Tardive dyskinesia: A clinical test of the supersensitivity hypothesis

Dogs were trained to pedal press for drinking water in a noncued, single-spatial alternation task. After the dogs were exhibiting stable performance at or above predetermined criteria levels, they were given three doses of four different drugs (methylphenidate, 0.2, 0.4, and 0.8 mg/kg; d-amphetamine, 0.15, 0.3, and 0.6 mg/kg; cocaine, 0.5, 1, and 2 mg/kg; and phenmetrazine, 0.6, 1.2, and 2.4 mg/kg). In general, all four drugs produced similar changes in performance. The number of correct responses was an especially sensitive indicator of drug effects. All four drugs also produced significant increases in both the average response latency and total session duration, but there were few significant changes in either the total number of responses or number of intertrial interval responses. Relative to d-amphetamine, the potencies of cocaine and phenmetrazine, but not methylphenidate, were generally higher for the measures of single-spatial alternation than for self-administration.     

Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbensd-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, bilateral guide cannulae were implanted within the nucleus accumbens, and experiments began. The effect of isolation rearing upon the reinforcing efficacy of the intravenous self-administration of cocaine (experiment 1), or the bilateral intra-accumbens self-administration ofd-amphetamine (experiment 2) was assessed. Self-administration was made contingent upon the acquisition of a novel lever-pressing response. Two identical levers were available within each operant chamber. Responding on one lever resulted in the delivery of drug (experiment 1: cocaine, 1.5 mg/kg per infusion; experiment 2:d-amphetamine, 0.25 µg/side), responding on the second, control lever was recorded but had no programmed consequences. Animals were not primed with noncontingent infusions at any time. For experiment 1, animals received intra-accumbens infusions of the D1 dopamine receptor antagonist SCH-23390, or the D2 dopamine receptor antagonist sulpiride over two test sessions. Within each session, animals received a cumulative series of doses of each dopamine receptor antagonist. A validation group received doses of each antagonist according to more conventional methods (one dose per session). In either case, intra-accumbens infusions of SCH-23390 or sulpiride enhanced the rate of the self-administration of cocaine in socially reared controls. However, isolation rearing impaired this response to intra-accumbens infusions of the dopamine receptor antagonists. Experiment 2a examined the acquisition of the intra-accumbens self-administration ofd-amphetamine. Socially reared controls acquired readily a selective response upon the drug lever. However, isolation reared animals acquired a selective response at a greatly retarded rate. In experiment 2b, a fulld-amphetamine dose-response function was examined. Isolation rearing impaired the response to a range of doses ofd-amphetamine. In experiment 2c, the infusate (1 µgd-amphetamine per infusion) was adulterated with either SCH-23390 or sulpiride. Adulteration with either dopamine receptor antagonist enhanced the rate of response by socially reared controls. Isolation rearing impaired this response to SCH-23390, and blocked the response to sulpiride. These data are discussed in relation to the functioning of cortico-limbicstriatal systems, with particular reference to the mesoaccumbens dopamine projection.     

The discriminative properties of amphetamine analogues tested in self-administering rats under maintained stimulus control

In a series of experiments, rats trained to self-administer amphetamine, were offered saline instead of amphetamine for self-administration during a 3 hr session. The self-administration behaviour was then extinguished. When a non-contingent injection of d-amphetamine (0.25 mg/kg), phenmetrazine (1.0 or 2.0 mg/kg), or diethylpropion (2.0 mg/kg) was given prior to self-administration of saline, the response rate was elevated, and the extinction delayed, in contradistinction to experiments which started with a non-contingent injection of fenfluramine (0.5 mg/kg) or saline. When fenfluramine instead of saline was offered for self-administration, non-contingent preinjections of amphetamine also increased the response rate.The maintenance of stimulus control in rats self-administering amphetamine was studied by lever contingency shifts. After a mean of 2.27 mg/kg of d-amphetamine, loss of stimulus control occured, and the rats developed a high rate of responding on only one lever.It is concluded that in the doses employed phenmetrazine and diethylpropion have reinforcing properties, whereas fenfluramine has not.     

Bilateral intra-accumbens self-administration ofd-amphetamine: Antagonism with intra-accumbens SCH-23390 and sulpiride

The efficacy ofd-amphetamine to support a selective bilateral intra-accumbens self-administration response was examined. Bilateral intra-accumbens infusions ofd-amphetamine were made contingent upon the acquisition of a lever-pressing response. Two identical levers were available within the operant chamber. Depression of the drug lever resulted in the intra-accumbens delivery of 1 µgd-amphetamine; responses upon the second, control lever were recorded but had no programmed consequences. Animals were not primed with non-contingent infusions ofd-amphetamine at any time during these experiments. Nonetheless, animals readily acquired a selective response upon the drug lever. Removal of thed-amphetamine moiety from the infusate resulted in a large decline in responding, and the abolition of the selectivity of the response for the drug lever. Adulteration of the infusate with either the D₁ dopamine receptor antagonist SCH-23390 or the D₂ dopamine receptor antagonist sulpiride enhanced the rate of response selectively upon the drug lever. Reductions in the dose ofd-amphetamine also increased the rate of response. The effect of co-adulteration of the infusate with both SCH-23390 and sulpiride together was purely additive. The implications of these data for the methodology of intracranial drug self-administration, and the relationship between D₁ and D₂ dopamine receptors within the nucleus accumbens are discussed.     

Comparison of behavior maintained by infusions of eight phenylethylamines in baboons

Doses of eight phenylethylamines were substituted for cocaine on a drug-maintained behavior baseline in baboons. Intravenous infusions of drug were contingent upon completion of 160 lever presses (a 160-response fixed-ratio schedule; FR 160). A 3-h time-out period followed each infusion, permitting a maximum of 8 infusions per day. Fenfluramine was the only drug that did not maintain self-infusion performance at any dose tested. d-amphetamine was approximately 10 times more potent than phentermine, phenmetrazine or diethylpropion, and 20 to 30 times more potent than methylenedioxyamphetamine (MDA), clortermine or chlorphentermine, in maintaining self-infusion behavior. Some doses of d-amphetamine and phentermine produced a cyclic pattern of drug intake over days. Increasing selfinfused doses of all drugs produced a substantial suppression of concurrent food-maintained behavior. There was no clear relation between the potency of the phenylethylamines in maintaining self-infusion performance and the potency in suppressing food-maintained behavior which indicates that different mechanisms may underlie the two effects. Examination of chemical structures indicates that substitution on the phenyl ring may decrease the potency of phenylethylamines in maintaining self-infusion behavior.     

The effects of chlorpromazine on psychomotor stimulant self-administration in the Rhesus monkey

The effects of acute and chronic chlorpromazine treatment on psychomotor stimulant self-administration behavior in the Rhesus monkey were determined. Chlorpromazine treatment significantly increased the frequency of self-administration of cocaine, pipradrol, phenmetrazine, d-amphetamine and methylphenidate. The basis of this effect was thought to either be due to an antagonism of the reinforcing effect of these compounds or an antagonism of those actions of the psychomotor stimulants which may function in limiting their self-administration.This study was supported by NIMH Grant No. 5r-10MH-12084 and by NIMH Grant No. MH-18245-01.     

Influence of intravenous self-administered psychomotor stimulants on performance of rhesus monkeys in a multiple schedule paradigm

Rhesus monkeys were trained to complete three multiple schedules. The schedules consisted of three components: a fixed interval (component 1), a variable interval (component 2), and a fixed ratio (component 3). During components 1 and 2, pressing lever 1 was always reinforced by food delivery. During component 3, pressing lever 2 resulted in either food delivery or intravenous infusions of saline solution, solutions of cocaine, of d-amphetamine, of phenmetrazine, or fenetylline. In schedule I, animals were presented with all three components independent of key-pressing behavior during components 1 and 2. In schedule II the availability of component 2 was dependent on completion of component 1. Component 3 was made available only on completion of component 2. Noncompletion of components 1 or 2 resulted in timeoutperiods of 15 and 10 min, respectively. Schedule III was identical with schedule II, except that in schedule III the completion of components was indicated only by a change in the lever lights. The influence of self-administered drugs on behavior in all three components was evaluated. Self-administration of psychomotor stimulants impaired the performance of animals and delayed completion of components 1 and 2 of schedules I, II, and III. The effects on behavior were similar with low drug intake in schedule III, moderate intake in schedule II, and high drug intake in schedule I. These effects were strong with self-administration of phenmetrazine, moderate with self-administration of cocaine and d-amphetamine, and weak with self-administration of fenetylline.Dedicated to Professor Dr. Herbert Grünewald on the occasion of his sixtieth anniersary.This study was in part supported by a grant of the Federal State Department of Youth. Family and Health of the Federal Republic of Germany     

The effect of non-contingent amphetamine injections on the extinction of food- and drug-reinforced lever pressing in rats

In a series of experiments rats were trained in either drug- or food-reinforced lever pressing. After this training period non-contingent injections of d-amphetamine (0.25 mg/kg), phenmetrazine (1.0 or 2.0 mg/kg), diethylpropion (1.0 mg/kg) or saline were given prior to self-administration of saline or responding without programmed consequences.Single doses of amphetamine, phenmetrazine, diethylpropion or saline were given before saline was offered for self-administration for 2 or 3 hr in rats previously made “dependent” on amphetamine. High rate of responding was observed when amphetamine was given before the session.Rats trained in food-reinforced lever pressing were given single doses of amphetamine, phenmetrazine or saline before the number of responses without programmed consequences were recorded for 3 hr. Low rate of responding was observed for all pre-treatment conditions.A rat trained in food-reinforced lever pressing was given a single dose of amphetamine (10 mg/kg) each day. Single doses of amphetamine, phenmetrazine or saline were given prior to sessions where the number of responses (without programmed consequences) were recorded for 3 hr. Low rate of responding was observed for all pre-treatment conditions.Rats pre-treated with single doses of amphetamine and trained in food-reinforced lever pressing were also given saline pre-treatment where lever pressing was followed by no programmed consequences, when single doses of amphethamine or saline were given before the sessions where the number of responses were recorded for 2 hr. High rate of responding was observed when amphetamine was given before the session.It is concluded that the increased rate of lever pressing for no programmed consequences after single doses of amphetamine is due to the experience of amphetamine during food-reinforced behavior, i.e. the drug acts as a discriminative stimulus for subsequent responding. Also the increased rate of saline self-injections after single doses of an amphetamine analogue can be explained in terms of the drug acting as a discriminative stimulus. It is therefore concluded that the increased rate of responding cannot be explained in terms of a general activity effect of amphetamine or amphetamine analogues.     

Reinforcing effects of methylphenidate: influence of dose and behavioral demands following drug administration

Rationale The reinforcing effects of stimulant drugs such as d-amphetamine, caffeine, and cocaine are modulated by behavioral demands following drug administration.Objective The objective of this study was to assess the reinforcing effects of methylphenidate under different behavioral demands using a modified progressive-ratio procedure.Methods The reinforcing effects of oral methylphenidate (0, 10, 20, and 40 mg) were assessed in seven healthy adult volunteers under both performance and relaxation conditions. Performance sessions required volunteers to complete simple arithmetic problems for three 50-min blocks. Relaxation sessions required volunteers to sit quietly in a semi-reclined position in a darkened room for three 50-min blocks. Two sampling sessions (one performance and one relaxation session) always preceded two self-administration sessions (one performance and one relaxation session) and the order of relaxation and performance sessions was constant within a dose condition.Results Methylphenidate significantly increased break point and number of capsules earned on the modified progressive-ratio procedure as an increasing function of dose under the performance, but not the relaxation, condition. Methylphenidate produced comparable stimulant-like subject ratings under both the performance and relaxation conditions.Conclusion The findings of the present experiment suggest that the reinforcing effects of methylphenidate, like d-amphetamine and cocaine, are influenced by behavioral demands following drug administration.     

Amphetamine self-administration by humans: modulation by contingencies associated with task performance

The effect of task performance feedback and associated monetary earnings on drug self-administration were evaluated using eight subjects in a residential laboratory setting. The hypothesis was that if subjects believed thatd-amphetamine impaired performance and reduced monetary earnings,d-amphetamine self-administration would decrease. Subjects performed computer tasks every day: on certain days that they received capsules, subjects were given bogus feedback regarding their performance (“better” or “worse” than average). On sample days, subjects were required to taked-amphetamine (10 mg BID) or placebo (0 mg BID) capsules. On choice days, subjects could choose between eitherd-amphetamine or placebo. Subjects received feedback on their task performance on 2 sample days and 2 of 4 choice days. Subjects received no feedback on the remaining two choice days. When subjects received no feedback, they chosed-amphetamine over placebo 78% of the time, and when they were given better feedback messages, they chosed-amphetamine 87.5% of the time. In contrast,d-amphetamine self-administration decreased significantly to 25% when subjects were told that it impaired their performance on work tasks and resulted in reduced earnings. In reality,d-amphetamine had little effect on work task performance. However, compared to placebo,d-amphetamine significantly increased subjective ratings of “Stimulated” and “Good Drug Effect” and significantly decreased ratings of “Tired” and “Sleepy”. These results demonstrate thatd-amphetamine served as a reinforcer under conditions in which drug self-administration did not influence monetary earnings, but thatd-amphetamine self-administration could be modified by feedback/monetary earnings. Thus, contingencies associated with performance have important implications for drug use in the workplace.     

Methylphenidate increases cigarette smoking

Rationale Methylphenidate (Ritalin) and d-amphetamine (Dexedrine), stimulants commonly prescribed for behavioral problems associated with atttention deficit hyperactivity disorder (ADHD), produce a similar constellation of behavioral effects. The results of previous studies suggest that d-amphetamine increases rates of smoking and the reinforcing effects of smoking. The effects of methylphenidate on smoking have not been assessed although it is the most commonly prescribed pharmacotherapy for ADHD and individuals with ADHD are at increased risk for smoking. Objective In this experiment the acute effects of a range of doses of methylphenidate (5, 10, 20, and 40 mg) and placebo were assessed in ten cigarette smokers who were not attempting to quit and were without ADHD or other Axis I psychiatric disorders. Methods Each dose of methylphenidate was tested once, whereas placebo was tested twice. One hour after ingesting drug, participants were allowed to smoke ad libitum for 4 h. Measures of smoking included total cigarettes smoked, total puffs, latency to the first cigarette, and carbon monoxide levels. Snacks and decaffeinated drinks were available ad libitum, and caloric intake during the 4-h smoking session was calculated. Results Methylphenidate dose dependently increased the total number of cigarettes smoked, number of puffs, and carbon monoxide levels. As expected, methylphenidate dose dependently decreased the number of food items consumed and caloric intake. Conclusions The results of this experiment suggest that methylphenidate, like d-amphetamine, increases rates of cigarette smoking.     

Discriminative stimulus properties of d-amphetamine-pentobarbital combinations

Pigeons were trained to discriminate IM injections of 1.0 mg/kg d-amphetamine from water, 5.6 mg/kg pentobarbital from water, or 1.0 mg/kg d-amphetamine from 5.6 mg/kg pentobarbital by requiring them to peck different response keys depending on which substance was administered prior to the session. Excellent stimulus control was achieved under all conditions with close to 100% of the responses occurring on the injection-correlated key. In tests with doses different from those used in training, the percentage of responses on the drug key was directly related to drug dose. When d-amphetamine was given to birds trained to discriminate pentobarbital from water or when pentobarbital was given to birds trained to discriminate d-amphetamine from water, responding occurred predominately on the water-correlated key. d-Amphetamine produced a dose-related antagonism of the effects of pentobarbital for birds trained to discriminate pentobarbital from water or from d-amphetamine. Rates of responding on the drug key were generally highes after administration of the drug doses used in discrimination training; but response rates were not systematically related to the percentage of responses occurring on the drug key. All birds were subsequently trained to discriminate a combination of 1.0 mg/kg d-amphetamine and 5.6 mg/kg pentobarbital from either 1.0 mg/kg d-amphetamine or 5.6 mg/kg pentobarbital alone, demonstrating that the discriminative stimulus properties of amphetamine-pentobarbital combinations are different from either drug alone. Several of the drug effects reported were related to the drug discrimination that had been established.Portions of this paper were reported at the 49th annual meeting of the Eastern Psychological Association, Washington, D.C., 1978     

Intravenous self-administration of cocaine and norcocaine by dogs

The potency of cocaine, relative to d-amphetamine, to initiate and maintain intravenous self-administration behavior by dogs (n=5) was determined. Response-contingent infusions of cocaine (at unit doses of 0.15, 0.30 and 0.60 mg/kg/infusion) and d-amphetamine (at unit doses of 0.05 and 0.10 mg/kg/infusion) were available during daily 4-h sessions on a FR1 reinforcement schedule. By comparing the dose-response curves of the two drugs, it was found that 1 mg of amphetamine is equivalent to 5.3 mg of cocaine (95% confidence limits=3.8–9.1 mg). In a second experiment, pretreatment with the -adrenergic antagonist phenoxybenzamine (in doses ranging from 0.125–2.0 mg/kg, IV) did not produce any appreciable changes in responding for cocaine (0.2 mg/kg/infusion) by dogs (n=9). In contrast, when the same animals were pretreated with the dopaminergic antagonist pimozide (in doses ranging from 5–40 mg/kg, IV), subsequent responding for cocaine was increased in a dose-dependent manner. In a third experiment it was determined that norcocaine, the N-demethylated metabolite of cocaine, would maintain self-administration behavior by dogs (n=4) when it was substituted for cocaine. As expected, when saline was substituted for cocaine, responding was not maintained.A preliminary report of these studies was presented at the 61st Annual Meeting, Federation of American Societies for Experimental Biology, April 1977 (Fed. Proc. 36: 1040, 1977)     

Drug level of d- and l-amphetamine during intravenous self-administration

Rats were allowed to self-administer dextro and levo isomers of amphetamine in doses of 0.25, 0.50, 0.75 and 1.0 mg/kg/injection for 6 h/day. Total body level of drug was calculated at the time of responding for each drug injection. Body level of amphetamine initially increased and then decreased (0–2 h), and thereafter remained relatively constant for the remainder of the experimental session (2–6 h). During 2–6 h of self-administration, calculated whole body levels of both d- and l-amphetamine remained relatively constant across injection doses. In another study, blood was removed several times during 2–6 h at the time of responding for drug injection. Again, no difference in blood level of ¹⁴C-amphetamine was found across a range of injection doses. Mean blood levels were 0.48 g/ml for l-amphetamine and 0.18 g/ml for d-amphetamine. Drug intake averaged 2.0 mg/kg/h for l-amphetamine and 0.79 mg/kg/h for d-amphetamine.     

Intravenous self-administration of d- and l-amphetamine by dog.

The relative potency of d- and l-amphetamine to maintain i.v. self-administration behavior was studied. 5 dogs were trained to work for response-contingent drug infusions until a stable drug intake per 4 hr daily session was achieved. Then 2 unit doses of d-amphetamine (0.05 and 0.10 mg/kg/infusion) and 3 unit doses of l-amphetamine (0.20, 0.40 and 0.80 mg/kg/infusion) were evaluated in a parallel line bioassay. Each combination of drug and unit dose was examined separately for 5 consecutive daily sessions. Order of treatment presentation was determined by a Latin square design. By comparing the unit doses of d- and l-amphetamine which yielded the same rate of self-administration it was found that 1 mg of the l-isomer is equivalent to 0.17 mg of the d-isomer.     

Conditioned aversion to saccharin by single administrations of mescaline and d-amphetamine

A constraint upon intravenous drug self-administration techniques is that they are suitable only for assessing positively reinforcing consequences of drug action; they do not permit a distinction among several possible explanations for reduced or zero rates of self-administration by animals. The possibility that there is a significant punishing component to drug administration was investigated in an aversive taste conditioning paradigm. Mescaline, which is refused by monkeys, and d-amphetamine, which is self-administered by both rats and monkeys, were compared. Five min after drinking saccharin solution for the first time, groups of rats were injected intraperitoneally with saline or different doses of each drug. Conditioned taste aversion was clearly demonstrated with both drugs; on a second exposure to saccharin solution, fluid consumption was greatly depressed compared to control values. This was true even with a dose of d-amphetamine (2 mg/kg) known to be self-administered by rats. The results suggest that intravenous drug self-administration may involve a punishing component which is detectable only in an appropriate behavioral test. It was also noted that aversive taste conditioning was demonstrable at doses frequently used in behavioral pharmacological investigations.     

d-amphetamine and adjunctive drinking in rats

In the first experiment four food-deprived rats developed high levels of adjunctive water drinking during daily sessions of intermittent food pellet delivery. When the water was removed and a solution of d-amphetamine sulfate (0.01 mg/ml) put in its place, adjunctive drinking was disrupted towards the end of each session although the rats ingested doses of approximately 0.5 mg/kg daily for over 40 sessions. Consumption of the d-amphetamine solution was increased by injections of several doses of -methyl-p-tyrosine (AMPT). In a second experiment injections of d-amphetamine (0.25, 0.5, 1.0, 2.0 mg/kg) were found to reduce adjunctive water consumption in six rats. It was also found that the actions of the two highest doses of d-amphetamine were reduced by pretreatment with a dose of AMPT (100 mg/kg), which itself slightly reduced levels of drinking. These results suggest that, although adjunctive drinking may be a useful technique for inducing rats to self-administer d-amphetamine, the amount of drug consumed is limited by a direct action of the drug on drinking.     

Cholinergic modulation of an opposed effect of d-amphetamine and methylphenidate on the rearing response

Rats given d-amphetamine (1 mg/kg) engage in frequent, short-duration rearing responses, whereas rats given methylphenidate (1 mg/kg) make less frequent, long-duration responses. The effects on this behavior of mixing d-amphetamine or methylphenidate with scopolamine or physostigmine suggest that this opposed action on rearing response duration is related to cholinergic-catecholaminergic balance. The anticholinergic agent scopolamine produces changes in rearing response duration similar to those produced by d-amphetamine, while the cholinergic agent physostigmine lengthens response duration and further potentiates this effect of methylphenidate.     

Acquisition of IV amphetamine and cocaine self-administration in rats as a function of dose

The effect of dose on the acquisition of IV amphetamine and cocaine self-administration was examined. Three unit doses of amphetamine (0.03, 0.06 and 0.12 mg/kg) and three unit doses of cocaine (0.05, 0.2 and 0.8 mg/kg) were tested in separate groups of ten (amphetamine) or 13 (cocaine) rats. Autoshaping methods were used to train rats to press a lever that resulted in drug infusion under a fixed-ratio (FR) 1 schedule. A daily 6-h autoshaping component non-contingently delivered 60 infusions according to a 60-s random time schedule with ten infusions delivered during the first half of each h. Each day autoshaping sessions were followed by a 6-h self-administration session. The criterion for acquisition was a 5-day period during which a daily mean of 100, 50 or 25 infusions for the three amphetamine doses and 400, 100 or 25 infusions were earned during the 6-h self-administration period for the three cocaine doses, respectively. As dose increased, more rats per group acquired drug self-administration and the mean number of days to meet the acquisition criterion decreased. The percentage of rats acquiring amphetamine self-administration increased with dose and ranged from 80 to 100%. Only one rat at the lowest cocaine dose met the acquisition criterion, but 100 percent of the rats at the two higher doses acquired. During the last 2 days of acquisition, mean infusions decreased and mean drug intake (mg/kg) increased as dose increased. On the last day of acquisition, the time course of infusions during the 6-h self-administration component was characterized by a steady rate of infusions per hour, and number of infusions was inversely related to dose. These findings indicate that the initial available dose of a drug is an important determinant of the rate and probability that successful acquisition will occur.     

Effects of morphine alone and in combination with naloxone or d-amphetamine on shock-maintained behavior in the squirrel monkey

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 a three-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.