Changes in brain norepinephrine associated with sensitization to d-amphetamine

Pretreatment of B6AF₁/J mice with d-amphetamine HCl 10 mg/kg, twice daily for 5 days, produced a 4-fold increase in the running response to a test dose of 5 mg/kg amphetamine. Amphetamine pretreatment decreased whole-brain norepinephrine levels to 50% of control values and whole-brain dopamine to 85%. The test dose of 5 mg/kg amphetamine lowered whole brain norepinephrine levels of control mice from 0.50 g/g to 0.28 g/g in 2 h. In amphetamine-pretreated mice, this injection caused an increase in whole-brain norepinephrine levels from 0.22 g/g to 0.55 g/g at 30 min, followed by a decrease to 0.22 g/g at 60 min. No change in whole brain dopamine levels was observed in either group. Amphetamine sensitization and norepinephrine depletion were still evident 25 days after pretreatment. No cross sensitization to morphine or cocaine was observed. Reserpine pretreatment resulted in a 3-fold increase in locomotor activity following injection of d-amphetamine, 5 mg/kg. No sensitization or changes in catecholamine levels were observed in amphetamine-treated A/J mice. These results suggest that the sensitization produced by amphetamine pretreatment may be related to the depletion of brain norepinephrine.     

The effects of intraventricular 6-hydroxydopamine and 5,6-dihydroxytryptamine on morphine induced locomotor stimulation

Summary Morphine has a biphasic action on locomotor activity in rats but in mice it mainly causes hyperactivity. The effects of intraventricular 6-hydroxydopamine and 5,6-dihydroxytryptamine (5,6-DHT) on the time course and intensity of the locomotor stimulation were examined in the two species. Pretreatment with 6-OHDA or 5,6-DHT significantly reduced the peak locomotor response of grouped mice and depleted cerebral catecholamines (mostly noradrenaline) and 5-hydroxytryptamine respectively. Pretreatment of mice with 6-OHDA and a monoamine oxidase (MAO) inhibitor depleted dopamine more than 6-OHDA alone and restored the morphine-induced hyperactivity to near normal. d- Amphetamine caused a hyperactivity response similar to morphine in mice but, in contrast to morphine, the peak d-amphetamine locomotor response was not affected by either 6-OHDA or 5,6-DHT. However, in both cases the duration of the d-amphetamine response was shortened and pretreatment with 6-OHDA and the MAO inhibitor potentiated the peak locomotor response.The hyperactivity response produced by morphine in rats, which followed a period of reduced activity, was only slightly diminished by 6-OHDA and 5,6-DHT but was almost completely abolished by pretreatment with 6-OHDA and the MAO inhibitor.These results, which emphasize differences in the way morphine affects monoamine neurones in rats and mice, suggest that morphine relies on catecholamines and 5-hydroxytryptamine to increase motor activity in mice whereas in the rat dopamine and 5-hydroxytryptamine are probably most important in this respect.     

Food deprivation and stimulant self-administration in rats: differences between cocaine and d-amphetamine

The effects of food deprivation (24 h) on response rates of rats self-administering d-amphetamine and cocaine were compared. Food deprivation clearly increased rates of responding for both drugs but did so to a significantly greater extent for cocaine than for d-amphetamine. Consistent with other findings, the results suggest that the neural substrates underlying cocaine and d-amphetamine reinforcement are not identical.     

Genetic analysis of the behavioral response to d-amphetamine in mice

The ambulatory and rearing responses to d-amphetamine were studied in a battery of recombinant inbred strains and in three closely related strains: C57BL/6J, C57BL/10J, and C57BL/6By. Differences in the increase of ambulation (stimulation) caused by d-amphetamine were seen between C57BL/6By and the other two C57BL strains. Analysis of F₁ and backcross matings suggests a one-gene model. A mutation at the genetic locus that affects the response to d-amphetamine seems to have taken place in the C57BL/6By strain. Strain differences in the decrease of rearing behavior (inhibition) produced by the drug were observed in recombinant inbred strains. Although the genetic analysis is not conclusive, it appears to be compatible with regulation by a single major gene.The two single-gene models reported here (one affecting the stimulatory response and the other the inhibitory response to d-amphetamine) may be useful in the study of neural mechanisms involved in stimulation and inhibition of behavior by d-amphetamine.     

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.     

On the role of noradrenaline in psychostimulant-induced psychomotor activity and sensitization

Rationale Psychostimulant drugs exert their behavioral effects primarily through enhancement of monoaminergic neurotransmission. Augmented dopamine activity is thought to play a critical role in the psychomotor stimulant effects of amphetamine and cocaine, as well as in the development of long-term behavioral sensitization evoked by repeated exposure to amphetamine. However, despite the fact that brain dopamine and noradrenaline systems are closely interconnected, the extent to which noradrenergic transmission contributes to these behavioral effects of psychostimulants is a relatively unexplored issue. Objectives By inhibiting noradrenergic neurotransmission with the α₂-adrenoceptor agonist clonidine, the α₁-antagonist prazosin and the β-antagonist propranolol, we investigated the involvement of noradrenaline neurotransmission in the psychomotor stimulant and long-term sensitizing effects of d-amphetamine and cocaine in rats. Methods Clonidine (0.003–0.1 mg/kg), prazosin (0.1–3.0 mg/kg) and propranolol (1.0–3.0 mg/kg) were administered prior to d-amphetamine (1.0 mg/kg), cocaine (15 mg/kg) or apomorphine (1.0 mg/kg) and psychomotor activity was measured. In separate studies, clonidine (0.03 mg/kg), prazosin (1.0 mg/kg) or propranolol (3.0 mg/kg) were co-administered with d-amphetamine (2.5 mg/kg) or cocaine (30 mg/kg) for 5 days, and locomotor sensitization was assessed 3 weeks post-treatment. Results The psychomotor stimulant effect of d-amphetamine, but not that of cocaine or apomorphine, was dose-dependently inhibited by clonidine and prazosin, and enhanced by propranolol. Clonidine, prazosin, and propranolol did not influence the induction of sensitization by amphetamine or cocaine. Conclusions Enhancement of synaptic noradrenaline concentrations contributes to the psychomotor stimulant effect of d-amphetamine, but not cocaine or apomorphine. In addition, noradrenergic neurotransmission is not critically involved in the induction of psychostimulant sensitization.     

Dissociating effects of cocaine and <Emphasis Type="Italic">d</Emphasis>-amphetamine on dopamine and serotonin in the perirhinal,entorhinal, and prefrontal cortex of freely moving rats

Rationale Neuroimaging studies with humans showed widespread activation of the cortex in response to psychostimulant drugs. However, the neurochemical nature of these brain activities is not characterized. Objective The aim of the present study was to investigate the effects of cocaine and d-amphetamine on dopamine (DA) and serotonin (5-HT) in cortical areas of the hippocampal network in comparison to the prefrontal cortex (PFC). Materials and methods We conducted in vivo microdialysis experiments in behaving rats measuring DA and 5-HT in the perirhinal cortex (PRC), entorhinal cortex (EC), and PFC, after application of cocaine (0, 5, 10, 20 mg/kg; i.p.) or d-amphetamine (0, 0.5, 1.0, 2.5 mg/kg; i.p.). Results Cocaine and d-amphetamine dose-dependently increased DA and 5-HT levels in the PRC, EC, and PFC. A predominant DA response to d-amphetamine was only found in the PFC, but not in the PRC and EC. Cocaine increased DA and 5-HT to an equal extent in the PFC and PRC but induced a predominant 5-HT response in the EC. When comparing the neurochemical responses between the drugs at an equal level of behavioral activation, cocaine was more potent than d-amphetamine in increasing 5-HT in the PFC, while no differences were found in the PRC or EC or in the DA responses in all three cortical areas. Conclusions We conclude that cocaine and d-amphetamine increase DA and 5-HT levels in PRC and EC largely to the same extent as in the PFC.     

Effects of chronic<Emphasis Type="Italic"> d</Emphasis>-amphetamine treatment on cocaine- and food-maintained responding under a progressive-ratio schedule in rhesus monkeys

Rationale. d-Amphetamine is a candidate agonist medication for the treatment of cocaine dependence, and evaluation of d-amphetamine effects on abuse-related effects of cocaine in preclinical assays is warranted. Objective. This study was designed to assess the effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a progressive-ratio schedule in rhesus monkeys. The effects of schedule manipulations on cocaine and food-maintained responding were also examined for comparison with d-amphetamine effects. Methods. Key-press responding under a progressive-ratio schedule resulted in the delivery of cocaine (0.032 mg/kg per injection) or 1 g food pellets. The effect of manipulating cocaine dose (saline, 0.001–0.1 mg/kg per injection) or the number of food pellets delivered (0, 1 and 4 pellets) was determined. Subsequently, three schedule parameters were manipulated: (1) starting ratio value, (2) increments of the ratio progression, and (3) duration of post-reinforcer time-outs when the ratio value was constant. Finally, the effects of 10-day treatment with d-amphetamine (0.01–0.1 mg/kg per hour) were examined. Results. Break points increased as a function of cocaine dose or the number of food pellets, and similar break points were maintained by delivery of 0.032 mg/kg per injection cocaine and 1 food pellet. Manipulation of schedule parameters produced similar effects on responding maintained by cocaine (0.032 mg/kg per injection) or food (1 pellet). In contrast, d-amphetamine produced a dose-dependent decrease in cocaine-maintained responding and had less consistent effects on food-maintained responding. Conclusions. These results are consistent with the hypothesis that chronic treatment with d-amphetamine decreases cocaine self-administration in rhesus monkeys, possibly by attenuating the reinforcing effects of cocaine. Electronic Publication     

Evidence for dissociable mechanisms of amphetamine-and stress-induced behavioral sensitization: effects of MK-801 and haloperidol pretreatment

The present study examined the ability of pretreatment with MK-801 or haloperidol to block the induction of behavioral sensitization to amphetamine challenge by repeated immobilization stress in male Sprague-Dawley rats. Fifteen minutes before each of ten 30-min restraint sessions, rats were administered saline, MK-801 (0.01, 0.10 or 0.25 mg/kg IP) or haloperidol (0.10 or 0.25 mg/kg IP). Control rats received the same injection regimen without restraint. An additional experiment examined the ability of MK-801 to block the induction of sensitization by repeatedd-amphetamine. In this experiment, rats were administered saline or MK-801 (0.25 mg/kg IP) 15 min before each of ten amphetamine injections (1.0 mg/kg IP, administered under the same regimen as immobilization stress). Four days after the final immobilization or amphetamine injection, rats were tested for locomotor response to novelty, saline andd-amphetamine (1.5 mg/kg IP). Exposure to repeated immobilization stress significantly enhanced the locomotor response to amphetamine challenge but not to saline challenge whether rats were pretreated with saline, MK-801 or haloperidol. Secondary analysis of dose effects in each pretreatment group revealed that at 0.25 mg/kg, repeated MK-801 in itself induced sensitization to the response to amphetamine in control rats and potentiated stress-induced sensitization in restrained rats. In contrast, the sensitization induced by repeated amphetamine was attenuated by MK-801 pretreatment. Neither dose of haloperidol affected the locomotor response to saline or amphetamine in control or stressed rats. These results indicate that the effects of MK-801 on the induction of sensitization are complex and suggest that amphetamine-and stress-induced behavioral sensitization may arise through different mechanisms.     

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.     

No tolerance to antiaggressive effect of d-amphetamine in mice

Agonistic, locomotor, and stereotyped behavior were measured in male Swiss-Webster mice in their home cage, normally shared with a female, while confronting an intruder mouse. Acute administration of d-amphetamine (2, 4, 8 mg/kg, IP) to resident mice decreased the frequency of attacks toward an untreated intruder, increased the resident's locomotor activity, and induced a small amount of stereotyped behavior. Redetermination of dose-effect functions during chronic treatment (8 or 16 mg/kg/day) indicated that tolerance did not develop to the antiaggressive effect of d-amphetamine. By contrast, the chronically treated mice showed sensitization to amphetamine-induced stereotypies and a diminished sensitivity to the drug's enhancement of locomotor activity. Subsequent tests with cocaine indicated no differences between amphetamine-maintained and saline control animals, providing no evidence for cross-tolerance or cross-sensitization between cocaine's and amphetamine's effects on attack, locomotion, and stereotypies.     

Perseveration and rotational behavior elicited by d-amphetamine in a Y-maze exploratory task: Differential effects of intraperitoneal and unilateral intraventricular administration

Mice received either intraperitoneal (1.0, 3.0, 5.0, or 15.0 mg/kg) or unilateral intraventricular injection (50.0, 100.0 or 200.0 g) or d-amphetamine. Both routes of injection produced circling behavior in a dose-related fashion when animals were tested in a circular alley-way. In contrast, performance in a free running Y-maze alternation task was differentially affected by the route of administration. Whereas intraperitoneal injection induced perseveration (i.e., animals consecutively visited only two arms of the maze), intraventricular injection augmented alternation behavior normally seen in saline-treated mice. It was suggested that Y-maze performance following intraventricular d-amphetamine injection reflects response perseveration, whereas systemic d-amphetamine treatment produced stimulus perseveration (repetition of location rather than direction). Moreover d-amphetamine-induced circling produced by intraperitoneal administration probably is an artifact of drug-induced stimulus perseveration as opposed to motor biases observed following intraventricular injections.     

Facilitation and disruption of the long-term store of memory with neural excitants

Male hybrid mice (C57BL/6J × DBA/2J) were trained for 2 days in a 6-unit brightness discrimination maze. Beginning 24 hr after training, mice were administered daily injections of strychnine sulphate, Metrazol, d-amphetamine sulphate, caffeine citrate, nicotine alkaloid, or saline for 5 days. Forty-eight hr after the injection series was completed, mice were trained to criterion in the maze. Mice administered strychnine sulphate or Metrazol showed significantly better retention than those administered saline while mice administered d-amphetamine sulphate were significantly poorer. Nicotine alkaloid produced a trend toward facilitation, while caffeine citrate had no effect. The observed facilitation and disruption were not due to enhancement or impairment of learning ability and could not be attributed to effects upon the consolidation process.     

Locomotion,stereotypy, and dopamine D1 receptors after chronic "binge" cocaine in C57BL/6J and 129/J mice

We have shown that C57BL/6J and 129/J mice differ in their behavioral response to "binge" pattern cocaine (three daily injections of 15 mg/kg separated by 1 h). To determine if these differences persist during chronic binge cocaine administration, we examined the effects of 14-day binge pattern cocaine on home cage behavior. Since the dopamine D(1) receptor may be an important mediator of cocaine-induced locomotor activity, we examined binding to the dopamine D(1) receptor. Locomotor activity was increased by chronic binge cocaine in C57BL/6J (P<.0001) but not in 129/J mice. C57BL/6J mice developed tolerance to the locomotor-activating effects of cocaine. Stereotypic responses were greater in C57BL/6J than in 129/J mice (P=.03), with neither tolerance nor sensitization in either strain. Dopamine D(1) receptor binding in the nucleus accumbens and olfactory tubercle did not differ between strains and was not affected by chronic binge cocaine. In the caudate putamen, subregion specific strain differences in dopamine D(1) receptor binding were observed; chronic binge cocaine increased dopamine D(1) receptor binding in the caudal (P<.05), but not rostral caudate putamen. There was no correlation between locomotor activity or stereotypy and dopamine D(1) receptor density. Thus, with chronic binge cocaine administration, behavioral differences persist between the C57BL/6J and 129/J mice, and cocaine-induced locomotor activity is not correlated with changes in dopamine D(1) receptor binding.     

Paradoxical constitutive behavioral sensitization to amphetamine in mice lacking 5-HT2A receptors

Rationale

Although locomotor response to d-amphetamine is considered as mediated by an increased release of dopamine in the ventral striatum, blockade of either α1b-adrenergic or 5-HT_2A receptors almost completely inhibits d-amphetamine-induced locomotor response in mice. In agreement with this finding, mice lacking α1b-adrenergic receptors hardly respond to d-amphetamine. However, we show here that, paradoxically, mice lacking 5-HT_2A receptors (5-HT_2A-R KO) exhibit a twofold higher locomotor response to d-amphetamine than wild-type (WT) littermates.

Objectives

To explore why there is a discrepancy between pharmacological and genetic 5-HT_2A receptor blockade.

Materials and methods

Locomotor response and behavioral sensitization to d-amphetamine were measured in presence of prazosin and/or SR46349B, α1b-adrenergic, and 5-HT_2A receptor antagonists, respectively.

Results

Repeating amphetamine injections still increases 5-HT_2A-R KO mice locomotor response to d-amphetamine at a level similar to that of sensitized WT mice. SR46349B (1 mg/kg) has, as expected, no effect in 5-HT_2A-R KO mice. One milligrams per kilogram of prazosin completely blocks d-amphetamine-induced locomotor response in 5-HT_2A-R KO naïve animals but 3 mg/kg is necessary in sensitized 5-HT_2A-R KO mice.

Conclusions

Because naïve 5-HT_2A-R KO mice exhibit an increased cortical noradrenergic response to d-amphetamine, our data suggest that repeated d-amphetamine modifies noradrenergic transmission in 5-HT_2A-R KO mice. Stimulation of specific 5-HT_2A receptors would inhibit noradrenergic neurons. Dramatic decrease in SR46349B efficiency in sensitized WT mice indicates that a disruption of the regulating role of 5-HT_2A receptors on noradrenergic transmission occurs during sensitization and thus represents the physiological basis of behavioral sensitization to d-amphetamine.     

Discriminative stimulus properties of cocaine and d-amphetamine,and antagonism by haloperidol: A comparative study

This paper presents a comparative study of the discriminative stimulus properties of cocaine and d-amphetamine in the rat. Using a discrete-trial, food-reward, two-lever drug discrimination procedure, one group of rats (n = 7) were trained to discriminate 10 mg/kg cocaine from saline, whereas 1.25 mg/kg d-amphetamine served as a cue to a second group (n = 6). Following training, stimulus generalization gradients were determined for cocaine and d-amphetamine in both groups, and so were the antagonistic effects of haloperidol vs the training drug conditions. The results indicate that the acquisition of discrimination proceeded at a comparable rate in the two groups. In both groups, d-amphetamine was about 5 times more potent than cocaine, and individual threshold doses for the two drugs showed a significant correlation. Haloperidol appeared equally effective in antagonizing 1.25 mg/kg d-amphetamine and 10 mg/kg cocaine. These findings converge to suggest that to a large extent the cueing properties of d-amphetamine and cocaine are similar.     

Influence of naloxone upon motor activity induced by psychomotor stimulant drugs

Naloxone, an opioid receptor antagonist, attenuates a wide range of behavioral effects ofd-amphetamine, such as the stimulation of motor activity. To investigate the pharmacological selectivity of the naloxone/amphetamine interaction, we assessed the effects of naloxone (5.0 mg/kg SC) upon motor activity induced in rats by a range of psychomotor stimulant drugs with a mechanism of action either similar to or different from that ofd-amphetamine. Each of the drugs tested caused dose-dependent increases in both gross and fine activity. Naloxone attenuated the gross but not the fine activity response tod- andl-amphetamine, but had no influence upon the other catecholamine-releasing drugs, methamphetamine and phendimetrazine. In contrast, naloxone increased the gross but not the fine activity response to the catecholamine uptake inhibitors cocaine and mazindol, but had no effects upon the motor response to methylphenidate. The responses to other stimulant drugs (apomorphine, caffeine, scopolamine) were unaffected by naloxone pretreatment. The present findings extend the range of conditions under which naloxone and, by inference, endogenous opioid systems, modulate the behavioral response to psychomotor stimulants. However, the differential effects of naloxone upon the motor response to individual stimulant drugs support previous suggestions of fundamental differences in mechanisms of action among these compounds.     

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.     

Effects of E-2078, a stable dynorphin A(1–8) analog, on sedation and serum prolactin levels in rhesus monkeys

Rationale: In previous comparisons with C57BL/6J mice, DBA/2J mice have been characterized as ”hyporesponsive” to cocaine’s rewarding effect in the conditioned place-preference paradigm. This finding contrasts with other studies showing greater sensitivity of DBA/2J mice to the rewarding effects of ethanol and morphine in the place conditioning task. Objectives: The purpose of the present study was to examine cocaine- induced place conditioning in both strains using apparatus and procedures similar to those used previously to assess ethanol and morphine preference conditioning. Methods: Mice from both strains were exposed to an unbiased place-conditioning procedure using 1, 10, or 30 mg/kg cocaine. Conditioning trial duration was 15, 30, or 60 min. Results: In general, C57BL/6J mice displayed a significant conditioned place preference that was relatively unaffected by cocaine dose or trial duration. In contrast, DBA/2J mice showed no place conditioning at the shortest trial duration, but an increasing level of preference as trial duration increased. At the longest trial duration, both strains showed similar levels of place preference. Conclusions: Genetic differences in sensitivity to cocaine’s rewarding effect depend critically on temporal parameters of the place-conditioning procedure. One possible interpretation of these findings is that short trial durations produce conditioned activity responses that interfere more with expression of conditioned place preference in DBA/2J mice than in C57BL/6J mice. More generally, these findings underscore the need for caution when drawing conclusions about genetic differences in place conditioning, especially when using this paradigm to evaluate the effects of gene knockouts or insertions on drug reward. Received: 31 December 1998 / Final version: 15 April 1999     

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.