Comparison of the discriminative stimulus properties of nefopam and morphine

Separate groups of rats were trained to discriminate nefopam or morphine from saline in a two-lever operant task. Nefopam produced saline-appropriate responding in morphine-trained rats. The highest dose of morphine tested in nefopam-trained rats produced responding appropriate for neither training treatment. This intermediate morphine responding was antagonized by a naloxone treatment that had no effect on the nefopam discrimination. These results suggest that the stimulus properties of nefopam and morphine are qualitatively different but also that morphine produces effects related to those that result in stimulus control by nefopam.To whom offprint requests should be sent     

Effects of nimodipine on the discriminative stimulus properties ofd-amphetamine in rats

The discriminative stimulus (DS) properties ofd-amphetamine (AMP) are thought to be mediated by enhanced release of catecholamines, which may involve neuronal calcium influx through voltage sensitive channels. The present study examined the influence of nimodipine, a calcium channel blocker, on the DS properties of AMP. Rats (N=8) were trained to discriminate AMP (0.5 mg/kg, IP) from saline in a two-lever, food-reinforced, drug discrimination paradigm. Nimodipine alone (2.0–5.6 mg/kg, IP) did not substitute for AMP. When given in combination with AMP, 2.0 mg/kg nimodipine increased by less than 2-fold the AMP dose necessary to induce AMP-appropriate responses. Higher doses of nimodipine combined with AMP did not increase the magnitude of this effect. Nimodipine enhanced the effects of AMP on response rate. Haloperidol (0.125 mg/kg) increased by approximately 4-fold, whereas diazepam (0.5 or 1.0 mg/kg) and morphine (5.0 mg/kg) increased by approximately 2-fold the AMP dose necessary to induce AMP-appropriate responses. The interaction with AMP was associated with enhanced reduction of response rate in the tests with diazepam and morphine but not haloperidol. These results suggest that nimodipine attenuates the DS properties of AMP, probably in a non-specific way, due to the ability of nimodipine itself to induce a discriminable internal state.     

Discriminative stimulus properties of psychomotor stimulants in the cat

Cats were trained to choose between two levers of an operant chamber using interoceptive cues provided by d-amphetamine or saline as the discriminative stimuli. Following training, stimulus generalization was observed to additional doses of d-amphetamine and cocaine, but not to morphine. Clozapine blocked the generalization of the drug discrimination response to d-amphetamine, but had no effect on generalization to cocaine. These data indicate that discriminative stimulus properties of psychomotor stimulants, previously described in rats, are similar in cats.     

The discriminative stimulus and subjective effects of d-amphetamine in humans

Seventeen normal, healthy adults were trained to discriminate between orally administered d-amphetamine (AMP; 10 mg) and placebo. Standardized subjective effects questionnaires were used to examine the relationship between the subjective and discriminative stimulus effects of AMP. Seven of the subjects were able to learn the discrimination reliably. These seven discriminators did not differ from the ten nondiscriminators in their subjective ratings of mood in the absence of drug. Discriminators were generally more sensitive than nondiscriminators to the subjective effects of AMP, although this difference in sensitivity reached statistical significance only for ratings of hungry. Stimulus substituion was tested in the discriminators with other doses of AMP (2.5 and 5 mg) and with 10 mg diazepam. The discriminative stimulus properties of AMP were dose-dependent, with 5 mg being the threshold dose. In five of the seven subjects the discriminative stimulus properties of diazepam did not substitute for those of AMP. The results demonstrate that the experimental paradigm can be used successfully to study the discriminative stimulus properties of drugs directly in humans.     

A comparative assay of nefopam,morphine and d-amphetamine

Nefopam is a non-opioid analgesic reported to have some stimulant properties. The subjective, behavioral and physiological effects of nefopam, morphine and d-amphetamine were compared in seven non-dependent substance abusers to assess the abuse potential of nefopam. Morphine and d-amphetamine had significant effects on a number of measures generally consistent with the effects of drugs of the opioid and psychomotor stimulant drug classes. Subjects correctly discriminated between morphine and d-amphetamine. Nefopam was most frequently identified by subjects as being amphetamine-like, though several measures indicated that nefopam produced some sedation. Little or no liking of the effects of nefopam was reported by subjects. Overall, nefopam was one fifth as potent as morphine and one quarter as potent as d-amphetamine in producing subjective and physiological effects. The results indicate that nefopam is neither entirely morphine-like nor d-amphetamine-like. In our opinion, nefopam has a lesser potential to be abused than morphine or d-amphetamine. Offprint requests to: Librarian, NIDA Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224, USA     

Apomorphine as a discriminative stimulus, and its antagonism by haloperidol.

At a non-stereotypogenic dose (0.16 mg/kg, s.c.), apomorphine was shown to produce a discriminative stimulus in rats. The apomorphine-produced stimulus was found to be effectively antagonized by haloperidol. It is suggested that apomorphine's ability to stimulate central dopamine receptors is directly related to its cueing action.     

Effects of d-amphetamine and morphine on discrimination: signal detection analysis and assessment of response repetition in the performance deficits

Signal detection analysis was used to examine the effects of d-amphetamine and of morphine on auditory discrimination in female rats. The probability of response repetition in the discrete trial two-choice discrimination procedure was used as an additional behavioral measure. d-Amphetamine (0.4–3.2 mg/kg) and morphine (1.88–15.0 mg/kg) decreased the sensitivity measures (A and SI) but did not consistently affect the response bias measures (B and RI). The probability of response repetition was increased by d-amphetamine and was not affected by morphine. It is concluded that the response bias measure B, derived from signal detection theory, and the empirical response bias measure RI, do not discriminate between the different ways in which d-amphetamine and morphine affect discriminative responding, under the conditions of this study.     

Acute tolerance to the discriminative stimulus properties of morphine

Two pigeons were trained to discriminate intramuscular injections of 1.0 mg/kg morphine from water by presenting food after keypeck responses on one key when morphine was administered and after responses on a second key when water was administered. Following training, close to 100% of responses occurred on the appropriate key following administration of 1.0 mg/kg morphine or water. Morphine (0.1–5.6 mg/kg) produced dose-dependent increases in the percentage of morphine-appropriate responses (discriminative stimulus properties) and decreases in the rate of responding. A shift to the right of the morphine dose-effect curve for the discriminative stimulus properties of morphine resulted from a single injection of morphine (10.0 mg/kg) 24 hrs prior to testing (i.e., acute tolerance) but not from a single injection of pentobarbital (17.0 mg/kg). Tolerance to the discriminative stimulus properties of morphine was reversible within five days of the single injection. Tolerance did not develop to the effects of morphine on response rate. Naloxone antagonized both the discriminative stimulus properties and the response rate-decreasing effects of morphine. Thus, a single administration of morphine can alter morphine discriminability without affecting other aspects of behavior.     

The discriminative stimulus and subjective effects of d-amphetamine,phenmetrazine and fenfluramine in humans

The discriminative stimulus (DS) and subjective effects of d-amphetamine (AMP), phenmetrazine (PMT) and fenfluramine (FFL) were studied in a group of normal healthy adults. Subjects (N=27) were trained to discriminate between placebo and 10 mg AMP (PO). Fourteen of the subjects (discriminators) reliably learned the discrimination, whereas the other 13 did not. Nearly all discriminators labelled AMP as a stimulant, and AMP, relative to placebo, increased ratings of drug liking and general activity level, and produced typical stimulant-like subjective effects, as measured by the Profile of Mood States, the Addiction Research Center Inventory, and a series of visual analog scales. The discrimination accuracy of discriminators increased as a function of hour after drug ingestion, as did analog ratings of how certain subjects were that their discrimination responses were correct. Discriminators were tested with doses of PMT (25 and 50 mg) and FFL (20 and 40 mg) to determine whether the DS properties of these drugs would substitute for those of AMP. Both doses of PMT consistently substituted for AMP, and PMT produced subjective effects very similar to those of AMP. Conversely, neither dose of FFL consistently substituted for AMP, and FFL produced essentially no subjective effects. These findings are consistent with results from discrimination studies with other species, and provide further evidence of the validity of this procedure for studying the DS properties of drugs in humans. Offprint requests to: L.D. Chait     

Effects of haloperidol and d-amphetamine on perceived quantity of foods and tones

The hypothesis that dopamine (DA) receptor agonists and antagonists affect hedonia associated with natural rewards was tested, using a psychophysical procedure previously shown to be sensitive to both the sweetness of food and the motivational state of rats. Rats were first trained to discriminate between two different quantities of a rewarding stimulus by pressing one of two levers. Perceived quantity was subsequently derived from generalization trials of intermediate quantities. Haloperidol (0.03–0.083 mg/kg), a DA receptor antagonist, did not influence perceived food quantity, an indirect marker of hedonic value. On the other hand, d-amphetamine (0.25–1.0 mg/kg) affected perceived food quantity in a dose-dependent fashion, and in the same direction as occurs after increasing hunger or food sweetness. Both haloperidol and amphetamine influenced the perceived quantity of a stimulus without natural reinforcing properties (a tone), but the effect of amphetamine on the perceived quantity of this initially neutral stimulus was opposite in direction to that observed with food. These results suggest that whereas amphetamine affects hedonic processes, haloperidol does not. In addition, it seems that haloperidol probably produces its actions through effects on motor mechanisms or by interfering with the response-facilitating properties of rewards.     

Effects of d-amphetamine and naloxone on brain stimulation reward

Self-stimulation thresholds were determined in rats by means of a modification of the psychophysical method of limits. Reinforcement values were determined after the administration of d-amphetamine alone, naloxone alone, and naloxone administered concurrently with d-amphetamine. d-Amphetamine yielded dose-related decreases in the threshold (0.25–2.00 mg/kg IP), while naloxone alone (2.0–16 mg/kg IP) caused no consistent changes. For each animal, a dose of d-amphetamine that substantially lowered the threshold was then selected to be administered with varying doses of naloxone. The threshold-lowering effect of d-amphetamine was blocked by naloxone at doses as low as 2.0 or 4.0 mg/kg. This finding suggests the possible involvement of an opiate receptor in the mediation of the enhancement by d-amphetamine of brain stimulation reward.     

Effects of d-amphetamine and morphine on delayed discrimination: Signal detection analysis and assessment of response repetition in the performance deficits

Signal detection analysis was used to examine the effects of d-amphetamine and of morphine on delayed visual discrimination (delay intervals: 0–4–8–16 s) in male rats. The probability of response repetition in the discrete trial two-choice discrimination procedure was used as an additional behavioral measure. d-Amphetamine (0.16–0.33 mg/kg) decreased SI (a measure of the animals' sensitivity to the discriminative stimuli) at delays between stimulus presentation and opportunity for responding of 4–16 s, and did not affect SI at the 0 s delay. Morphine (1–3 mg/kg) decreased SI at all delay conditions. d-Amphetamine, but not morphine, affected RI (a measure of the animals' bias towards responding on one lever or the other) and increased the probability of response repetition. The bias measure B was affected neither by d-amphetamine nor by morphine. It is concluded that d-amphetamine, but not morphine, produces a deterioration of delayed discrimination performance, probably as a result of drug-induced response perseveration. It is suggested that under the conditions of the present study, the selective deterioration of discrimination performance after d-amphetamine at delays which are longer than 0 s may not be primarily related to a drug-induced disruption of a short-term memory mechanism, but may be related to drug effects on response output.     

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     

Acquired preference for morphine but not d-amphetamine as a result of saccharine adulteration

Consumption of morphine sulfate and d-amphetamine was studied in two groups of rats. In a choice situation, preference for both drugs remained low after 46 days of drinking. In two additional groups morphine and d-amphetamine solutions were prepared with 1% saccharine. Morphine drinking was significantly increased by saccharine adulteration, whereas drinking of amphetamine solutions decreased. Addition of saccharine to morphine solutions increased drinking in more than a simple additive way. Saccharine facilitates the acquisition of drug-directed behavior. The slope of the acquisition trials for the morphine-saccharine group was significantly different from horizontal (O-slope) and significantly different from the slope found for the morphine without saccharine group.     

Effects of opiates on the discriminative stimulus properties of dopamine agonists

Two groups of rats were trained to discriminate the dopamine agonists amphetamine (0.75 mg/kg) or apomorphine (0.38 mg/kg) from saline in a two-lever operant task. Various doses of morphine and pentazocine were tested for generalization to and interference with the discriminative stimulus complexes produced by the dopamine agonists. Low doses of morphine appeared to produce a stimulus complex which is similar to that produced by apomorphine, but which differs from that produced by amphetamine. Pentazocine showed no evidence of generalization to either the apomorphine or the amphetamine cue. Neither opiate interfered with the discriminative stimuli produced by the dopamine agonists, although decreases in the number of animals responding occured.     

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.     

Potentiation of morphine analgesia by d-amphetamine

Rats were trained to escape from aversive electrical brain stimulation delivered to the mesencephalic reticular formation (MRF). The threshold for this escape behavior was determined by a modification of the classic psychophysical method of limits. Escape thresholds were determined after the administration of morphine alone, d-amphetamine alone, and the combination of d-amphetamine and an ineffective dose of morphine. Morphine alone caused a dose-dependent raising of the escape threshold (1.0–16.0 mg/kg IP) while d-amphetamine alone (0.06–2.0 mg/kg IP) had no effect or caused a slight lowering of threshold. For each animal, a dose of morphine that produced no change in escape threshold was then selected to be administered concomitantly with various doses of d-amphetamine. The co-administration of morphine and d-amphetamine resulted in a significant, dose-dependent increase in the escape threshold, which was not seen with d-amphetamine alone and was as great or greater in magnitude than the increase seen with the highest dose of morphine tested. The results of this study clearly demonstrate that opiate analgesia is potentiated by concomitant d-amphetamine administration. The mechanisms involved in this potentiation warrant further investigation for the clinical management of pain.     

An experimental paradigm for studying the discriminative stimulus properties of drugs in humans

An experimental paradigm for studying the discriminative stimulus effects of drugs in human subjects is presented. The paradigm was tested by training subjects to discriminate 10 mg d-amphetamine from placebo. Subjects who successfully learned the discrimination were then tested with two lower doses of d-amphetamine and with 10 mg diazepam. The discriminative stimulus properties of d-amphetamine were dose-dependent, and in two of five subjects the d-amphetamine stimulus generalized to diazepam. The simplicity and versatility of the paradigm give it the potential for use in a wide variety of experimental and clinical situations.     

Discrimination of stimulus duration and d-amphetamine in pigeons: A psychophysical analysis

Pigeons discriminated visual stimulus duration in a psychophysical choice procedure. Following short durations, one of two responses was reinforced; following long durations, the other response was reinforced. Discrimination accuracy decreased as a function of increasing dose level of d-amphetamine. Decrements in accuracy were greater for two of three pigeons following long-than following short-stimulus durations. Position response biases increased as dose level incraesed. Similar effects of the drug on behavior occurred over two temporal ranges of stimulus durations studied.The opinions and statements contained herein are the private ones of the writers and are not to be construed as official or reflecting the views of the Navy Department or of the naval service at large.The animals used in this study were handled in accordance with the provisions of Public Law 89-44 as amended by Public Law 91-579, the Animal Welfare Act of 1970 and the principles outlined in the Guide for the Care and Use of Laboratory Animals, U.S. Department of Health, Education and Welfare Publication No. (NIH) 73-23.     

Effects of nicotine and d-amphetamine on intracranial self-stimulation in a shuttle box test in rats

Rats were permitted to turn on and off electrical stimulation of the medial forebrain bundle, by alternating between two photobeams running along opposite walls of a shuttle box. Entry into one beam (the ON beam) triggered the delivery of a succession of short, regularly occurring (1 Hz) pulse trains, which could be terminated by breaking the other (OFF beam). The two beams were frequently reversed. When this occurred, the rat was given a free period of 10 s in which to reorient, and brain stimulation reward was then assessed by the amount of time spent receiving brain stimulation (SST) within a fixed interval of time. SST increased with increasing current intensity.After training, subjects were tested for 10 consecutive days, alternately with saline and nicotine bitartrate (0.4 mg/kg SC base), and received a constant daily dose of the drug (0.4 mg/kg). Initially, nicotine visibly impaired motor performance for several minutes after injection, which may at least partly explain the observed reduction of SST; both effects waned across successive nicotine tests. Later in each 78 min session, nicotine consistently increased SST over a range of current, and drugged subjects entered the photobeams more frequently even when electrical stimulation was unavailable. d-Amphetamine sulphate (0.25, 0.75 mg/kg SC salt), given 15 min before testing, also increased SST and stimulated responding. The possible effects of motor impairment or activation on SST are discussed, and it is concluded that nicotine and d-amphetamine may have enhanced the rewarding properties of medial forebrain bundle stimulation.