The effects of (+/-)-methylenedioxymethamphetamine and (+/-)-methylenedioxyamphetamine in monkeys trained to discriminate (+)-amphetamine from saline

Recently, attention has been focused on (+/-)-methylenedioxymethamphetamine (MDMA), a psychotomimetic agent chemically closely related to the psychomotor stimulant methamphetamine, and also to the hallucinogen mescaline. In the present experiment, the effects of MDMA and (+/-)-3,4-methylenedioxyamphetamine (MDA) were determined in rhesus monkeys that were trained to discriminate intravenously administered (+)-amphetamine (AMPH) from saline in a two-lever, food-maintained paradigm or to discriminate intragastrically administered AMPH from saline in a signalled electric shock avoidance paradigm. MDMA produced 100% drug-appropriate responding in all six monkeys, regardless of the procedure and route of administration while MDA substituted completely for AMPH in only two of three monkeys in each paradigm. The results suggest that MDMA has subjective effects that are similar to those of AMPH while MDA is somewhat less like AMPH.     

Neurometabolic effects of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine in healthy volunteers. A double-blind, placebo-controlled PET study with [18F]FDG.

The neurometabolic effects of the hallucinogen psilocybin (PSI; 0.2 mg/kg), the entactogen 3,4-methylenedioxyethylamphetamine (MDE; 2 mg/kg) and the stimulant d-methamphetamine (METH; 0.2-0.4 mg/kg) and the drugs' interactions with a prefrontal activation task were investigated in a double-blind, placebo-controlled human [F-18]fluorodeoxyglucoseFDG-positron emission tomographicPET study (each group: n = 8). Subjects underwent two scans (control: word repetition; activation word association) within 2-4 weeks. Psilocybin increased rMRGlu in distinct right hemispheric frontotemporal cortical regions, particularly in the anterior cingulate and decreased rMRGlu in the thalamus. Both MDE and METH induced cortical hypometabolism and cerebellar hypermetabolism. In the MDE group, cortical hypometabolism was more pronounced in frontal regions, with the exception of the right anterior cingulate, which tended to be hyperactive. Cognitive activation-related increases in left frontocortical regions were attenuated under all three psychoactive substances, but less so under MDE. Taking into account performance data and subjective reports on task difficulty, these effects may result from different mechanisms across the three groups. Our PSI data are in line with studies on acute schizophrenic patients suggesting frontal overactivity at rest, but diminished capacity to activate prefrontal regions upon cognitive demand. The MDE data support the hypothesis that entactogens constitute a distinct psychoactive substance class, which takes an intermediate position between stimulants and hallucinogens.     

Pavlovian conditioning of psychomotor stimulant-induced behaviours: has convenience led us astray?

In order to classically condition the behavioural effects of psychomotor stimulants within a test context, rats were treated for 10 days with (+)-amphetamine (1.5mg/kg), (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, 30μg/kg) or vehicle prior to a 1h placement into a test box. Conditioned behavioural effects were then measured in the previously drug-paired context after a vehicle injection (drug-free test day). Each rat was videotaped for the 1h test box exposure on days 1, 4, 7 and 10 of the drug conditioning trials, and on the drug-free test day. Eleven of 28 behaviours that were scored for frequency, duration and mean bout duration (bout length) were significantly influenced by at least one of the two drugs. Amphetamine predominantly increased bout lengths while PHNO predominantly increased bout frequency. Only two measures that were influenced by the drugs exhibited clear increases over controls in a manner consistent with a classical conditioning interpretation. Behavioural sensitization clearly occurred to some of the effects of amphetamine and PHNO, but these were not the same effects as those increased on the non-drug day testing for classical conditioning. Most behavioural effects of amphetamine and PHNO are not classically conditioned, and behavioural sensitization to these drugs, while perhaps context-specific, is not due to classical conditioning. Automated measures of behaviours have provided misleading evidence concerning the similarity among behavioural effects of stimulants, sensitization and effects of exposure to an environment previously paired with stimulants. Analysis of transitions between behaviours does not support the view that stimulants increase switching or response competition, or that behavioural reorganization is responsible for sensitization. Rather, it is suggested that stimulants selectively facilitate current stimulus-guided behaviours.     

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.     

Stimulus effects of N-monoethyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDE) and N-hydroxy-1-(3,4-methylenedioxyphenyl)-2-aminopropane (N-OH MDA) in rats trained to discriminate MDMA from saline

Tests of stimulus generalization were conducted using rats trained to discriminate 1.5 mg/kg of N-monomethyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane HCl (MDMA) from saline in order to determine if two structurally related analogs (MDE and N-OH MDA) would produce similar stimulus effects. The MDMA-stimulus (MDMA, ED50 value = 0.76 mg/kg) generalized both to MDE (ED50 value = 0.73 mg/kg) and N-OH MDA (ED50 value = 0.47 mg/kg). Administration of (+)amphetamine resulted in partial generalization (maximum of 49% MDMA-appropriate responding) in the MDMA-trained animals. Taken together with our previous studies showing that MDMA substitutes for the phenylisopropylamine stimulant (+)amphetamine, but that neither MDE nor N-OH MDA substitute for (+)amphetamine or for the phenylisopropylamine hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), the present results [i.e., MDMA-stimulus generalization to MDE, N-OH MDA, but not to (+)amphetamine] suggest that 1) MDMA produces effects other than those that may be considered amphetamine-like, and 2) MDE and N-OH MDA are MDMA-like agents with even less of an amphetamine-like component of action than MDMA itself.     

Does locomotor response to novelty in rats predict susceptibility to develop sensitization to cocaine and PHNO?

It has been suggested that the locomotor response of rats to novelty is positively correlated with motor stimulant effects of acute injections with psychomotor stimulants, and liability to self-administer these drugs. In addition, response to novelty appears to be inversely correlated with an individual's susceptibility to develop behavioural sensitization (an increase in the behavioural response to a given dose of stimulant after repeated treatments). To test some of these putative relationships, 96 rats were allocated to one of two subgroups based on a median split of locomotor responses to novelty. Animals then received 10 successive injections of either vehicle, cocaine (10 mg/kg), or the direct D2 agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO: 15 microg/kg), and locomotor activity was monitored. Conditioning tests and additional sensitization and cross-sensitization tests were conducted. Results showed that locomotor responses to novelty are not significantly correlated with locomotor effects of either acute injection with cocaine or PHNO, or rate of development of behavioural sensitization to these drugs. However, locomotor responses to novelty did predict level of locomotor and stereotypy responses to cocaine, and to a lessor extent to PHNO. Cocaine-treated, but not PHNO-treated, rats exhibited drug-conditioned-like effects. Cross-sensitization between cocaine and PHNO was not observed, indicating independent mechanisms for sensitization. It is concluded that the locomotor response to novelty can predict level of locomotion and stereotypy produced by cocaine and PHNO, but does not predict the degree or rate of behavioural sensitization to either of these drugs.     

Neurochemical analysis of rat strain differences in the startle gating-disruptive effects of dopamine agonists

The disruption of prepulse inhibition (PPI) in rats by dopamine (DA) agonists is used to study the neural basis of strain differences in dopaminergic function. We reported that, compared to Long-Evans (LEH) rats, Sprague-Dawley (SDH) rats are more sensitive to the PPI-disruptive effects of the direct D1/D2 agonist apomorphine (APO) and the indirect DA agonist d-amphetamine (AMPH). This strain difference is heritable, with PPI drug sensitivity following a generational pattern (SDH>N2>F1>LEH) suggestive of additive effects of multiple genes. Here, we assessed the neurochemical bases for these heritable strain differences by measuring tissue levels of dopamine, serotonin (5HT) and their respective metabolites in several forebrain regions after vehicle, APO or AMPH administration. SDH rats were more sensitive than LEH rats to the PPI-disruptive effects of both APO (0.5 mg/kg) and AMPH (4.5 mg/kg). Several significant SDH vs. LEH strain differences in regional neurochemical levels were detected, as were drug effects on these chemicals. However, SDH, LEH and F1 rats did not exhibit differential drug sensitivity in any neurochemical indices measures. These findings suggest that inherited differences in the dopaminergic regulation of sensorimotor gating do not likely reflect differences in presynaptic forebrain dopaminergic or serotonergic processes.     

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 and both isomers of 3,4-methylenedioxyamphetamine (MDA) all produced complete substitution for MDMA. The serotonin-receptor antagonist pirenpirone only partially blocked MDMA discrimination.     

Acute effects of d-amphetamine during the follicular and luteal phases of the menstrual cycle in women

Rationale: Little is known about the interactions between ovarian hormones across the menstrual cycle and responses to psychoactive drugs in humans. Preclinical studies suggest that ovarian hormones such as estrogen and progesterone have direct and indirect central nervous system actions, and that these hormones can influence behavioral responses to psychoactive drugs. Objectives: In the present study, we assessed the subjective and behavioral effects of d-amphetamine (AMPH; 15 mg orally) at two hormonally distinct phases of the menstrual cycle in women. Methods: Sixteen healthy women received AMPH or placebo capsules during the follicular and mid-luteal phases of their cycle. During the follicular phase, estrogen levels are low initially and then rise while progesterone levels remain low. During the mid-luteal phase, levels of both estrogen and progesterone are relatively high. Dependent measures included self-report questionnaires, physiological measures and plasma hormone levels. Results: Although there were no baseline differences in mood during the follicular or luteal phase, the effects of AMPH were greater during the follicular phase than the luteal phase. During the follicular phase, subjects reported feeling more “High”, “Energetic and Intellectually Efficient”, and “Euphoric” after AMPH than during the luteal phase, and also reported liking and wanting AMPH more. Further analyses showed that during the follicular phase, but not the luteal phase, responses to AMPH were related to levels of estrogen. Higher levels of estrogen were associated with greater AMPH-induced increases in “Euphoria” and “Energy and Intellectual Efficiency”. During the luteal phase, in the presence of both estrogen and progesterone, estrogen levels were not related to the effects of AMPH. Conclusions: These findings suggest that estrogen may enhance the subjective responses to a stimulant drug in women, but that this effect may be masked in the presence of progesterone. Received: 26 August 1998/Final version: 19 February 1999     

“Paradoxical” effects of psychomotor stimulant drugs in hyperactive children from the standpoint of behavioural pharmacology

Following a brief review of the effectiveness of psychomotor stimulant drugs in treating childhood hyperkinesis, the hypothesis of a “paradoxical” drug response is examined. The importance of three main factors, besides dosage, derived from consideration of studies in behavioural pharmacology. is assessed: rate-dependency; attention and stereotypy; and subjective and social effects. Rate-dependent effects of drugs in animals occur when the control rate of responding is related to the drug effect. A dose-dependent inverse relationship between control rate and drug effect is generally found within individual cases responding in operant situations, after treatment with stimulant drugs. This rate-dependency also occurs between organisms, such that those organisms with high control rates (for example, of operant behaviour, or spontaneous motor activity) show proportionately smaller increases in rate, or reductions in rate with amphetamine-like drugs. This article extends this form of analysis to hyperactive children in two populations receiving methylphenidate. In a third population, of normal adults and normal children, as well as hyperactive children, an inverse relationship between control rate of activity and the effects of 0.5 mg/kg of d-amphetamine is found, accounting for about 38% of the variability. Therefore, the rate-reducing effects of psychomotor stimulants might arise in part as a consequence of the high rates of control responding in the hyperactive child, rather than from a unique “paradoxical” response. The effects of stimulants on “attention” in hyperactive children similarly might be predicted from studies on normal adults. Some evidence of an “over-focusing” of attention in hyperactive children treated with methylphenidate is presented in a test of cognitive flexibility. This lack of cognitive flexibility might be related to behavioural stereotypies found in animals and Man following stimulants. Finally, many of the subjective and social responses to stimulants in hyperactive children are not necessarily anomalous. The implications for clinical practice and for animal models of the hyperkinetic syndrome are discussed.     

Long-lasting effects of escalating doses of d-amphetamine on brain monoamines, amphetamine-induced stereotyped behavior and spontaneous nocturnal locomotion

The repeated intermittent administration of relatively low doses of amphetamine (AMPH) produces an enduring hypersensitivity to the motor stimulant effects of AMPH (behavioral sensitization), and this is accompanied by enhanced mesotelencephalic dopamine (DA) utilization/release. In contrast, chronic treatment with very high doses of AMPH does not produce sensitization, but is neurotoxic, resulting in the depletion of brain DA (and often other monoamines). However, gradually escalating doses of AMPH provide protection against the neurotoxic effects of higher doses given later. Therefore, the purpose of the present experiment was to determine if a regimen of gradually escalating doses of AMPH, culminating in much higher doses than usually used to study sensitization, would produce neural and behavioral changes associated with AMPH neurotoxicity (DA depletion) or behavioral sensitization (increased DA utilization). Female rats were given 60 injections (2/day) of increasing (1 to 10 mg/kg) doses of d-AMPH, culminating in rats receiving 20 mg/kg/day for four consecutive days. This treatment did not deplete brain DA or serotonin, but did produce a long-lasting enhancement (at least 12 days) in striatal and nucleus accumbens DOPAC concentrations, and DOPAC/DA ratios. These neurochemical changes were accompanied by an enduring hypersensitivity to the stereotypy-producing effects of a subsequent AMPH 'challenge.' In contrast to this enhanced response to a challenge, AMPH-pretreated rats showed a marked reduction in spontaneous nocturnal motor activity. It is concluded that rats can be given escalating doses of AMPH, which mimic to some extent the AMPH 'runs' common in addicts and that this produces neural and behavioral changes consistent with the development of sensitization; not neurotoxicity.     

Changes in Proenkephalin mRNA expression in forebrain areas after amphetamine-induced behavioural sensitization

Acute and repeated psychostimulant administration induces a long-lasting enhanced behavioural response to a subsequent drug challenge, known as behavioural sensitization. This phenomenon involves persistent neurophysiological adaptations, which may lead to drug addiction. Brain dopaminergic pathways have been implicated as the main neurobiological substrates of behavioural sensitization, although other neurotransmitters and neuromodulators may also participate. In order to investigate a possible involvement of opioid systems in amphetamine (AMPH) behavioural sensitization, we studied the AMPH-induced changes in Proenkephalin (Pro-Enk) mRNA expression in forebrain areas in both drug-na?ve and AMPH-sensitized rats. Male Sprague-Dawley rats were sensitized to AMPH by means of a single AMPH (1 mg/kg s.c.) injection and the same dose was injected 7 days later to assess the expression of sensitization. Pro-Enk mRNA levels were evaluated by in situ hybridization in coronal brain sections. AMPH injection induced an increase in Pro-Enk mRNA expression in the nucleus accumbens and the medial-posterior caudate-putamen in drug-na?ve rats. Challenge with AMPH to rats injected 1 week earlier with AMPH induced motor sensitization and increased and decreased Pro-Enk mRNA expression in the prefrontal cortex and the anterior medial caudate-putamen, respectively. Our results suggest that alterations in cortical and striatal enkephalinergic systems could contribute to the expression of AMPH behavioural sensitization.     

(-)-Norpseudoephedrine, but not (+/-)-amphetamine, prevents the increase in fluid intake associated with ethanol presentation in rats

The effects of daily intraperitoneal administration of (+/-)-amphetamine (AMPH: 4 mg/kg) and (-)-norpseudoephedrine (NPE: 15 or 30 mg/kg) on drinking were evaluated in rats allowed to drink water or a 5% ethanol solution during the 5 h following drug administration. AMPH, but not NPE, significantly increased water intake. Substitution of ethanol for water produced a significant increase in fluid intake in the control group, whereas drinking levels remained unchanged in both AMPH and NPE treated rats. Discontinuation of drug treatment during the regimen of ethanol presentation produced a prompt increase in fluid intake in the NPE, but not AMPH, treated groups. Finally, substitution of water for ethanol led to a significant reduction of fluid intake in all the groups. These results suggest that a light (i.e. NPE), but not a strong (i.e. AMPH) psychomotor stimulant, is able to weaken rewarding properties of diluted ethanol.     

Isolation-induced social behavioural deficit in mice and its relation to stimulant drugs

The effect of stimulant drugs was studied in isolated mice on spontaneous motor activity and in the isolation-induced social behavioural deficit test. Amphetamine, atropine, caffeine, oxolinic acid and RU 24969 all increased significantly the spontaneous locomotor activity. The social behavioural deficit was reduced with RU 24969, unchanged with atropine and oxolinic acid, increased with amphetamine and caffeine. These results show that no relation exists between the effect of a drug on spontaneous motor activity on one hand and the social behavioural deficit on the other hand; they confirm the high specificity of the effect of agonists of the 5-HT1B receptors in the social behavioural deficit test; they suggest that an increase in the social behavioural deficit as elicited by amphetamine and caffeine may result from an increase in attention and anxious vigilance.     

Could Modafinil Prevent Psychostimulant Addiction? An Experimental Study in Rats

Addiction is a serious health problem which leads to general social impairment. The period of adolescence plays a significant role in drug abuse liability. Psychostimulants, such as modafinil (MOD), are majorly used by teenagers seeking improvements in cognition, which contributes to its indiscriminate use. This study aimed to investigate the influence of MOD (64 mg/kg by gavage, once a day) treatment during adolescence [post‐natal day (PND) 28‐42] on amphetamine (AMPH, 4 mg/kg i.p.)‐conditioned place preference (CPP) in early adulthood (PND 60). Our findings showed that AMPH increased CPP for the drug and anxiety‐like behaviours; on the other hand, AMPH decreased the number of crossings and recognition index. In addition, AMPH decreased catalase activity and increased reactive species, malondialdehyde and carbonyl protein levels in the hippocampus. AMPH also increased pro‐brain derived neurotrophic factor (BDNF), tyrosine kinase receptor B, dopamine transporter, D1R and decreased BDNF and D2R immunoreactivity. Contrarily, animals pre‐exposed to MOD showed reduced AMPH‐CPP, no locomotor impairment, less anxiety‐like behaviours and no memory deficits. In addition, MOD showed antioxidant activity by preventing AMPH‐induced oxidative damage in the hippocampus. Moreover, molecular analysis showed that MOD was able to modulate the hippocampal dopaminergic system, thus preventing AMPH‐induced impairments. Animals that received MOD during adolescence showed reduced AMPH‐CPP in early adulthood. These unexpected behavioural effects of MOD on CPP could be due to its hippocampal dopaminergic system modulation, mainly by its action on D1R, which is closely linked to drug addiction. Nevertheless, further studies are necessary.     

Behavioral characterization of alpha-ethyltryptamine,a tryptamine derivative with MDMA-like properties in rats

Several reports have speculated that the tryptamine-derived drug alpha-ethyltryptamine (AET) may have effects similar to those of the amphetamine-derived drug 3,4-methylenedioxymethamphetamine (MDMA). Indeed, the US Drug Enforcement Administration has recently placed AET on the Schedule I list because of its putative similarity to MDMA. The Behavioral Pattern Monitor, which quantifies locomotor and investigatory responses of rats, was used to characterize the effects of AET in a paradigm that distinguishes between the effects of traditional hallucinogens, amphetamine-like stimulants, and MDMA-like drugs. First, a dose-response study revealed that all doses of AET tested (5, 10, 20 mg/kg) significantly increased locomotor activity. Locomotor hyperactivity is produced by MDMA or amphetamine-like stimulants, but not by classical hallucinogens, such as LSD or mescaline. Additionally, AET significantly decreased measures of investigatory behavior. Similar decreases occur with MDMA or hallucinogen administration, but not with amphetamine-like stimulant administration. Second, as with MDMA, the locomotor hyperactivity induced by AET was attenuated by pretreatment (10 mg/kg) with the serotonin reuptake inhibitor fluoxetine. Thus, AET, a tryptamine-derived drug, appears to produce an MDMA-like profile of behavioral changes by virtue of releasing presynaptic serotonin.     

Naloxone reduces amphetamine-induced stimulation of locomotor activity and in vivo dopamine release in the striatum and nucleus accumbens.

This study tested the possibility that naloxone (NX), an opioid antagonist, reduces the behavioral effects of amphetamine (AMPH) in rats by attenuating the dopaminergic response to AMPH. In the first experiment, adult, male rats were injected SC with either NX (5.0 mg/kg) or saline and 30 min later received doses of AMPH (0.0, 0.1, 0.4, 1.6, and 6.4 mg/kg) cumulatively at 30-min intervals. Gross locomotor counts following AMPH administration were significantly lower for rats pretreated with NX than for rats pretreated with saline. In the second experiment, the same drug treatments were given while performing microdialysis in either the striatum (STR) or nucleus accumbens (NACC). STR rats treated with vehicle showed a larger percentage increase in DA levels following AMPH treatment than did NACC rats treated with vehicle. NX pretreatment did not affect dopamine concentrations in either brain region. However, compared to pretreatment with saline pretreatment with NX significantly decreased the dopaminergic response to AMPH in the STR. There was no difference between the two groups in the peak dopaminergic response to AMPH in the NACC, but there was a significant AMPH x treatment x time interaction due to differences between the groups during the later portion of the response to 6.4 mg/kg AMPH. There was also a difference in locomotor activity following AMPH treatment between NX- and saline-treated subjects during dialysis. These findings suggest that a decrease in the dopaminergic response to AMPH is the mechanism by which NX attenuates behavioral stimulant effects of AMPH. In addition, there is a difference between the STR and NACC in dopaminergic responsiveness to AMPH.