Psychopharmacology 49, 225- 234 (1976)

Psychopharmacology 9 by Springer-Verlag 1976

Effects of Morphine ,Alone and in Combination with Naloxone or d-Amphetamine on Shock-Maintained Behavior in the Squirrel Monkey L. D. BYRD* Laboratory of Psychobiology, Department of Psychiatry, Harvard Medical School at the New England Regional Primate Research Center, Southborough, Massachusetts

Abstract. Key-pressing behavior in the squirrel monkey was maintained under an 8-min fixed-interval (FI) schedule of electric-shock delivery. The acute i.m. administration of morphine prior to a daily session decreased response rates at doses of 1.0-3.0 mg/kg but had little systematic effect on rate at doses of 0.03-0.3 mg/kg. When naloxone was administered concomitantly with morphine prior to a session, 0.01 mg/kg naloxone required athree-fold increase in the dose of morphine necessary to obtain decreased response rates, 0.1 mg/kg naloxone required a 30-fold increase in morphine, and 1.0 mg/kg required more than a 30-fold increase in morphine. Moreover, the administration of naloxone with morphine resulted in increased rates of responding at certain combinations of doses of the two drugs. The administration of d-amphetamine (0.03 or 0.1 mg/kg) alone increased mean response rates under the FI schedule; when combined with 0.03-0.3 mg/kg morphine the increases in responding were greater than obtained with d-amphetamine alone. The negative slope of the linear regression lines relating the effects of morphine to control rates of responding engendered under the FI schedule was decreased when morphine was combined with naloxone, but not with d-amphetamine. These results show that naloxone, but not d-amphetamine, can antagonize the response-rate decreasing effect of morphine when responding in the squirrel monkey is maintained by response-produced electric shock. Key words." Morphine - Naloxone - d-Amphetamine - Schedule-controlled behavior - FI schedule Squirrel monkeys.

* Send offprint requests to; Dr. L. D. Byrd, Division of Primate Behavior, Yerkes Regional Primate Research Center, Emory University, Atlanta, Ga. 30322, U.S.A.

Morphine, an opiate and potent analgesic, can have pronounced effects on learned or conditioned behavior in animal subjects who are not tolerant to or physically dependent on the drug (Adams et al., 1972; Byrd, 1975; Cook and Catania, 1964; Cook and Kelleher, 1962; Goldberg et al., 1976; Holtzman and Jewett, 1971, 1972; Kelleher and Morse, 1964; McMillan and Morse, 1967; Thompson et al., 1970; Tsou, 1963; Verhave et al., 1959; Weiss and Laties, 1964; Woods, 1969; Woods and Schuster, 1971). Recent observations have shown that the dose-dependent effects of morphine on schedule-controlled behavior in nontolerant monkeys are modified when certain types of drugs are administered in combination with morphine. The administration of naloxone or nalorphine in combination with morphine, for example, results in a shift of the dose-effect curve for morphine to the right, i.e. an increase in the dose of morphine necessary to affect responding (Goldberg et al., 1976). These results show that naloxone and nalorphine can antagonize the effects of morphine on responding under fixed-interval (FI) and fixed-ratio (FR) schedules of food presentation in the squirrel monkey, that naloxone is approximately ten times as potent an antagonist as nalorphine, and that the behavioral effects of morphine can be antagonized with doses of naloxone that have little or no behavioral effect when administered alone. The present study was undertaken to determine the behavioral effects of morphine alone and in combination with other drugs when responding in the squirrel monkey was maintained under a schedule of response-produced electric shock. The experiments were designed to test the generality of the effects of morphine administered alone and in combination with various doses of naloxone on responding maintained under schedules of food presentation (Goldberg et al., 1976). Recent reports by McKearney (1974, 1975) indicate that the effects of narcotic analgesics and

226

antagonists on responding in the squirrel monkey under schedules of shock delivery contrast with the effects obtained under schedules of food delivery. On that basis, one might expect morphine in combination with naloxone to have effects on shock-maintained behavior unlike those reported by Goldberg et al. (1976). The present experiments were also designed to study the effect of administering a drug other than a narcotic antagonist in combination with morphine. d-Amphetamine, a sympathomimetic amine, was chosen because its effects on schedule-controlled behavior in the squirrel monkey have been reported to be unaffected by the type o f event maintaining responding and, therefore, its effects on food-maintained responding and shock-maintained responding would be similar (Goldberg et al., 1976; Kelleher and Morse, 1964, 1968 ; McKearney, 1974). Studies have shown that the behavioral effects of a variety of drugs including chlorpromazine (Davis, 1965), reserpine (Smith, 1964), tetrabenazine (McMillan, 1968), and naloxone (Holtzman, 1974) can be altered when d-amphetamine is administered in combination with each of them, and McMillan, Wolf and Carchman (1970) have reported that d-amphetamine can reverse morphineinduced decreases in rate of responding in the pigeon.

METHODS Subjects. Two mature, male squirrel monkeys (Saimiri sciureus) weighing 850-1000 g were housed between daily sessions in individual wire mesh cages where food and water were always available. The monkeys (SM-158 and SM-562) had previously been used in behavioral experiments with response-produced shock (Byrd, 19"72). They were handled in a manner similar to that described by Kelleher et al., (1963). Apparatus. Daily experimental sessions were conducted in a ventilated refrigerator shell containing a plexiglas restraining chair of the type described by Hake and Azrin (1963) and Kelleher and Morse (1964). Sitting in the restraining chair, the monkey faced a wall supporting a response key (Coulbourn Instruments, No. E21-03) and a rectangular stimulus panel of translucent plexiglas. The 3 x 4 cm stimulus panel was transilluminated by 6-w (ac) colored bulbs. The response key was 10 cm above the waist plate of the chair and 9 cm below the bottom of the stimulus panel. Each depression of the key with a force of at least 20 g (0.19 N) registered a response and operated a feedback relay. A small plexiglas stock held the tail motionless so that an electric current could be passed through two brass plates resting on a shaved area 6 - 1 2 cm from the tip of the tail. Electrode paste (EKG Sol) was applied to the shaved area to minimize changes in resistance between the monkey and a 650-v (ac), 60 Hz, shock source. Continuous white noise and an exhaust fan masked extraneous sounds. Electromagnetic relay equipment in a remote room controlled the experiments and recorded data.

Procedure. Responding (key pressing) was initially engendered as described previously (Byrd, ~1972). In brief, each response postponed for 30 65 s the periodic delivery of electric shock (Sidman, 1953). After responding on the shock-postponement schedule had stabilized, shock was delivered at fixed periods of time (16 min for SM-158 ; 12 min for SM-562) independently of responding and concurrent

Psychopharmacology49 (1976) with the schedule of shock postponement. Subsequently, the schedule of shock postponement was omitted and the delivery of shock was made dependent on the first response occurring after 16 min (SM-158) or 12 rain (SM-562) had elapsed. Responsing was maintained thereafter under a fixed-interval (FI) schedule of durations ranging between 4 and 16 rain. During the present experiment, responding was maintained under an 8-rain FI schedule of shock delivery. In the presence of a red stimulus panel, the first response occurring after 8 rain had elapsed was followed by the delivery of a 200-ms, 8-mA electric shock through the brass electrodes resting on the tail. A 15-s timeout during which the experimental chamber was darkened and responses had no scheduled consequences followed delivery of the electric shock. If the 8-rain interval elapsed without a response, the stimulus panel remained red until a response occurred or the session was terminated. Experimental sessions in the chamber were conducted at approximately the same time daily, Monday through Friday. Each session terminated after the completition of ten 8-min intervals or 90 rain, whichever occurred first. Morphine sulfate, d-amphetamine sulfate, and naloxone hydrochloride were dissolved in distilled water for injection. Control injections were made using 0.9~ sodium chloride solution. The drugs were typically injected once per week and never more frequently than twice per week. Drug injections were in a volume, of approximately 0.5 ml and were given in the thigh muscle. When two drugs were studied in combination, one was injected in one thigh and, immediately thereafter, the second was injected in t h e other thigh. The time elapsing between drug injection and beginning the session was 5 - 10 rain. All drug doses were determined in terms of the salts and, except where noted, each dose or combination of doses was studied at least twice. The drug experiments were conduced in the following order: morphine, morphine plus 0.1 mg/kg d-amphetamine, morphine plus 0_03 mg/kg d-amphetamine, morphine plus 1.0 mg/kg naloxone, morphine plus 0.1 mg/kg naloxone, morphine plus 0.01 mg/kg naloxone. In addition, 3.0 mg/ kg morphine alone was administered once to SM-562 and twice to SM-158 after studying the effect of morphine in combination with 0.1 mg/kg naloxone. The order of doses was mixed during each phase of the study.

RESULTS Control Data. Performance under the 8-min FI schedule of shock delivery during sessions without drugs was similar to the performance typically engendered under an FI schedule of food presentation (Goldberg etal., 197~; Kelleher and Morse, 1964) or shock delivery (Byrd, 1972; McKearney, 1968, 1969, 1974) in the squirrel monkey. Mean response rate in the presence of the red stimulus averaged 0.50 (SM-158) and 0.44 (SM-562) responses per second over all phases of the study. The pattern of responding engendered under the FI schedule comprised an initial period of responding at a very low rate followed by a gradual increase in responding during the remainder of the interval, i.e. a pattern of positively accelerated responding. Quarter-life, a quantitative measure of the pattern of responding under the FI schedule (Gollub, 1964; Herrnstein and Morse, 1957), averaged 69~o in SM-158 and 51~ in SM-562. These quarter-life values reflected the fact that most of the responses occurred during the last half of the

227

L. D. Byrd: Drugs and Shock-Maintained Behavior MORPHINE MORPHINE + NALOXONE (0.01 mg/kg)

200

: MORPHINE + NALOXONE (0.! rng/kg) o MORPHINE + NALOXONE (1,0 mg/kg)

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Fig. 1. Effect of morphine alone and in combination with three doses of naloxone on mean rate of responding in squirrel monkeys SM-158 and SM-562. The horizontal broken iine a~; 100 ~ represents the mean response rate (control) when only saline was injected. Vertical lines through the four symbols nearest the Y-axis indicate the standard error of the mean (SEM) when saline was administered alone as a control during each of the four drug experiments. The three symbols above NAL show the mean response rates when the three doses of naloxone were administered without morphine. Mean response rate at each drug close is displayed as a percent of the respective saline control rate. The unconnected symbols (zX)at 3.0 mg/kg morphine show results obtained when 3,0 mg/kg morphine was administered alone near the end of the study. Most of the data points comprising the dose-effect curves were based on at least two observations

interval. If responding had occurred at a relatively constant rate throughout the interval, quarter-life would have been 25~. Mean response rate and quarter-life following saline administrations changed in no systematic way during the period of time required to complete the series of' experiments. Responding seldom occurred during the 15-s timeout period that immediately followed the completion of each 8-rain FI.

Effects of Morphine. A dose of 0.03 mg/kg morphine had little or no effect on responding under the FI schedule, and a dose of 3.0 mg/kg markedly decreased and disrupted responding. Morphine did not increase mean rate of responding beyond one standard error of the mean (SEM) at any dose in SM-158 (Fig. 1). Only one dose increased rate of responding in SM-562, and this effect was slight and due primarily to increased responding during the first half of the interval.

The effect of morphine on the pattern of responding engendered under the FI schedule is reflected in the cumulative records of Figure 2. In general, the pattern of positively accelerated responding maintained under non-drug conditions was also maintained when doses of 0.03 and 0.1 mg/kg were administered. At 0.3 mg/kg, responding increased during the first half of the interval and decreased during the second half, yielding little change in the overall mean response rate. At 1.0 mg/kg, and especially at 3.0 mg/ kg, the rate of responding decreased markedly and the pattern of responding was disrupted. The effect of morphine on response pattern was similar in the two monkeys.

Effects of Naloxone in Combination with Morphine. Naloxone (0.01 - 1.0 mg/kg) when administered alone had no effect on responding. The dose-effect curve describing the effect of morphine on mean rate of responding under the FI schedule was shifted

228

Psychopharmacology 49 (1976)

SM-158

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Fig. 2. Effect of morphine on pattern of responding engendered under an 8-min FI schedule of shock delivery in squirrel monkey SM-158. Cumulative response records show performance during the 17 - 50th minute of the session. A vertical mark on the event pen line and resetting of the response pen to the baseline indicate shock delivery

to the right, however, when naloxone was administered in combination with morphine (Fig. 1). Naloxone at a dose of 0.01 mg/kg required a three-fold increase in the dose of morphine necessary to obtain a decrease in response rates, 0.1 mg/kg naloxone required a 30-fold increase in morphine, and 1.0 mg/kg naloxone required more than a 30-fold increase in morphine. At 30.0 mg/kg, the highest dose of morphine studied, 1.0 mg/kg naloxone antagonized the ratedecreasing effect of morphine and resulted in mean response rates that were 9 3 ~ (SM-158) and 74~o (SM-562) of saline control rates. Certain doses of morphine and naloxone in combination increased mean rates of responding. In SM158, a dose of 0.01 mg/kg naloxone with 0.1 or 0.3 mg/kg morphine, and a dose of 0.1 mg/kg naloxone with 0 . 3 - 3.0 mg/kg morphine, resulted in mean rates of responding that were more than one SEM above saline-control levels. The highest response rates in SM-158 (138~ of control) were observed when 1.0 mg/kg naloxone and 10.0 mg/kg morphine were administered together (Fig. l, top). In SM-562, a similar increase in rate of responding was observed when 0.01 mg/kg naloxone was given with 0.3 or 1.0 mg/kg morphine, when 0.1 mg/kg naloxone was

given with 1.0-10.0 mg/kg morphine, and when 1.0 mg/kg naloxone was administered with 10.0 rag/ kg morphine (Fig. 1, bottom). The effect of increased response rate when naloxone was administered with morphine contrasted with the effect of either drug alone. The increases in response rate were not due to tolerance to the effect of morphine; the unconnected symbols at 3.0 mg/kg morphine in Figure 1 show little change in the effect of this dose in either monkey near the end of the study. Figure 3 comprises segments of cumulative records which show the effect of three doses of naloxone alone and in combination with three doses of morphine on the pattern of responding engendered under the FI schedule. A dose of 0.01 mg/kg naloxone in combination with 0.3-3.0 mg/kg morphine resulted in more responding than was obtained with morphine alone (cf. Fig.2), but the cessation of responding at 1.0 and 3.0 mg/kg morphine indicated that this dose of naloxone did not provide complete antagonism (Fig. 3, left). The administration of 0.1 mg/kg naloxone with 0 . 3 - 3.0 mg/kg morphine further increased responding over that obtained with 0.01 mg/kg naloxone plus morphine with only slight alteration of the pattern of positively accelerated responding.

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L, D, Byrd: Drugs and Shock-Maintained Behavior SM-t58

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At 1.0 and 3.0 mg/kg morphine, for example, responding exceeded that obtained with morphine alone (cf. Fig.2) or in combination with 0.01 mg/kg naloxone (Fig. 3, left). When a dose of 1.0 mg/kg naloxone was administered alone or with 0.03- 3.,0 mg/kg morphine, the rate and pattern of responding at each dose of morphine were very similar to the rate and pattern of responding maintained under saline control conditions. The cumulative records showed no effect on performance when the dose of morphine administered with 1.0 mg/kg naloxone was as large as 3.0 mg/kg (Fig. 3, right).

(0.1 mg/kg) also increased rate of responding when administered alone and in combination with morphine, but the effect was greater in magnitude. In general, the effects of administering 0.03 or 0.1 mg/kg d-amphetamine with morphine were additive and resulted in three dose-effect curves that were relatively parallel. The three curves were displaced from each other along a vertical axis in contrast to the naloxoneplus-morphine curves that were displaced along a horizontal axis (cf. Fig. 1 and 4).

Effects of d-Amphetamine in Combination with Morphine, d-Amphetamine displaced the morphine dose-

obtained fi'om administering naloxone or d-amphetamine with morphine are further demonstrated in Figures 5 and 6. The 6 panels of Figure 5 show the effects of 1.0 and 3.0 mg/kg morphine when administered alone, or in combinatioa with two different doses of d-amphetamine or three different doses of naloxone in SM-562. The effects of the drugs on response rate during individual J-rain periods of the 8-min FI schedule are plotted as a function of saline (control) response rate during those 1-min segments. According to this type of analysis (Dews, 1958;

effect curve upward rather than to the right (Fig.4). The upward shift was obtained at alt doses of morphine (0.03-3.0 mg/kg) studied in SM-562 and at morphine doses of 0.03-0.3 mg/kg in SM-158. The lower dose of d-amphetamine (0.03 mg/kg) alone resulted in an increase in mean rate of responding under the FI schedule, and in combination with morphine response rates were higher than with d-amphetamine alone. The higher dose of d-amphetamine

Contrasting Effects of Naloxone and d-Amphetamine in Combination with Morphine. The contrasting effects

230

Psychopharmacology49 (1976) A MORPHINE 9 MORPHINE + 0.03 mg/kg d - A M P H E T A M I N E 9 MORPHINE + 0.1 m g / k g d_-AMPHETAMINE 200

Fig. 4. Effect of morphine alone and in combination with two doses of d-amphetamine on mean rate of responding in squirrel monkeys SM-158 and SM-562. Data are presented in the same format as in Figure 1. All drug effects are based on at least two observations

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Kelleher and Morse, 1968; Sanger and Blackman, 1976), a regresssion line having zero slope and a Yintercept at 100 ~o indicates no drug effect. Inspection of Figure 5 shows that the effects of 1.0 or 3.0 mg/kg morphine alone can be described by regression lines that are steep and negative in slope, and that the slope became more negative as the dose of morphine increased (upper left panel). Moreover, the upper middle and upper right panels of Figure 5 show that the administration of d-amphetamine with 1.0 or 3.0 mg/kg morphine did little to alter the slope of the regression lines describing the effect of morphine alone. Even though 0.03 or 0.1 mg/kg d-amphetamine in combination with morphine generally increased responding during some of the 1-min periods, neither dose substantially altered the slope of the regression lines for 1.0 mg/kg morphine and, to a lesser extent, for 3.0 mg/kg morphine. In contrast, the bottom three panels of Figure 5 show that naloxone in combination with 1.0 or 3.0 mg/kg morphine decreased the slope

and Y-intercept of the regression lines obtained with morphine alone. The lowest dose of naloxone administered with morphine had the least effect on the regression lines, and the shift of the regression lines toward a less negative slope was greater as the dose of naloxone increased. When 1.0 mg/kg naloxone was administered with 1.0 or 3.0 mg/kg morphine, the slopes of both regression lines were slightly positive (lower right frame). Figure 6 shows that similar effects were obtained in SM-158.

DISCUSSION The effects of acutely administered morphine on responding in the squirrel monkey under an FI schedule of shock delivery were similar to the effects of morphine on responding in the squirrel monkey under an FI schedule of food delivery. Doses of 0.03"0.3 mg/kg morphine had little consistent, systematic effect on

L. D. Byrd: Drugs and Shock-Maintained 3ehavior

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CONTROL RATE (RESPONSES PER SECOND) Fig. 5. Effect of 1.0 (O)or 3.0 (O)mg/kg morphine alone and in combination with 0.03 or0.1 mg/kg d-amphetamine or 0.01, 0.1 or 1.0 mg/kg naloxone as a function of control (saline) response rate during individual 1-min segments of an 8-min FI schedule of shock delivery in squirrel monkey SM-562. Rate of responding during each l-min segment when saline was administered.is plotted with respect to the X-axis; rate of responding (as percent of saline control rate) during each l-rain segment when drugs were administered is plotted with respect to the Y-axis. Regression lines were fitted by the method of least squares

mean response rate in the present experiment, and doses of 1 . 0 - 3.0 mg/kg decreased responding. Similar dose-effect functions describing the effects of morphine on schedule-controlled behavior maintained by food delivery have been reported for the squirrel monkey (Goldberg et al., 1976), the rhesus monkey (Woods, 1969; Woods and Schuster, 1971), and the baboon (Byrd, 1975). In those experiments, responding was maintained under multiple FI FR schedules of food delivery and response rates decreased monotonically as the dose of morphine increased. Naloxone (0.01-1.0 mg/kg) administered alone had no systematic effect on rates or patterns of responding under the FI schedule cf shock delivery in the present experiment. When naloxone was administered in combination with morphine, however, naloxone antagonized the rate-decreasing effect of morphine and shifted the dose-effect curve for morphine to the right. Goldberg et al. (19;76) similarly found little effect of naloxone on responding in the squirrel monkey under an FI schedule of food delivery at doses of 0.01-i.0mg/kg. Yet, they found these doses of naloxone to shift the morphine curve to the

right. The amount of shift in the morphine curve was quantitatively similar to the shift obtained in the present experiment, and Was a function of the dose of naloxone. This shift of the morphine dose-effect curve to the right when naloxone was administered with morphine is characteristic of competitive pharmacological antagonism (Fingl and Woodbury, 1965; Goth, 1974). The absence of a similar shift in the morphine dose-effect curve when d-amphetamine was administered with morphine suggests that the results obtained when the two drugs were administered together were not attributable to competitive antagonism. McMillan et al. (1970) studied the behavioral effects of d-amphetamine in combination with morphine in the pigeon and obtained results similar to those reported here. In their study as in the present one, the data points comprising the morphine dose-effect curve were displaced upward by a relatively constant amount when d-amphetamine was administered with morphine. Moreover, the dose of morphine that resulted in the highest response rate when morphine was administered alone also resulted in the highest rate when morphine

232

Psychopharmacology 49 (1976)

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Fig. 6. Effect of 0.3 (O) or 1.0 (9 mg/kg morphine alone and in combination with 0.03 or 0.1 mg/kg d-amphetamine or 0.01, 0.1 or 1.0 mg/kg naloxone in monkey SM-158. Data are presented in the same format as in Figure 5

and d-amphetamine were administered together (cf. Fig. 4). The similarity of the present data to those reported by McMillan et al. (1970) suggests that their interpretation applies equally well here. The effect of administering morphine and d-amphetamine together depends upon the rate-increasing effect of d-amphetamine and not competitive antagonism. Although the displacement of the morphine curve to the right by naloxone is characteristic of competitive antagonism, the increased rate of responding observed when certain doses of morphine and naloxone were administered together is unusual. The increased responding following the administration of 1.0 mg/kg naloxone with 10.0 mg/kg morphine, for example, indicated that this dose of naloxone not only blocked the rate-decreasing effect of morphine but also resulted in a higher rate of responding than was observed when either drug was administered alone. Holtzman (1976) described a similar effect in squirel monkeys responding under a schedule of shock avoidance. In his study, doses of naloxone that had no effect on responding when administered alone resulted in increased response rates (more than 160 ~o of control rates in one group of monkeys) when administered with morphine. However, in experiments reported by Dykstra, Mc-

Millan and Harris (1974), Goldberg et al. (1976), and McMillan et al. (1970), naloxone antagonized the rate-decreasing effect of morphine without also producing rate increases when responding was maintained under schedules of food presentation. Therefore, the type of event involved in maintaining responding may be a determinant of increased response rates. McKearney (1974) has suggested that certain environmental events interacting with or controlling behavior may determine the behavioral effects of some drugs. The present data and those reported by Holzman (1976) and McKearney (1974, 1975) suggest that electric shock may be such an event. The regression lines that resulted from administering morphine alone provided a basis for contrasting the effects of administering naloxone or d-amphetamine in combination with morphine, and for measuring the efficacy of naloxone in antagonizing the behavioral effects of morphine. Figures 5 and 6 showed that the effects of morphine alone and in combination with naloxone or d-amphetamine can be expressed as the slope of the regression line. At the higher doses of morphine the regression lines were steep and negative in slope when morphine was administered alone, but the administration of naloxone with morphine re-

L. D. Byrd: Drugs and Shock-Maintained Behavior

sulted in regression lines that decreased in steepness as the dose of naloxone increaased. At 12 mg/kg naloxone, the effects of 1.0 and 3.0 mg/kg morphine were antagonized and the regression lines were slightly positive in slope. In contrast, there was little systematic change in the slope of the regression lines when d-amphetamine was administered with morphine. The regression lines were equally steep and negative whether morphine was administered alone or with d-amphetamine` Therefore, the analysis in terms of slopes of regression lines differentiated between the antagonistic action of naloxone and the effect of d-amphetamine, a drug that is not known to be a narcotic antagonist. In addition, analysis of the effects of morphine in terms of changes in the slope of regression lines revealed subtle changes in performance that were not evident in the mean response rates. For example, 0.3 mg/kg morphine resulted in mean response rates that differed little from the mean rates obtained when saline was administered (Fig. 1), yet the slope of the regression line in each monkey was quite negative when 0.3 mg/kg morphine was administered alone. Consequently, the slope of the regression line fitted to logarithmic plots of the data was a more sensitive measure of the behavioral effects of the drug, and the amount of deviation from zero slope provided a quantitative index of the magnitude of the drug effect on responding under the FI schedule. The effects obtained with d-amphetamine alone in the present experiments were quite similar to the effects this drug has been reported to have on responding in the squirrel monkey maintained under an FI schedule of food presentation (Goldberg et al., 1976), an FI schedule of stimulus-complex termination (Kelleher Morse, 1964), and an FI schedule of shock delivery (McKearney, 1974). The results of the present experiments contrast in two respects, however, with reports by McKearney (1974, 1975) that either morphine or naloxone produce substantial increases in responding in the squirrel monkey. Neither morphine alone nor naloxone alone produced the increases in response rates McKearney described for these drugs in squirrel monkeys responding under a similar schedule. There was an increase in response rate when morphine and naloxone were administered together at certain doses, but consistent increases in rate above control levels were not obtained when either drug was administered alone. It is not clear at this point whether the effects McKearney reported for morphine and naloxone were due to procedural matters or something unique in the experimental histories of his subjects. The absence of a substantial change in the effect of 3.0 mg/kg morphine during the course of the present study (cf. Fig. 1) suggests that

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tolerance to the effect of morphine did not occur and, therefore, tolerance could not be responsible for the absence of a rate-increasing effect of morphine. Acknowledgements. This research was supported by U.S. Public Health Service Grants MH 02094, MH 07658, MH 07084 and DA 00499 with facilities and services furnished by the New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts (U.S. Public Health Service Grant RR 00168, Division of Research Resources, National Institutes of Health). Preparation of the manuscript was supported by U.S. Public Health Service Grants DA 01161 and RR 00165, Division of Research Resources, National Institutes of Health. June Ludlam provided technical assistance in conducting the experiments, and Peggy Plant and Russell Penrod helped in preparing the manuscript and figures.

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Received January 5, 1976; Final Version May 17, 1976