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.     

Antagonism of the behavioral effects of cocaine and d-amphetamine by prazosin

Key pecking by pigeons was maintained under a 30-response fixed-ratio schedule of food delivery; lever pressing by squirrel monkeys was maintained under a 3-min fixed-interval schedule of food delivery. Administered alone, d-amphetamine (0.1–3.0 mg/kg), cocaine (1.0–3.0 mg/kg) and bupropion (1.0–30 mg/kg) either did not affect or decreased fixed-ratio responding of pigeons, whereas d-amphetamine (0.056–0.3 mg/kg) either increased or decreased (0.56 mg/kg) responding of monkeys maintained under the fixed-interval schedule. Prazosin, a selective centrally-active alpha₁ antagonist, produced a dose-dependent reversal of the rate-decreasing effects of d-amphetamine and cocaine but not of bupropion on fixed-ratio responding in pigeons. Prazosin also reversed both the rate-increasing and rate-decreasing effects of d-amphetamine on fixed-interval responding of squirrel monkeys. In contrast, the non-selective alpha-antagonist phentolamine enhanced d-amphetamine-induced decreases in fixed-ratio responding. These findings suggest that the behavioral effects of d-amphetamine and cocaine are produced at least in part by activation of central alpha₁ receptors. Prazosin may be a useful tool for better understanding the mechanisms through which cocaine, amphetamine, and other abused stimulant drugs exert their potent behavioral effects.     

Effects of d-amphetamine and ethanol alone and in combination on schedule-controlled responding of pigeons

Key pecking by pigeons was maintained under either a 5-min fixed-interval or a 30-response fixed-ratio schedule of food delivery. d-Amphetamine (0.1–1.0 mg/kg) either increased or did not affect overall rates of responding under the fixed-interval schedule; the lowest dose of ethanol (0.5 g/kg) did not affect or slightly decreased response rates, whereas higher doses (1.0–2.0 g/kg) substantially decreased rates. Combinations of low noneffective ethanol doses with most doses of d-amphetamine increased rates of responding under the fixed-interval schedule above those obtained with d-amphetamine alone; decreases produced by the higher doses of ethanol were attenuated by most doses of d-amphetamine. Doses of d-amphetamine (0.1–1.0 mg/kg) and ethanol (0.5–1.5 g/kg) alone generally had no effect on responding maintained under the fixed-ratio schedule; higher doses of these drugs decreased responding. The effects of dose combinations other than the highest ones generally differed little from those obtained with ethanol alone; the effects of high doses of each drug were antagonized by low to moderate doses of the other. Combinations of ethanol with d-amphetamine can result in higher rates of responding than are obtained with either drug alone. Further, effects of the drugs alone and in combination depend on the schedule under which behavior is maintained.     

Comparison of the effects of morphine,pentazocine, cyclazocine and amphetamine on intracranial self-stimulation in the rat

Rats were trained to press a lever in order to stimulate their lateral hypothalamus through a chronically implanted electrode. Dose-response curves were determined for the effects of morphine (0.3–10 mg/kg), pentazocine (1.0–30 mg/kg), cyclazocine (0.03–3.0 mg/kg) and d-amphetamine (0.1–3.0 mg/kg) on responding for intracranial stimulation, and then were redetermined in the presence of one or two doses of naloxone. The three analgesics produced only dose-related decreases in responding with the following relative potencies: cyclazocine>morphine>pentazocine. The well-documented rate-increasing effects of d-amphetamine on intracranial self-stimulation were observed at 0.3 and 1.0 mg/kg of the drug; decreases in responding at 3.0 mg/kg were associated with stereotyped behavior. Naloxone, which had no effect of its own on self-stimulation, increased the dose of the analgesics required to depress response rate in a manner consistent with a competitive antagonism. In contrast, response rates were reduced at all doses of d-amphetamine tested in the presence of naloxone. Thus, the interaction between naloxone and d-amphetamine is qualitatively different from the one between naloxone and the analgesics. This finding extends to intracranial self-stimulation the generality of a previous report of interactions between d-amphetamine and naloxone on behavior in the rat.Publication No. 1303 of the Division of Basic Health Sciences of Emory University. This investigation was supported by USPHS Grant DA-00541.Recipient of Research Scientist Development Award K02-DA00008.     

Effects of chlorpromazine and d-amphetamine on schedule-controlled and schedule-related behavior of rabbits

A lever-lifting response by Dutch Belted and New Zealand White rabbits was maintained in water-deprived animals by 0.25% saccharin solution and in food-deprived animals by food pellets under a multiple 3-min fixed-interval (FI) 30-response fixed-ratio (FR) schedule. Rabbits responding for the saccharin solution had food freely available during the session and in the home cage, whereas those responding for pellets had water continuously available during the session as well as in the home cage. Under nondrug conditions the FR and FI schedules controlled different rates and patterns of responding in the rabbit that were characteristic of those found with other species. In addition, eating or drinking occurred during the inital portion of the FI under the saccharin solution and initial food presentation schedules, respectively. Doses of d-amphetamine (0.1–10.0 mg/kg) increased responding under the FI and FR schedules of food delivery, but increased only FI responding maintained by the saccharin solution. Doses of 3.0–10.0 mg/kg d-amphetamine produced extremely high (300–800% of control) rates of stereotyped perseverative lever responding. Schedule-related eating or drinking were unaffected or decreased at doses of d-amphetamine that increased schedule-controlled responding. Chlorpromazine (0.03–0.3 mg/kg) increased FI responding maintained both by saccharin and food, whereas FR responding generally was unaffected at these dose levels; eating but not drinking was increased with chlorpromazine. Since the behavioral effects of drugs such as amphetamine and chlorpromazine differ somewhat in the rabbit from those found with other typically studied nonhuman mammals, further studies with the rabbit may yield useful information for comparative behavioral pharmacology.     

Role of specific dopamine receptor subtypes in amphetamine discrimination

Biochemical, electrophysiological, and behavioral experiments suggest that the dopamine D-1 and D-2 receptor subtypes functionally interact. In rats trained to discriminate 1.0 mg/kg d-amphetamine, substitution with the D-2 agonist quinpirole (0.1–2.0 mg/kg) produces amphetaminelever responding, whereas the D-1 agonist SKF 38393 (0.3–10.0 mg/kg) elicits only saline-appropriate responding. Combining either quinpirole (0.05–0.5 mg/kg) or SKF 38393 (0.5–10.0 mg/kg) with 0.3 mg/kg d-amphetamine results in dose-dependent increases in amphetamine-lever responding. Conversely, the D-1 antagonist SCH 23390 (0.02–0.1 mg/kg) antagonizes the discrimination produced by 0.7 mg/kg d-amphetamine. Additional combination studies examined the effect of DA receptor drugs on discrimination when quinpirole is substituted in d-amphetamine trained rats. SKF 38393 (0.5–7.0 mg/kg) fails to increase the amphetamine-appropriate lever response produced by either 0.05 or 0.2 mg/kg quinpirole. Similarly, SCH 23390 (0.01–0.1 mg/kg) fails to antagonize the amphetamine-lever responding produced by either 0.2 or 0.5 mg/kg quinpirole. Haloperidol (0.02–0.2 mg/kg) does antagonize the amphetamine-appropriate response produced by quinpirole substitution. The d-amphetamine discrimination studies indicate that stimulating D-2 receptors alone or D-1 receptors in the presence of d-amphetamine yields d-amphetamine-lever responding, and suggests that D-1/D-2 receptors can functionally interact to alter discrimination behavior. Quinpirole substitution, on the other hand, shows an insensitivity to D-1 receptor manipulations.     

Shifting of the d-amphetamine dose-response curve in rats with frontal cortical ablations

Rats trained to bar-press on a FI 15 sec schedule for water reinforcement were administered various doses of d-amphetamine (0.25–4.0 mg/kg) both before and 6–8 weeks after bilateral ablation of frontal cortex. Preoperatively, low doses (e.g. 0.25–0.5 mg/kg) of (d-amphetamine increased responding and high doses (e.g. 2.0–4.0 mg/kg) of d-amphetamine depressed responding. Postoperatively, frontal rats showed larger facilitatory effects in response to low doses of d-amphet-amine but lesser depressant effects in response to high doses of d-amphetamine; the whole dose-response curve was generally shifted higher by the frontal lesions. These results indicate that frontal lesions differentially influence mechanisms mediating two different actions of d-amphetamine.This research was supported by NIMH grant MH21156 and NIMH Research Scientist Development Award (Type 2) DA70082 to S. D. Glick.     

Long-term chlorpromazine in rhesus monkeys: Production of dyskinesias and changes in social behavior

Squirrel monkeys responded under a multiple schedule in which 30 responses during a specified time limit resulted in either food presentation or termination of visual stimuli associated with impending shock delivery. Schedule components were associated with different colored lights and were separated by 60-s timeout periods in which all lights were extinguished. If the response requirement was not met within the time limit, either the time-out period alone (food components) was presented or a single shock was delivered coincident with onset of time-out. In experiments with d-amphetamine, different control rates of responding were engendered by varying the time limit. When the time limit was 60 s, all monkeys responded at higher overall rates during food presentation components. When the time limit was reduced to 15s, rates of responding in both components increased and became more similar than under the 60-s limit. When control rates in the two components differed under the 60-s time limit, d-amphetamine sulfate (0.01–1.0 mg/kg) increased the normally lower rates under the shock schedule at intermediate doses, but generally only decreased the higher rates under the food schedule. With more comparable control rates under the 15-s time limit, the effects of amphetamine were also more comparable. In most cases low and moderate doses either had little effect or slightly increased responding in both schedule components and higher doses decreased responding. Morphine sulfate (0.03–1.7 mg/kg) and clozapine (0.1 – 3.0 mg/kg) decreased responding comparably under both food and shock schedules with the 15-s time limit.     

Disruption of primate social behavior by d-amphetamine and cocaine: Differential antagonism by antipsychotics

Psychostimulants lead to withdrawal from social interactions and to a decline of affective behavior in squirrel monkeys. These changes, in addition to motor stereotypies, may be related to stimulant-induced psychosis in humans. In the first of two series of experiments, 1 mg/kg d-amphetamine or 10 mg/kg cocaine, administered orally three times over 24 h to one adult male member of an established group (n=6–9), engendered stereotyped movements of the head and hands, reduced rest postures, and greatly reduced all forms of social initiatives. Chlorpromazine (0.25–1.0 mg/kg), haloperidol (0.25, 0.5 mg/kg), and physostigmine (0.04, 0.08 mg/kg), administered before the third amphetamine or cocaine injection, blocked the motor stereotypies and hyperactivity. Chlorpromazine, haloperidol, and physostigmine did not reliably antagonize the pronounced reduction in social behavior. The second series of experiments focused on agonistic behavior in the context of resident-intruder confrontations and on affiliative behavior toward group members. d-Amphetamine (3×0.5 mg/kg) and, to a lesser extent, cocaine (3×10 mg/kg) decreased affiliative and agonistic behavior. Chlorpromazine (0.5, 1.0 mg/kg) and haloperidol (0.1, 0.25 mg/kg) did not block the severe disruption of the affiliative and agonistic behavior in amphetamine-treated monkeys; physostigmine (0.06 mg/kg) reversed the decline in time spent close to the familiar monkey in amphetamine-treated monkeys. By contrast, stimulant-induced stereotypies were effectively antagonized by chlorpromazine, haloperidol, and physostigmine. These results suggest that psychostimulant-induced changes in primate social behavior may be mediated by mechanisms other than those underlying motor stereotypies.     

Effects of triadimefon on a multiple schedule of fixed-interval performance: Comparison with methylphenidate, d-amphetamine and chlorpromazine

Triadimefon is a fungicide that has recently been shown to increase motor activity and rates of schedule-controlled responding. These findings indicate that triadimefon resembles psychomotor stimulants and in this respect is a unique pesticide. The present experiment was designed to evaluate triadimefon's effects on performance maintained by a multiple schedule of reinforcement and to compare triadimefon to known psychomotor stimulants. Four rats were trained to perform under a mult FI 1-min FI 5-min schedule of milk reinforcement. They then received a series of dosages of triadimefon (10–170 mg/kg, IP) and of methylphenidate (1–17.3 mg/kg, IP) in a counterbalanced order. Triadimefon increased response rates in both the FI 1-min and FI 5-min components. Methylphenidate did not consistently alter response rates in either component. Temporal patterns of responding were disrupted much more in the FI 5-min component than in the FI 1-min component by both triadimefon and methylphenidate. Performances were then evaluated following a series of dosages of d-amphetamine (0.3–3.0 mg/kg, IP) and chlorpromazine (0.5–2.0 mg/kg, IP). Response rates were increased d-amphetamine in the FI 1-min component but not in the FI 5-min component. Like triadimefon and methylphenidate, d-amphetamine produced a greater disruption of response patterning in FI 5-min than in FI 1-min. Only chlorpromazine decreased response rates in both components. Chlorpromazine also disrupted FI 5-min response patterning, but left FI 1-min patterning intact. Although triadimefon did not closely resemble any of the comparison drugs, it had opposite effects on response rates from chlorpromazine in both components of the schedule and resembled d-amphetamine in its effects on FI 1-min response rates. The rate-increasing effects frequently obtained with psychomotor stimulants were more evident for triadimefon than for either methylphenidate or d-amphetamine.     

Dose- and time-dependent effects of narcotic analgesics on intracranial self-stimulation in the rat

Rats were trained to bar-press in order to obtain electrical stimulation of the medial forebrain bundle through chronically implanted electrodes. Dose-response and time-effect curves were determined for morphine (1.0–30 mg/kg), levorphanol (0.1 to 3.0 mg/kg), methadone (0.1–3.0 mg/kg), meperidine (1.0–30 mg/kg), oxymorphone (0.03–1.0 mg/kg), and d-amphetamine (0.1–3.0 mg/kg). Dose-response and time-effect curves were also determined for morphine (1.0–30 mg/kg) in rats that had received multiple injections of morphine over a period of 3 days. All of the narcotic analgesics produced dose-related decreases in responding; the durations of these decreases were also dose-related. The relative potencies of the five narcotic analgesics with respect to the rate-decreasing effects for self-stimulation responding were: oxymorphone > levorphanol > methadone > morphine > meperidine. In morphine-tolerant rats the rate-decreasing effects of morphine on responding for self-stimulation were attenuated. These findings suggest that narcotic analgesics from diverse chemical families have a similar, predominantly depressant, effect on self-stimulation behavior and that the relative potencies of a series of narcotics for this effect are similar to those demonstrated for other properties of these drugs.     

Some behavioral effects of repeated d-amphetamine administrations

Effects of daily administrations of d-amphetamine were studied on key peck responses of pigeons maintained under a multiple fixed-interval 2-min, fixed-ratio 30-responseschedule. Under the fixed-interval schedule, a pause was followed by a transition to increasing rates of responding until food presentation. Under the fixed-ratio schedule, higher sustained rates of responding were maintained. Low to intermediate doses (0.3-1.0 mg/kg) of d-amphetamine changed the temporal patterns and occasionally increased rates of responding under the fixed-interval schedule. Higher doses decreased rates of responding under bothschedules. With daily injections of 1.0 mg/kg d-amphetamine prior to experimental sessions, the effects of this dose on rates and patterns of responding were attenuated, and d-anphetamine dose-effect curves were shifted to the right, primarily under the fixed-ratio schedule. Similar results were obtained with daily presession injections of 5.6 mg/kg d-amphetamine in a second group of pigeons, except that rates of responding under both schedules were decreased by this daily dose, and did not return completely to control values with repeated injections. In a third group of pigeons, 1.0 mg/kg d-amphetamine administered daily, after experimental sessions, did not alter dose-effect functions for d-amphetamine. In a second experiment, pigeons were trained to peck one response key when given 1.0 mg/kg d-amphetamine and a different key when given presession water injections. Increasing doses of d-amphetamine produced incresing percentages of d-amphetamine-key responses. Repeated administration of 5.6 mg/kg d-amphetamine shifted these dose-effect functions to the right one-half log unit. Results suggested that decreases in reinforcement frequency are not a necessary condition for the development of behavioral tolerance to d-amphetamine.     

Alterations by centrally acting drugs of the suppression of self-stimulation behavior in the rat by tetrabenazine,physostigmine, chlorpromazine and pentobarbital

The effects of pre-treatment (32 min) with d-amphetamine (2 mg/kg), scopolamine (0.5 mg/kg), and chlordiazepoxide (5 mg/kg) were studied on the suppression of self-stimulation behavior in the male albino rat by central depressants. The antagonism of each compound was determined against the suppressant action of tetrabenazine (2 mg/kg), physostigmine (0.1 mg/kg), chlorpromazine (2.5 mg/kg) and pentobarbital sodium (10 mg/kg).Against the suppression produced by tetrabenazine, only d-amphetamine gave partial protection throughout the test. Scopolamine and chlordiazepoxide had a transient delaying action. Against the suppressant effect of chlorpromazine, protection was given by d-amphetamine, scopolamine and chlordiazepoxide.Against physostigmine, scopolamine gave full protection, d-amphetamine partial protection, and chlordiazepoxide was without effect.Against the effect of pentobarbital on self-stimulation behavior, there was no protection by d-amphetamine and scopolamine when the animal showed motor deficits, and a stimulant action when these had worn off, but the rates of responding were still depressed. Chlordiazepoxide potentiated the action of pentobarbital.These results are interpreted in terms of a short-run stimulant action on depressed rates of responding, and a longer-run protective action against changes produced by the compounds suppressing self-stimulation behavior in levels of transmitter-like substances.Supported by grant MH-16978, U. S. Public Health Service.The author is indebted to Mrs. S. Foster and Mrs. H. Cevallos for technical assistance.     

Discriminative and reinforcing effects of brotizolam in rhesus monkeys

The reinforcing and discriminative stimulus effects of brotizolam, a benzodiazepine-hypnotic, were evaluated in rhesus monkeys. In one experiment, separate groups of monkeys (N=3/group) were trained to discriminate pentobarbital (10 mg/kg, IG) ord-amphetamine (0.56–1.0 mg/kg, IG) from saline, in a discrete-trials avoidance/escape paradigm. Pentobarbital (5.6–10 mg/kg), diazepam (1.0–1.7 mg/kg), and brotizolam (0.3–1.7 mg/kg) resulted in 100% drug-lever responding in all three pentobarbital-trained monkeys. Ind-amphetamine-trained monkeys brotizolam administration resulted only in saline-lever responding. In another experiment, monkeys were surgically prepared with indwelling intravenous catheters and lever pressing resulted in an injection of 0.1 mg/kg/injection sodium methohexital under a fixed-ratio 10 (FR 10) schedule. Pentobarbital (0.01–0.3 mg/kg/injection) and diazepam (0.003–0.10 mg/kg/injection) maintained responding above saline control levels when substituted for methohexital. Brotizolam (0.001–0.01 mg/kg/injection) resulted in more injections received compared to saline, but fewer injections compared to pentobarbital or diazepam. Thus, results from the present experiment suggest that brotizolam would have pentobarbital-like subjective effects. However, the abuse liability of brotizolam may be lower than that for diazepam.     

Discriminative stimulus properties of cocaine in pigeons

The present study was designed to assess the discriminative stimulus properties of cocaine in pigeons. Six pigeons were trained to discriminate IM injections of cocaine (2 mg/kg) from saline with responding maintained under a fixed-ratio 30 schedule of food delivery. Cocaine, d-amphetamine, and l-cathinone substituted completely for the training dose of cocaine in all pigeons. When nicotine (0.25–4.0 mg/kg), apomorphine (0.03–1.0 mg/kg), procaine (4–32 mg/kg), and lidocaine (4–16 mg/kg) were substituted, both partial substitutions and individual differences between pigeons were observed. Oxazepam (0.5–4.0 mg/kg) and pentobarbital (2–8 mg/kg) failed to substitute for the training dose of cocaine. Discriminative stimulus control by cocaine was greatest when the drug was administered 10–40 min prior to the session and the effects disappeared after 2 h. The substitution results indicate drug class specificity of the cocaine cue but, in addition, suggest its multidimensional nature.     

Interactions of naloxone with morphine,amphetamine and phencyclidine on fixed interval responding for intracranial self-stimulation in rats

Rats were implanted with stimulating electrodes aimed at the medial forebrain bundle-lateral hypothalamus (MFB-LH) and were trained to lever-press for brain self-stimulation on a fixed interval: 60 s schedule of reinforcement. The effects of graded doses of naloxone (0.1–30 mg/kg), morphine (0.3–5.6 mg/kg), naloxone plus morphine,d-amphetamine (0.03–1.0 mg/kg), naloxone plusd-amphetamine, phencyclidine (0.3–5.6 mg/kg), and naloxone plus phencyclidine were tested. Naloxone produced a significant decrease in rates at 30 mg/kg. Naloxone (0.1–1.0 mg/kg) plus morphine blocked the dose-dependent decrease produced by morphine alone. In contrast, naloxone (1.0–10 mg/kg) plusd-amphetamine attenuated the graded increase in response rates produced byd-amphetamine. Naloxone (1.0–10 mg/kg) plus phencyclidine did not reliably change the increase in response rates produced by phencyclidine alone. The use of the fixed interval schedule of brain self-stimulation to study these drug interactions is novel, and further demonstrates that the highly reinforcing aspects of brain stimulation, known to be influenced by dopamine, may also be modulated by the endogenous opiate system.     

Punished behavior: Increases in responding after d-amphetamine

Responding maintained in squirrel monkeys under a 10-min fixed-interval schedule of food presentation was suppressed by presenting a shock after every 30 th response (punishment). During alternate 10-min periods of the same experimental session, but in the presence of a different discriminative stimulus, responding either had no effect (extinction) or postponed delivery of an electric shock (avoidance). During sessions when the avoidance schedule was not in effect, d-amphetamine sulfate decreased punished responding. When the avoidance schedule was present during alternate 10-min periods, however, d-amphetamine (0.01–0.56 mg/kg, i.m.) markedly increased responding during punishment components. Increases in responding during avoidance components were also evident. The effects of d-amphetamine on punished responding depend on the context in which that responding occurs.     

Habituation of aggression in mice: Pharmacological evidence of catecholaminergic and serotonergic mediation

A pharmacological study was undertaken to evaluate the role of catecholamines and serotonin in the mediation of aggression. The dose-effect relationship of d-amphetamine, apomorphine, methysergide, lisuride, and the time-dependent effects of 10 mg/kg p-chloroamphetamine (PCA) were determined on aggressive behavior in a habituation paradigm. The frequency of attacks and sideways threats exponentially declined in ten consecutive confrontations between resident and intruder mice, and recovered when a new intruder was introduced. d-Amphetamine (0.1 – 5.0 mg/kg) and apomorphine (0.03 – 1.0 mg/kg), administered IP 5 min before the first confrontation, attenuated the usual decline of attack and threat in subsequent trials. PCA enhanced attack, sideways threat, and locomotion at day 1 after injection. Methysergide (1, 3, 10 mg/kg) and lisuride (0.03, 0.3, 1.0 mg/kg) suppressed all activity, including locomotion and aggression. The data support the hypothesis that catecholamines mediate the activation of aggression, but do not indicate an inhibitory role for serotonin. Aggression in the resident-intruder paradigm appears to require intact serotonin activity.     

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     

Amphetamine and the reward system: Evidence for tolerance and post-drug depression

Existing reports of tolerance to the behavioral effects of d-amphetamine are most parsimoniously interpreted as reflecting behavioral adaptation to the disruptive effects of the drug rather than physiological tolerance. The present study shows that physiological tolerance does develop to the facilitation of self-stimulation behavior which the drug produces. Rats were trained to bar-press for electrical stimulation of the medial forebrain bundle and tested for facilitation of responding following the administration of 0.25 or 0.50 mg/kg d-amphetamine. Testing was terminated for 4 days during which increasing doses (1.0–12.0 mg/kg) of the drug were given. 16 h after the last injection, the test doses (0.25 or 0.50 mg/kg) no longer produced facilitation of self-stimulation. In addition, testing on the following day with no further drug administration showed a depression of responding indicating depression of the sensitivity of the reward system of the brain.