Discriminative Stimulus and Self-Reported Effects of Methylphenidate, d-Amphetamine, and Triazolam in Methylphenidate-Trained Humans.

Asymmetrical generalization between drugs on drug-discrimination procedures has been demonstrated for sedative and stimulant drugs in animals and to some extent with sedative drugs in humans. The aim of this experiment was to examine the discriminative-stimulus effects of d-amphetamine in methylphenidate-trained humans. A previous study demonstrated that methylphenidate substitutes for d-amphetamine in d-amphetamine-trained humans. Six healthy human participants first learned to discriminate 30 mg oral methylphenidate. Doses of oral methylphenidate, d-amphetamine, triazolam, and placebo were then tested to determine whether they share discriminative-stimulus and self-reported effects with 30 mg methylphenidate. Methylphenidate and d-amphetamine dose-dependently increased methylphenidate-appropriate responding and produced prototypical stimulant-like effects. Triazolam produced low levels of methylphenidate-appropriate responding and prototypical sedative-like effects. The results of this experiment are concordant with previous studies and suggest that the behavioral effects of oral methylphenidate and d-amphetamine overlap extensively and that the discriminative-stimulus effects of methylphenidate and d-amphetamine are symmetrical. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative-stimulus and participant-rated effects of methylphenidate, bupropion, and triazolam in d-amphetamine-trained humans.

The discriminative-stimulus and participant-rated effects of a range of doses of d-amphetamine (2.5–20 mg), methylphenidate (5–40 mg), bupropion (50–400 mg), and triazolam (0.0625–0.5 mg) were tested in 5 humans trained to discriminate between oral d-amphetamine (20 mg) and placebo. d-Amphetamine and methylphenidate generally dose dependently increased drug-appropriate responding. Bupropion and triazolam on average occasioned less than or equal to 40% drug-appropriate responding. d-Amphetamine, methylphenidate, and bupropion produced stimulant-like participant-rated effects, while triazolam produced sedative-like effects. These results further demonstrate that the acute behavioral effects of d-amphetamine and methylphenidate overlap extensively in humans, which is concordant with preclinical studies. Bupropion produced some d-amphetamine-like, participant-rated drug effects but did not occasion significant levels of d-amphetamine-appropriate responding. These findings are concordant with previous findings of a dissociation between the discriminative-stimulus and participant-rated effects of drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nicotine as a conditioned stimulus: Impact of attention-deficit/hyperactivity disorder medications.

People diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at an increased risk to start smoking and have greater difficulty quitting. Nicotine, one of the principal addictive components of tobacco smoke, functioned as a conditioned stimulus (CS) for intermittent sucrose delivery in a Pavlovian drug discrimination task with rats. This study compared the ability of commonly prescribed ADHD medications (i.e., methylphenidate, atomoxetine, and bupropion) and additional dopamine reuptake inhibitors (i.e., cocaine and GBR 12909) to substitute for the CS effects of nicotine. Atomoxetine was also used to antagonize these CS effects. Rats acquired the discrimination as evidenced by increased dipper entries in nicotine (0.2 mg base/kg) sessions as compared with saline sessions. Nicotine generalization was dose dependent. Bupropion (10 and 20 mg/kg), methylphenidate (10 mg/kg), and cocaine (5 and 10 mg/kg) partially substituted for the 0.2 mg/kg nicotine CS. Atomoxetine did not substitute for the nicotine CS; however, atomoxetine (1 to 10 mg/kg) partially blocked nicotine's CS effects. These results suggest that atomoxetine, bupropion, and/or methylphenidate may be effective treatments for people diagnosed with ADHD and addicted to nicotine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral pharmacological similarities between methylphenidate and cocaine in cocaine abusers.

Six human participants with recent histories of cocaine use were trained to discriminate 200 mg oral cocaine hydrochloride. A range of doses of oral cocaine (50–300 mg), methylphenidate (15–90 mg), triazolam (0.125–0.75 mg), and placebo were then tested to determine whether they shared discriminative–stimulus and participant-rated effects with 200 mg cocaine. Cocaine and methylphenidate dose-dependently increased cocaine-appropriate responding, produced prototypical stimulant-like participant-rated drug effects (e.g., increased participant ratings of Drug Liking), and increased heart rate and blood pressure. Triazolam produced low levels of cocaine-appropriate responding and impaired performance. Thus, consistent with previous studies, humans can reliably discriminate oral cocaine. Consistent with in vivo behavioral neuropharmacological data, the discriminative–stimulus, participant-rated, and physiological effects of oral cocaine and methylphenidate were similar. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Characteristics of unlimited access to self-administered stimulant infusions in dogs

When drug-naive dogs were given unlimited access to response-contingent intravenous infusions of either d-amphetamine, phenmetrazine, or methylphenidate, a regular cycle of drug intake interspersed with periods of voluntary abstinence was seen. During the drug self-administration phases there was a marked increase in locomotor behavior and stereotypy along with a decrease in body weight; the rest periods were characterized by minimal activity. These results are similar to those observed when humans engage in high-dose intravenous abuse of psychomotor stimulants.     

Aripiprazole as a potential pharmacotherapy for stimulant dependence: Human laboratory studies with d-amphetamine.

Amphetamine and cocaine dependence present significant public health concerns, yet no broadly effective pharmacotherapy for stimulant dependence has been developed. Two human laboratory studies are reviewed that tested the ability of aripiprazole, a novel antipsychotic with partial agonist activity at D2 dopamine receptors, to alter the behavioral effects of stimulants using d-amphetamine as a model agent. In each of these experiments, volunteers learned to discriminate 15 mg d-amphetamine (i.e., ≥80% drug-appropriate responding over 4 consecutive sessions). The effects of a range of doses of d-amphetamine (0, 2.5, 5, 10, and 15 mg) were then tested alone and following pretreatment with aripiprazole (20 mg in Experiment 1; 10 mg in Experiment 2). In Experiment 1, aripiprazole (20 mg) attenuated the discriminative stimulus and many of the subject-rated effects of amphetamine. Aripiprazole alone produced performance decrements. To determine whether a lower dose of aripiprazole would also attenuate the behavioral effects of d-amphetamine without impairing performance, Experiment 2 was conducted. Aripiprazole (10 mg) failed to alter the discriminative-stimulus effects but attenuated some of the subject-rated effects of d-amphetamine. This dose of aripiprazole did not impair performance. The results of these experiments indicate that aripiprazole may have clinical utility in treating stimulant dependence. Future human laboratory research should better model the clinical use of aripiprazole by examining the effects of chronic aripiprazole combined with either methamphetamine or cocaine in dependent individuals. A large-scale clinical trial is also needed to evaluate the efficacy of aripiprazole for the treatment of stimulant dependence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Intravenous self-injection of psychomotor stimulant--anorectics in the baboon.

The present study evaluated the intravenous (IV) self-injection of 3 psychomotor stimulantanorectics in 5 baboons (Papio cynocephalus) A cocaine substitution procedure was used. IV self-injections were available 24 hr/day according to a fixed-ratio (FR) schedule with a 3-hr time-out following each injection. Doses of aminorex (0.01–0.32 mg/kg/injection), propylhexedrine (0.1–3.2 mg/kg/injection), mazindol (0.001–0.1 mg/kg/injection), and their vehicles were substituted for cocaine for 15 or more days. A concurrent FR schedule of food pellet delivery allowed evaluation of changes in food intake. The highest dose of each drug maintained self-injection at rates higher than vehicle control, suppressed food intake, and produced gross behavioral changes similar to those produced by classic psychomotor stimulants such as d-amphetamine. The present data indicate that each of the drugs functions as a positive reinforcer in baboons and suggest that each may have abuse potential. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A three-choice discrimination procedure dissociates the discriminative stimulus effects of d-amphetamine and (±)-MDMA in rats.

(±)-3,4-Methylenedioxymethamphetamine (MDMA) produces subjective effects in humans that are similar to, but distinguishable from, those of psychostimulants. Drug discrimination studies in nonhumans have yielded inconsistent results regarding the similarities between MDMA and the psychomotor stimulant d-amphetamine. This study successfully used a 3-choice operant procedure to establish MDMA and d-amphetamine as discriminative stimuli in rats. Cocaine produced complete substitution for d-amphetamine, and LSD produced dose-dependent increases in MDMA-appropriate responding with nearly complete substitution (78%) for MDMA. The hallucinogen 2,5-dimethoxy-4-bromoamphetamine only partially substituted for MDMA and severely disrupted response rate. Fenfluramine, 3,4-methylenedioxyamphetamine-hydrochloride([+]-MDA), and (-)-MDA all produced complete substitution for MDMA. The serotonin-receptor antagonist pirenpirone only partially blocked MDMA discrimination. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reinforcing and Subjective Effects of Methylphenidate: Dose and Time in Bed.

So that reinforcing and subjective effects of methylphenidate as a function of dose and level of sleepiness could be evaluated, 21 volunteers received methylphenidate (5, 10, or 20 mg) or placebo on 2 sampling days. After 4 and 8 hr time in bed (TIB), they chose their preferred capsule on 5 days. Methylphenidate was chosen more frequently after 4 hr TIB (60%) than it was after 8 hr TIB (33%). The strongest preference (68%) was seen in the 10-mg group. At 10 and 20 mg, stimulant-like subjective effects were reported. The 10-mg group was more adversely affected by the restricted bedtime and showed more pronounced drug effects with methylphenidate. These results indicate that sleepiness modulates the reinforcing and subjective effects of methylphenidate. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative and participant-rated effects of methylphenidate in children diagnosed with attention deficit hyperactivity disorder (ADHD)

Despite the demonstrated beneficial effects of methylphenidate and d-amphetamine for the treatment of attention-deficit hyperactivity disorder (ADHD), the discriminative and subjective effects of these compounds in children are not well understood. This study was designed to characterize such effects in children diagnosed with ADHD. In a series of 3 experiments, 17 children were examined to determine whether methylphenidate (n = 12) and d-amphetamine (n = 5) could be reliably discriminated at doses typically used in clinical practice. Under some conditions (e.g., when they were instructed to attend to the drug effects or when a wide range of doses was used), children discriminated methylphenidate (5.0-30.0 mg) from placebo. Children tested under a range of doses of d-amphetamine (2.5-20.0 mg) were unable to discriminate this drug from placebo reliably. Neither methylphenidate nor d-amphetamine produced reliable participant-rated effects.     

Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine

Methylphenidate promotes a dose-dependent behavioral profile that is very comparable to that of amphetamine. Amphetamine increases extracellular norepinephrine and serotonin, in addition to its effects on dopamine, and these latter effects may play a role in the behavioral effects of amphetamine-like stimulants. To examine further the relative roles of dopamine, norepinephrine, and serotonin in the behavioral response to amphetamine-like stimulants, we assessed extracellular dopamine and serotonin in caudate putamen and norepinephrine in hippocampus in response to various doses of methylphenidate (10, 20, and 30 mg/kg) that produce stereotyped behaviors, and compared the results with those of a dose of amphetamine (2.5 mg/kg) that produces a level of stereotypies comparable to the intermediate dose of methylphenidate. The methylphenidate-induced changes in dopamine and its metabolites were consistent with changes induced by other uptake blockers, and the magnitude of the dopamine response for a behaviorally comparable dose was considerably less than that with amphetamine. Likewise, the dose-dependent increase in norepinephrine in response to methylphenidate was also significantly less than that with amphetamine. However, in contrast to amphetamine, methylphenidate had no effect on extracellular serotonin. These results do not support the hypothesis that a stimulant-induced increase in serotonin is necessary for the appearance of stereotyped behaviors.     

Assessment of the discriminative stimulus effects of the D3 dopamine antagonist PNU-99194A in rats: comparison with psychomotor stimulants

The present study examined the discriminative stimulus effects of the D3 dopamine receptor antagonist PNU-99194A [5,6-di-methoxy-2-(dipropylamino)indan-hydrochloride] in male Sprague-Dawley rats. Eight rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline in a two-choice, water-reinforced drug discrimination procedure. In tests of stimulus generalization, PNU-99194A (1.25-40.0 mg/kg, s.c. and i.p.) did not substitute for cocaine. PNU-99194A (5.0-20 mg/kg) also did not significantly block the discrimination of cocaine (10 mg/kg), nor did it potentiate a low dose (1.25 mg/kg) of cocaine. A separate group of eight rats were trained to discriminate PNU-99194A from saline. These subjects met the discrimination criterion within an average of 68 (S.E.M. = 6.5) training sessions; the ED50 for PNU-99194A was 2.6 mg/kg. In stimulus generalization tests, cocaine (1.25-10 mg/kg) did not substitute for PNU-99194A, when administered by either i.p. or by s.c. injection. In addition, neither amphetamine (0.25-1.0 mg/kg) nor caffeine (8.0-64 mg/kg) produced stimulus generalization in these rats. These results indicate that D3 receptors do not play a critical role in the discriminative stimulus effects of cocaine. Furthermore, although PNU-99194A is capable of establishing and maintaining discriminative stimulus control in rats, the effects of this D3-preferring antagonist are dissimilar from those of psychomotor stimulants. Given the unique behavioral profile of D3 receptor antagonists, the potential utility of these agents as adjunctive treatments for psychostimulant abuse is discussed.     

Reinforcement magnitude modulation of rate dependent effects in pigeons and rats.

Response rate can influence the behavioral effects of many drugs. Reinforcement magnitude may also influence drug effects. Further, reinforcement magnitude can influence rate-dependent effects. For example, in an earlier report, we showed that rate-dependent effects of two antidepressants depended on reinforcement magnitude. The ability of reinforcement magnitude to interact with rate-dependency has not been well characterized. It is not known whether our previous results are specific to antidepressants or generalize to other drug classes. Here, we further examine rate-magnitude interactions by studying effects of two stimulants (d-amphetamine [0.32–5.6 mg/kg] and cocaine [0.32–10 mg/kg]) and two sedatives (chlordiazepoxide [1.78–32 mg/kg] and pentobarbital [1.0–17.8 mg/kg]) in pigeons responding under a 3-component multiple fixed-interval (FI) 300-s schedule maintained by 2-, 4-, or 8-s of food access. We also examine the effects of d-amphetamine [0.32–3.2 mg/kg] and pentobarbital [1.8–10 mg/kg] in rats responding under a similar multiple FI300-s schedule maintained by 2- or 10- food pellet (45 mg) delivery. In pigeons, cocaine and, to a lesser extent, chlordiazepoxide exerted rate-dependent effects that were diminished by increasing durations of food access. The relationship was less apparent for pentobarbital, and not present for d-amphetamine. In rats, rate-dependent effects of pentobarbital and d-amphetamine were not modulated by reinforcement magnitude. In conclusion, some drugs appear to exert rate-dependent effect which are diminished when reinforcement magnitude is relatively high. Subsequent analysis of the rate-dependency data suggest the effects of reinforcement magnitude may be due to a diminution of drug-induced increases in low-rate behavior that occurs early in the fixed-interval. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Role of dopamine in d-amphetamine-induced euphoria in normal, healthy volunteers.

The present study evaluated the role of dopamine in the euphorigenic effects of d-amphetamine in normal volunteers. d-Amphetamine (20 mg) was administered alone and after pretreatment with pimozide (4 mg), fluphenazine (3 or 6 mg), or prazosin (1 or 2 mg) in 3 separate groups of participants. Subjective effects were measured at regular intervals. It was hypothesized that pimozide and fluphenazine, but not prazosin, would attenuate the euphorigenic effects of d-amphetamine. In all studies, d-amphetamine produced robust stimulant-like effects (e.g., increased scores on measures of arousal and euphoria). Although none of the antagonists significantly attenuated subjective responses to d-amphetamine, there were trends for both dopamine antagonists to reduce some responses. Both dopamine antagonists also produced modest effects when administered alone. These findings are inconsistent with those of studies with laboratory animals, perhaps because of differing experimental conditions. Alternatively, these findings raise the possibility that separate processes mediate drug reinforcement and euphoria. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital, and caffeine in zolpidem-trained humans.

Six non-drug-abusing humans were trained to discriminate 15 mg zolpidem in the present experiment. After participants acquired discrimination, a range of doses of zolpidem (2.5–15.0 mg), triazolam (0.0625–0.3750 mg), pentobarbital (25–150 mg), caffeine (100–600 mg), and placebo were tested to determine whether they shared discriminative-stimulus effects with 15 mg zolpidem. The participant-rated and performance-impairing effects of zolpidem, triazolam, pentobarbital, and caffeine were assessed concurrently. Triazolam and pentobarbital dose dependently increased zolpidem-appropriate responding. Caffeine occasioned low levels of zolpidem-appropriate responding. Zolpidem, triazolam, and pentobarbital, but not caffeine, generally produced a similar constellation of participant-rated drug effects (e.g., increased scores for the Pentobarbital, Chlorpromazine, and Alcohol Group subscale on the Addiction Research Center Inventory) and dose dependently impaired performance. These results suggest that humans can reliably discriminate zolpidem. Despite its unique benzodiazepine-receptor binding profile, the discriminative-stimulus, participant-rated, and performance-impairing effects of zolpidem are similar to those of the barbiturates and benzodiazepines. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral effects of psychomotor stimulants in rats with dorsal or ventral subiculum lesions: Locomotion, cocaine self-administration, and prepulse inhibition of startle.

Compelling evidence suggests a primary role for the mesoaccumbens dopaminergic pathway in the behavioral effects of amphetamine and cocaine, but the roles of other projections to the accumbens, including those arising in the hippocampal formation, are less clear. The authors evaluated the effects of discrete excitotoxic lesions of either the dorsal or ventral subiculum on the locomotor activating, reinforcing, and sensorimotor gating-disruptive effects of psychomotor stimulant drugs. Whereas dorsal subiculum-lesioned rats were hyperactive in tests of exploratory locomotion and startle reactivity, ventral subiculum-lesioned rats exhibited an attenuated locomotor response to amphetamine, moderately impaired acquisition of cocaine self-administration, and reduced levels of prepulse inhibition of startle. These 2 behavioral profiles overlap considerably with those previously observed in rats with lesions of the rostrodorsal and caudomedial accumbens, respectively, and suggest that projections from dorsal subiculum to accumbens core and ventral subiculum to accumbens shell exert distinct influences on behavioral responses that are amplified by psychomotor stimulant drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral profiles in rats distinguish among “ecstasy,” methamphetamine and 2,5-dimethoxy-4-iodoamphetamine: Mixed effects for “ecstasy” analogues.

3,4-methylenedioxymethamphetamine (MDMA; “ecstasy”) is a psychoactive drug structurally related to other phenylisopropylamines acting as stimulants or hallucinogens in humans. Although MDMA has a pharmacological identity of its own, the distinction of its acute effects from those of stimulants or even hallucinogens is controversial. In this work, dose-response curves (0.25, 0.5, 1, 3, 5, and 10 mg/kg) representing the acute in vivo effects of MDMA were compared with those of a structurally related stimulant (methamphetamine, MA) and a hallucinogenic analogue (2,5-dimethoxy-4-iodoamphetamine, DOI) in a set of behavioral protocols in rats, including spontaneous psychomotor activity, anxiolytic/anxiogenic-like effects and active avoidance conditioning responses. The behavioral profiles obtained allowed us to differentiate among racemic MDMA, MA, and DOI at different dose ranges. In addition, the evaluation of four MDMA analogues (1, 5, and 10 mg/kg) comprising two well-known MDMA analogues (MDA [3,4-methylenedioxyamphetamine] and MDE (N-ethyl-MDA, believed to substitute for MDMA) and two other structural analogues (MDOH [N-hydroxy-MDA] and MMDA-2 [2-methoxy-4,5-methylenedioxyamphetamine]) showed that none of these exactly resembles MDMA in their pharmacological profiles, highlighting the unique character of this prototypical entactogen. In fact, their effects exhibited similarities with the behavioral profiles of either MA or DOI, as well as novel profiles in specific behavioral paradigms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Abuse liability of flunitrazepam among methadone-maintained patients

Abuse liability and acute subjective and psychomotor effects of flunitrazepam were assessed in ten methadone-maintained males with history of benzodiazepine and alcohol use, who voluntarily participated in a double-blind, controlled, cross-over, randomized clinical trial. There were six experimental sessions in which a single oral dose of flunitrazepam 1, 2, and 4 mg; triazolam 0.5 and 0.75 mg; and placebo was given. Evaluations included physiological measures; psychomotor performance tasks (simple reaction time, Digit Symbol Substitution Test, balance task, Maddox-wing device); and self-administered subjective effects questionnaires [Addiction Research Center Inventory (ARCI), Profile of Mood States (POMS), a series of visual analog scales (VAS)]. All drugs but flunitrazepam 1 mg caused an impairment of psychomotor tasks. Effects were more evident with the highest doses of both drugs. Only flunitrazepam 4 mg produced a significant decrease in balance time. Triazolam 0.75 mg induced increases in sedation measured by ARCI-PCAG, depression in POMS, and VAS-drowsiness scores. Flunitrazepam 4mg caused euphoria-related effects as measured by increases in ARCI-MBG and "high" scores in the VAS. Our findings of flunitrazepam-induced euphoria in methadone-maintained subjects together with epidemiological evidence of flunitrazepam abuse by opioid dependents, suggest that it may be included in the group of benzodiazepines with a relatively high abuse potential.     

The NMDA receptor antagonist MK-801 elicits conditioned place preference in rats

(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate, (MK-801) a potent noncompetitive antagonist of central NMDA receptors, has been hypothesized to have rewarding properties indicative of abuse potential. To test this hypothesis, the effects of MK-801 on the acquisition of a conditioned place preference and on locomotor activity were assessed and compared with d-amphetamine. Both MK-801 (0.03 and 0.1 mg/kg, SC) and d-amphetamine (1.0 mg/kg, SC) administration resulted in the acquisition of a conditioned place preference. However, while both amphetamine and the higher dose of MK-801 produced a behavioral activation during the training period the lower dose of MK-801 did not. These results suggest that MK-801, at doses that produce behavioral activation and below, is rewarding and therefore may have abuse potential.     

Zolpidem is differentiated from triazolam in humans using a three-response drug discrimination procedure

The discriminative stimulus effects of the imidazopyridine hypnotic zolpidem and the classic benzodiazepine hypnotic triazolam were examined in seven healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 20 mg/70 kg zolpidem, and 0.5 mg/70 kg triazolam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made 3.75 h after drug administration. Five out of seven subjects acquired the three-response discrimination. Analyses of standardized and unstructured self-report questionnaires revealed that zolpidem and triazolam produced different profiles of effects; zolpidem was associated with a number of negative somatic symptoms including nausea, blurred vision, visual images/hallucinations, and heavy limbs, whereas triazolam was associated with greater sedative effects. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for zolpidem, relative to triazolam, which is consistent with its somewhat distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure for detecting between-drug differences.