (1973). The salient features are presented below. The subjects for the experiments were 12 dogs of the mongrel beagle type weighing between 8 and 12 kg. Both male
208 and femaledogs were used. Each dog was individuallyhoused in a galvanized sheet metal and mesh cage. They were given ad libitum access to water and dry food (Purina Dog Chow) throughout the experiment. A food and water pan, in addition to a black pedal and white pedal, were affixed to the front of each cage. The pedals measured 11 cm (H) by 6 cm (W) and protruded approximately 10 cm into the cage. For each experimental cage, one of the two pedals was randomly selected to be the reinforced pedal and the other became the non-reinforced pedal. The pedal contingencies remained unchanged for the duration of the study. Two 25 watt lights, whose functions are described below, were mounted on top of the cage. In the first phase of the study, each dog was placed in a cage and fitted with a leather harness. A steel spring ran from a swivel atop the cage to the harness on the dog. The dogs had complete freedom of movement within the cage except for rolling over. Following adaptation to the harness-swivel combination (generally 3 - 6 days), each dog was surgically prepared with a chronic intravenous catheter positioned in the external jugular. The catheter was connected to a piece of flexible plastic tubing which continued up through the spring and swivel to an infusion pump (Sigmamotor, Model AL-2-E) operated by electromechanical programming equipment. Approximately 10 to 14 days after surgery the rear stimulus light (located near the top rear of the cage) was illuminated 24 hr/day, 7 days/week. Every pedal press on the reinforced pedal resulted in one saline infusion at a volume of 0.1 ml/kg. During the infusion cycle, which lasted from 5 0 - 6 5 sec depending on the weight of the animal, the front stimulus light (located near the top front of the cage) was illuminated, and pedal presses were counted, although they had no programmed consequences. All responses on both the reinforced and non-reinforced pedals, and the number of infusions were recorded at regular intervals throughout the study. After the response rate stabilized during the saline control period (usually from 1 0 - 15 days), the saline was replaced with one of three drug solutions: d-amphetamine sulfate, phenmetrazine hydrochloride, or methylphenidate hydrochloride. The particular drug and unit dose (mg/kg/infusion) were arbitrarily determined for each dog. The drugs were dissolved in physiological saline and given in a volume of 0.1 ml/kg. All unit doses were calculated on the basis of the salts. When the drug-naive dogs were given ad libitum access to response-contingent infusions they began to self-administer the drug solution within 1 - 6 days after it became available. The ad libitum training phase was continued for a period of 2 - 6 weeks. A cyclical
Psychopharmacologia(Berl.), Vol. 43, Fasc. 3 (1975) pattern of drug use was seen for all three agents during this training period. Experiment I
In Experiment I the relationship between magnitude of reinforcement (i.e., unit dose) and number of infusions per session was examined. Previous studies have shown an inverse relationship between these two variables (Wilson et al., 1971). The drug availability period was shortened from 24 hr/day to one 4-hr period/day (1000-1400 hrs). Daily drug sessions were signalled to the subject by illumination of the rear stimulus light (positioned near the top rear of the cage). During the 20-hr period between sessions the light was off and pedal responses, although recorded, had no programmed consequences. To aid the change from ad libitum to limited access, each dog was initially continued on the same drug (at the same unit dose) that was used for their ad libitum training. A continuous reinforcement schedule was used throughout the experiment. After each dog established stable self-administration response rates, the drug solution used for training was replaced with either d-amphetamine, phenmetrazine, or methylphenidate. Four unit doses of each drug were selected for examination. Subjects were maintained at each unit dose for at least five consecutive daily sessions. Then another combination of drug and unit dose was substituted for another period of at least 5 days. Order of presentation was determined arbitrarily for each dog. From 4 - 6 dogs were tested at each of the 12 combinations of drug and unit doses examined in Experiment I. Fig. 1 illustrates the mean number of infusions per session and the mean drug intake per session as a function of d-amphetamine unit dose. Each point represents the mean of data obtained from Days 2 through 5 of each combination of drug and unit dose. The vertical lines drawn through each data point depict the standard errors of the means. The mean number of infusions per session decreased from 49 to 13 as unit dose was increased from 0.025-0.2 rag/ kg/infusion. Although unit dose was raised by a factor of eight, mean drug intake only doubled, increasing from 1.35 mg/kg/session to 2.7 mg/kg/session. Responding on the control pedal was near zero, or did not vary regularly with d-amphetamine unit dose. The effects of phenmetrazine magnitude of reinforcement on number of infusions self-administered per session are shown in Fig. 2. As was the case with d-amphetamine, there was a negative relationship between phenmetrazine unit dose and number of infusions per session. While the amount of drug per injection was increased by a factor of eight from
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Original Investigations Self-Administration of CNS Stimulants by Dog MARC E. RISNER and B. E. JONES National Institute on Drug Abuse, Division of Research, Addiction Research Center, Lexington, Kentucky and U. S. Department of Health, Education and Welfare, Public Health Service, Alcohol, Drug Abuse and Mental Health Administration Received September 24, 1974; Final Version May 13, 1975 Abstract. Drug-naive dogs were trained to respond for intra-
venous infusions of either d-amphetamine, phenmetrazine, or methylphenidate until a stable response rate per 4-hr daily session was achieved. The magnitude of reinforcement (i.e., 'mg/kg/infusion) was then varied systematically across a wide range for each drug. An inverse relationship between unit dose and number of self-administered infusions per session was seen. Thus, total drug intake per session remained relatively constant and was independent of unit dose. Using a parallel line bioassay design, the relative potencies of d-
amphetamine, phenmetrazine, and methylphenidate to maintain self-administration were estimated. By comparing the unit doses of d-amphetamine which yielded the same rate of self-administration it was found that 1 mg of phenmetrazine is equivalent to 0.1 mg of d-amphetamine. It was also determined that 1 mg of methylphenidate is equivalent to 0.75 mg of d-amphetamine. These data indicate the dog can be used to assess the reinforcing properties of psychomotor stimulants.
Key words. Self-Administration - Dog - d-Amphetamine - Phenmetrazine - Methylphenidate - Parallel Line Bioassay.
Introduction
Several investigators (Schuster and Thompson, 1969; Thompson and Pickens, 1971) have shown that opioids, barbiturates, and psychomotor stimulants can serve as positive reinforcers when intravenously selfadministered on a response-contingent basis by either the rat or the monkey. The purpose of the present study was to determine if the dog is a suitable animal for assessing the reinforcing properties of psychoactive agents, particularly the CNS stimulants. Information about the parameters of drug self-administration by the dog will complement and enlarge an existing body of data describing the pharmacodynamics of several drugs in this species. Additional reasons make the dog, instead of the rat or monkey, a desirable subject for self-administration research. First, since rats have a relatively short life span and present some special technical problems, they are not particularly useful for longterm studies of this type. Second, a shortage of primates for research purposes is expected to occur soon due to recent cutbacks (up to 40 ~o) in Rhesus monkey exportation from foreign countries into the United States (National Society for Medical Research, 1974). Jones and Prada (1973) have previously demonstrated that the dog is capable of performing an operant reinforced by intravenous infusions of morphine. To a limited extent they als0 examined the
ability of d-amphetamine to maintain responding. The 2 experiments described below were designed to expand this latter finding and attempt to establish an animal model for assessing the reinforcing properties of the stimulants. The quantitative aspects of intravenous self-administration were determined for d-amphetamine, phenmetrazine, and methylphenidate, all known to be abused by humans (Russo, 1968 ; Angrist and Gershon, 1969). Preliminary studies in our laboratory have shown that drug-naive dogs will initiate and maintain responding for intravenous infusions of these three drugs. The behavioral characteristics were similar to those reported for humans. A regular cycle of drug intake (1 - 3 days), interspersed with voluntary abstinence ( 1 - 3 days) was observed in all cases. During the drug self-administration phases there was a marked increase in locomotor behavior and stereotypy along with a decrease in body weight; the abstinence periods were characterized by minimal activity.
Method
In general the surgical methods and mechanical equipment were adaptations of those developed by Headlee et al. (1955), Weeks (1962), and Yanagita et al. (1963) as described by Jones and Prada (1973). The salient features are presented below. The subjects for the experiments were 12 dogs of the mongrel beagle type weighing between 8 and 12 kg. Both male
208 and femaledogs were used. Each dog was individuallyhoused in a galvanized sheet metal and mesh cage. They were given ad libitum access to water and dry food (Purina Dog Chow) throughout the experiment. A food and water pan, in addition to a black pedal and white pedal, were affixed to the front of each cage. The pedals measured 11 cm (H) by 6 cm (W) and protruded approximately 10 cm into the cage. For each experimental cage, one of the two pedals was randomly selected to be the reinforced pedal and the other became the non-reinforced pedal. The pedal contingencies remained unchanged for the duration of the study. Two 25 watt lights, whose functions are described below, were mounted on top of the cage. In the first phase of the study, each dog was placed in a cage and fitted with a leather harness. A steel spring ran from a swivel atop the cage to the harness on the dog. The dogs had complete freedom of movement within the cage except for rolling over. Following adaptation to the harness-swivel combination (generally 3 - 6 days), each dog was surgically prepared with a chronic intravenous catheter positioned in the external jugular. The catheter was connected to a piece of flexible plastic tubing which continued up through the spring and swivel to an infusion pump (Sigmamotor, Model AL-2-E) operated by electromechanical programming equipment. Approximately 10 to 14 days after surgery the rear stimulus light (located near the top rear of the cage) was illuminated 24 hr/day, 7 days/week. Every pedal press on the reinforced pedal resulted in one saline infusion at a volume of 0.1 ml/kg. During the infusion cycle, which lasted from 5 0 - 6 5 sec depending on the weight of the animal, the front stimulus light (located near the top front of the cage) was illuminated, and pedal presses were counted, although they had no programmed consequences. All responses on both the reinforced and non-reinforced pedals, and the number of infusions were recorded at regular intervals throughout the study. After the response rate stabilized during the saline control period (usually from 1 0 - 15 days), the saline was replaced with one of three drug solutions: d-amphetamine sulfate, phenmetrazine hydrochloride, or methylphenidate hydrochloride. The particular drug and unit dose (mg/kg/infusion) were arbitrarily determined for each dog. The drugs were dissolved in physiological saline and given in a volume of 0.1 ml/kg. All unit doses were calculated on the basis of the salts. When the drug-naive dogs were given ad libitum access to response-contingent infusions they began to self-administer the drug solution within 1 - 6 days after it became available. The ad libitum training phase was continued for a period of 2 - 6 weeks. A cyclical
Psychopharmacologia(Berl.), Vol. 43, Fasc. 3 (1975) pattern of drug use was seen for all three agents during this training period. Experiment I
In Experiment I the relationship between magnitude of reinforcement (i.e., unit dose) and number of infusions per session was examined. Previous studies have shown an inverse relationship between these two variables (Wilson et al., 1971). The drug availability period was shortened from 24 hr/day to one 4-hr period/day (1000-1400 hrs). Daily drug sessions were signalled to the subject by illumination of the rear stimulus light (positioned near the top rear of the cage). During the 20-hr period between sessions the light was off and pedal responses, although recorded, had no programmed consequences. To aid the change from ad libitum to limited access, each dog was initially continued on the same drug (at the same unit dose) that was used for their ad libitum training. A continuous reinforcement schedule was used throughout the experiment. After each dog established stable self-administration response rates, the drug solution used for training was replaced with either d-amphetamine, phenmetrazine, or methylphenidate. Four unit doses of each drug were selected for examination. Subjects were maintained at each unit dose for at least five consecutive daily sessions. Then another combination of drug and unit dose was substituted for another period of at least 5 days. Order of presentation was determined arbitrarily for each dog. From 4 - 6 dogs were tested at each of the 12 combinations of drug and unit doses examined in Experiment I. Fig. 1 illustrates the mean number of infusions per session and the mean drug intake per session as a function of d-amphetamine unit dose. Each point represents the mean of data obtained from Days 2 through 5 of each combination of drug and unit dose. The vertical lines drawn through each data point depict the standard errors of the means. The mean number of infusions per session decreased from 49 to 13 as unit dose was increased from 0.025-0.2 rag/ kg/infusion. Although unit dose was raised by a factor of eight, mean drug intake only doubled, increasing from 1.35 mg/kg/session to 2.7 mg/kg/session. Responding on the control pedal was near zero, or did not vary regularly with d-amphetamine unit dose. The effects of phenmetrazine magnitude of reinforcement on number of infusions self-administered per session are shown in Fig. 2. As was the case with d-amphetamine, there was a negative relationship between phenmetrazine unit dose and number of infusions per session. While the amount of drug per injection was increased by a factor of eight from
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