Alpha1-adrenergic receptors mediate the locomotor response to systemic administration of (+/-)-3,4-methylenedioxymethamphetamine (MDMA) in rats

The recreational drug 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) increases locomotor activity when administered to rats. Although the published pharmacology of MDMA has focused almost exclusively on the roles of serotonin and dopamine, in vitro studies indicate that MDMA induces serotonin and norepinephrine release with equal potency. The present experiments tested the hypothesis that blockade of alpha(1)-adrenoceptors with systemic or local administration of the antagonist prazosin would attenuate the locomotor response to systemic administration of (+/-)-MDMA. Pretreatment with systemic prazosin (0.5 mg/kg) or microinjections into either the prefrontal cortex or ventral tegmental area completely blocked the locomotor stimulant effects of 5 mg/kg (+/-)-MDMA, assessed using a computerized Behavioral Pattern Monitor. Prazosin was more potent in blocking the locomotor stimulant effects of (+/-)-MDMA than a 2 mg/kg dose of (+)-amphetamine that produced a similar locomotor activity increase. These results indicate that activation of alpha(1)-adrenoceptors in both the prefrontal cortex and ventral tegmental areas modulates the locomotor response to MDMA.     

Serotonin synthesis inhibition reveals distinct mechanisms of action for MDMA and its enantiomers in the mouse

Rationale Drug challenges in “intact” and p-chlorophenylalanine (p-CPA)-treated animals can be used to distinguish agents that act as direct serotonin (5-HT) agonists from agents that function as 5-HT releasers. Objectives The objective of the study was to investigate the effect of p-CPA treatment on the capacity of racemic 3,4-methylenedioxymethamphetamine (MDMA) and its stereoisomers to induce the head twitch response, hyperthermia, and locomotor stimulation in mice. Methods Pretreatments with either 100 mg/kg p-CPA or equivolume saline were administered for three consecutive days. The following day, mice were either euthanized (to quantify 5-HT tone), tested with various doses of racemic MDMA or one of its enantiomers in the head twitch assay, or challenged with 32 mg/kg racemic MDMA or one of its enantiomers, while temperature and locomotor activity were monitored via radiotelemetry. Results p-CPA reduced cortical 5-HT turnover by >70% without altering dopamine turnover. Racemic MDMA did not induce a significant head twitch response in intact or p-CPA-treated mice. S(+)-MDMA and R(−)-MDMA elicited similar head twitch curves in intact mice; p-CPA treatment attenuated this response when induced by S(+)-MDMA but not when elicited by R(−)-MDMA. Neither the hyperthermic nor locomotor-stimulant effects of racemic MDMA were altered by p-CPA treatment. The hyperthermic effects, but not the locomotor-stimulant effects, of S(+)-MDMA were attenuated in mice treated with p-CPA. R(−)-MDMA did not alter core temperature or induce significant locomotor stimulation in intact or p-CPA-treated mice. Conclusions The effects of S(+)-MDMA on core temperature and head twitch behavior are consistent with a mechanism involving 5-HT release, whereas the effects of R(−)-MDMA on head twitch behavior are consistent with a direct agonist mechanism of action. The actions of the racemate on core temperature and locomotor activity likely involve a combination of 5-HT release and direct agonism at 5-HT receptors.     

Differential contributions of dopamine D1, D2, and D3 receptors to MDMA-induced effects on locomotor behavior patterns in mice.

MDMA or 'ecstasy' (3,4-methylenedioxymethamphetamine) is a commonly used psychoactive drug that has unusual and distinctive behavioral effects in both humans and animals. In rodents, MDMA administration produces a unique locomotor activity pattern, with high activity characterized by smooth locomotor paths and perseverative thigmotaxis. Although considerable evidence supports a major role for serotonin release in MDMA-induced locomotor activity, dopamine (DA) receptor antagonists have recently been shown to attenuate these effects. Here, we tested the hypothesis that DA D1, D2, and D3 receptors contribute to MDMA-induced alterations in locomotor activity and motor patterns. DA D1, D2, or D3 receptor knockout (KO) and wild-type (WT) mice received vehicle or (+/-)-MDMA and were tested for 60 min in the behavioral pattern monitor (BPM). D1 KO mice exhibited significant increases in MDMA-induced hyperactivity in the late testing phase as well as an overall increase in straight path movements. In contrast, D2 KO mice exhibited reductions in MDMA-induced hyperactivity in the late testing phase, and exhibited significantly less sensitivity to MDMA-induced perseverative thigmotaxis. At baseline, D2 KO mice also exhibited reduced activity and more circumscribed movements compared to WT mice. Female D3 KO mice showed a slight reduction in MDMA-induced hyperactivity. These results confirm differential modulatory roles for D1 and D2 and perhaps D3 receptors in MDMA-induced hyperactivity. More specifically, D1 receptor activation appears to modify the type of activity (linear vs circumscribed), whereas D2 receptor activation appears to contribute to the repetitive circling behavior produced by MDMA.     

Effects of dopamine D1- or D2-like receptor antagonists on the hypermotive and discriminative stimulus effects of (+)-MDMA

Rationale Both dopamine (DA) and serotonin (5-HT) release are evoked by (+)-MDMA; however, little is known of the contribution of DA D₁- and D₂-like receptors (D₁R and D₂R, respectively) in the behavioral effects of (+)-MDMA.Objectives To test the hypothesis that a D₁R or D₂R antagonist would attenuate the hypermotive or discriminative stimulus effects of (+)-MDMA.Methods Male Sprague-Dawley rats (n=164) were pretreated with the D₁R antagonist SCH 23390 (3.125–50 g/kg, SC) or the D₂R antagonist eticlopride (12.5–50 g/kg, SC) prior to treatment with (+)-MDMA (3 mg/kg, SC) and locomotor activity was recorded using photobeam monitors. Twelve additional rats trained to discriminate (+)-MDMA (1 mg/kg, IP) from saline in a two-lever water-reinforced FR20 task were administered SCH 23390 (6.25 g/kg, IP) or eticlopride (12.5 g/kg, IP) prior to (+)-MDMA (0.375–1.0 mg/kg, IP). Rats were then placed in the drug discrimination chambers and the percent (+)-MDMA appropriate responding and response rate were measured.Results Both SCH 23390 and eticlopride blocked (+)-MDMA-evoked hyperactivity in a dose-related manner; the highest doses of the antagonists also effectively suppressed basal locomotor activity. In rats trained to discriminate (+)-MDMA from saline, SCH 23390 (6.25 g/kg), but not eticlopride (12.5 g/kg), blocked the stimulus effects of (+)-MDMA without altering response rate.Conclusion These data indicate that DA released indirectly by (+)-MDMA administration results in stimulation of D₁R and D₂R to enhance locomotor activity. Furthermore, the D₁R appears to play a more prominent role than the D₂R in the discriminative stimulus properties of (+)-MDMA.     

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.     

Drug discrimination studies with MDMA and amphetamine

The term entactogen has recently been introduced to describe a new pharmacological class of compounds best represented by 3,4-methylenedioxymethamphetamine, MDMA, and its alpha-ethyl homologue MBDB. The present study was designed to test the similarities of the discriminative stimulus properties produced by MDMA and MBDB, as well as to elaborate further the distinction between entactogens, hallucinogens and stimulants. Two groups of rats were trained to discriminate saline from either racemic MDMA hydrochloride (1.75 mg/kg) or S-(+)-amphetamine sulfate (1.0 mg/kg) in a two-lever drug discrimination task. The (±)-MDMA cue completely generalized to S-(+)-MDMA, S-(+)-amphetamine, (±)-MDA, S-(+)-MBDB, (±)-MBDB, R-(-)-MDMA, and R-(-)-MBDB, but not to LSD or DOM. The S-(+)-amphetamine cue generalized to (±)-methamphetamine, but not to racemic MDMA or MBDB, nor to their optical isomers. The S-(+)-isomers of both MDMA and MBDB were more potent than the R-(-)-isomers. The results indicate that MDMA and MBDB may share a component of their discriminative stimulus properties which is different from both stimulants and hallucinogens. Although MDA and MDMA have been shown to be amphetamine-like, the lack of stimulant effects for MBDB suggests that amphetamine-like stimulant activity is not necessary for a compound to share discriminative stimulus properties with MDMA.     

MDMA (N-methyl-3,4-methylenedioxyamphetamine) and its stereoisomers: Similarities and differences in behavioral effects in an automated activity apparatus in mice

Racemic MDMA (0.3-30 mg/kg), S(+)-MDMA (0.3-30 mg/kg), R(-)-MDMA (0.3-50 mg/kg) and saline vehicle (10 ml/kg) were comprehensively evaluated in fully automated and computer-integrated activity chambers, which were designed for mice, and provided a detailed analysis of the frequency, location, and/or duration of 18 different activities. The results indicated that MDMA and its isomers produced stimulation of motor actions, with S(+)-MDMA and (+/-)-MDMA usually being more potent than R(-)-MDMA in measures such as movement (time, distance, velocity), margin distance, rotation (clockwise and counterclockwise), and retraced activities. Interestingly, racemic MDMA appeared to exert a greater than expected potency and/or an enhanced effect on measures such as movement episodes, center actions (entries and distance), clockwise rotations, and jumps; actions that might be explained by additive or synergistic (i.e. potentiation) effects of the stereoisomers. In other measures, the enantiomers displayed different effects: S(+)-MDMA produced a preference to induce counterclockwise (versus clockwise) rotations, and each isomer exerted a different profile of effect on vertical activities and jumps. Furthermore, each isomer of MDMA appeared to attenuate the effect of its opposite enantiomer on some behaviors; antagonism effects that were surmised from a lack of expected activities by racemic MDMA. S(+)-MDMA (but not R(-)-MDMA), for example, produced an increase in vertical entries (rearing) and a preference to increase counterclockwise (versus clockwise) rotations; (+/-)-MDMA also should have induced such effects but did not. Apparently, R(-)-MDMA, when combined with S(+)-MDMA to form (+/-)-MDMA, prevented the appearance of those increases (from control) in activities. Similarly, R(-)-MDMA (but not S(+)-MDMA) produced increases in episodes (i.e. jumps) and vertical distance that racemic MDMA also should have, but were not, exhibited. Evidently, the presence of S(+)-MDMA in the racemic mixture inhibited the appearance of those increases (from control) in behavior. Taken together, the various and complex effects of MDMA and its stereoisomers are noted and a strategy is suggested for future studies that stresses the importance of steric effects and interplay, probable interaction(s) with various neurotransmitters, and interaction(s) with the particular behavioral or biological event (or action) being measured.     

A pharmacokinetic analysis of 3,4-methylenedioxymethamphetamine effects on monoamine concentrations in brain dialysates.

Interpretation of the in vivo actions of 3,4-methylenedioxymethamphetamine (MDMA) is complicated by the formation of the active metabolite, 3,4-methylenedioxyamphetamine (MDA). This study evaluates the role of MDA in the dopamine releasing actions of (+)-MDMA. In the study, rats were given subcutaneous doses of (+)-MDMA and concentrations of monoamines and their metabolites in striatal dialysate were measured at 15 min intervals. In parallel experiments, plasma concentrations of (+)- and (-)-MDMA and MDA were determined by GC/MS procedures. The time course of MDMA levels was comparable for the two isomers as were their bioavailabilities. In contrast, the plasma levels of MDA were about three times higher after (+)-MDMA. (+)-MDMA caused a rapid increase in striatal dialysate levels of dopamine and decreased extracellular levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). There was a significant correlation between dopamine concentration in striatal dialysate and plasma MDMA concentration, but not with plasma MDA. These results indicate that MDMA itself has stereoselective actions on dopamine neurons. However, the higher plasma MDA levels after (+)-MDMA may account for part of the enantiomeric differences in the behavioral and neurotoxicological effects of MDMA.     

Pharmacological characterization of the effects of 3,4-methylenedioxymethamphetamine ("ecstasy") and its enantiomers on lethality,core temperature,and locomotor activity in singly housed and crowded mice

Abstract Rationale. Few studies have directly compared the effects of methylenedioxymethamphetamine (MDMA, "ecstasy") and its enantiomers across measures. Objectives. To investigate the capacity of MDMA and its stereoisomers to produce aggregate toxicity in mice, the influence of 5-HT₂ receptors, 5-HT transporters, and ambient temperature on this effect, and to directly compare the racemate and its enantiomers in terms of their effects on core temperature and locomotor activity with and without various serotonergic pretreatments. Methods. Mice were injected with various doses of MDMA and its stereoisomers in various housing conditions, with and without pretreatments of serotonergic drugs, and at two distinct ambient temperatures; lethality was quantified 2 h after MDMA administration. For temperature/activity studies, mice were injected with various doses of MDMA and its enantiomers, with and without ketanserin, MDL100907, or fluoxetine pretreatments, and core temperature and locomotor activity data were collected for 24 h. Results. Racemic MDMA and its isomers produced aggregate toxicity in mice. The lethal effects of racemic MDMA and its enantiomers were differentially attenuated by the various serotonergic pretreatments and manipulation of the ambient temperature across housing conditions. Racemic and S(+)-MDMA produced hyperthermic effects in mice, while R(–)-MDMA did not. The pretreatment drugs attenuated the hyperthermic effects of racemic MDMA, but were less effective in blocking S(+)-MDMA-induced hyperthermia. Racemic MDMA and both enantiomers stimulated locomotor activity, although R(–)-MDMA was least effective. The pretreatments all reduced the locomotor stimulant effects of racemic MDMA but potentiated S(+)-MDMA-induced hyperlocomotion. Conclusions. The MDMA isomers have heterogeneous effects that can be demonstrated across a wide range of endpoints. Electronic Publication     

MDMA-like behavioral effects of N-substituted piperazines in the mouse

Few studies have characterized the subjective effects of N-substituted piperazines, but these drugs show potential for abuse in humans, and have often been associated with MDMA ("ecstasy") in this regard. The aim of the present study was to test the capacity of N-substituted piperazines to induce a head twitch response, alter locomotor activity, and induce MDMA-like discriminative stimulus effects in mice. Various doses of l-benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl) piperazine (TFMPP), 1-(3-methoxybenzyl) piperazine (m-MeO-BZP) or meta-chlorophenyl piperazine (m-CPP) were administered to mice to determine the effects on these behavioral endpoints. BZP, but not its meta-methoxyl analogue, increased locomotor activity in a dose-dependent manner; the phenylpiperazines and m-MeO-BZP only decreased locomotor activity. TFMPP was the only compound active in the head twitch assay, eliciting a moderate head twitch response which was comparable to that previously observed with the MDMA enantiomers. BZP, TFMPP and m-CPP fully substituted in S(+)-MDMA-trained animals, but did not elicit significant drug lever responding in mice trained to discriminate R(-)-MDMA. m-MeO-BZP partially substituted for both training drugs. The present results suggest that BZP has stimulant-like effects, and that TFMPP has hallucinogen-like effects. Their structural analogues, however, do not share these behavioral profiles. Further studies into the relationships between the N-substituted piperazines and MDMA are warranted.     

Lipopolysaccharide-induced hypoactivity and behavioral tolerance development are modulated by the light-dark cycle in male and female rats

Rationale Although the behavioral effects of systemic injection of lipopolysaccharide (LPS) have been extensively investigated, the modulation of these effects by natural environmental factors has received little attention.Objectives The present study investigated whether or not locomotor activity reductions and the development of behavioral tolerance in response to LPS treatment would occur to the same degree if male and female rats were treated with LPS at four distinct time points across the light-dark (LD) cycle.Methods On day 1, male and female rats were injected with either LPS (200 g/kg IP) or saline at light onset (0400 hours), 2 h into light period (0600 hours), at dark onset (1600 hours) or 2 h into the dark period (1800 hours). Two hours after injection, rats were placed in non-novel, automated open-fields and locomotor activity was assessed. The development of behavioral tolerance to LPS was evaluated three days later (day 4) using the same procedure.Results On day 1, LPS-treated animals displayed robust activity decrements during the light period with males displaying greater reductions than females. During the dark period, LPS-treated animals showed a similar hypoactivity response. After LPS treatment on day 4, all rats exhibited some behavioral tolerance to LPS. Rats given LPS treatment at light onset and during the dark period showed complete tolerance development while LPS-treated rats during the light phase at dark onset showed incomplete tolerance, still displaying significant reductions in some activity variables.Conclusions It appears that the magnitude of hypoactivity and the development of behavioral tolerance in response to LPS depend on the phase of the LD cycle during which it is administered.     

Stimulant effects of apomorphine and (+)-amphetamine in rats with varied habituation to test environment

The stimulants (+)-amphetamine and apomorphine are known to increase motility and induce stereotypy in rats. The present study examined the effects of an habituation period immediately prior to injection on these stimulant effects. Male Wistar rats received doses of either drug including 0, 0.01, 0.1, 0.25, 1.0, 2.0 and 4.0 mg/kg in a random order. Activity was assessed in 6 automated chambers where horizontal and vertical activity were tabulated hourly for 4 hours. Initially all rats had equal exposure to the chambers over 5 days. In the subsequent drug phase, habituated rats were placed in the chambers for the 1-hr period prior to each injection whereas non-habituated rats were in their home cages at the corresponding time. (+)-Amphetamine stimulated horizontal activity, although under either condition the effect was not seen until the second hour post-injection, but lasted until the fourth hour. Vertical activity was similarly enhanced, but with habituation there was a significant stimulant effect in the first hour as well. With apomorphine the habituation period resulted in an absence of a significant stimulant effect. Non-habituated rats showed a significant stimulant effect with the highest dose only on vertical activity in the first hour and a stimulant effect with horizontal activity in the second hour. It is suggested that the relative novelty of the environment affected the behavioral response to apomorphine but not to (+)-amphetamine. Furthermore, the activating effects accompanying drug administration should be taken into account as a factor affecting responses to drugs. Such environmental factors may be of particular importance when considering drugs with a short duration of action.     

Effect of clonidine,amphetamine, and their combinations on the locomotor activity of CD-1 and C57BL/6 mice

Clonidine inhibited the exploratory motor activity of C57BL/6 mice non-habituated to the testing conditions. In CD-1 mice clonidine did not depress exploratory activity but did elevate the basal locomotor activity of animals both non-habituated and habituated to testing conditions. Amphetamine increased the locomotor activity of many C57BL/6 mice and conversely inhibited the locomotion of many CD-1 mice. In both strains, amphetamine in doses up to 2 mg/kg was unable to alter effects produced by clonidine. Results suggest that the locomotor activity of C57BL/6 mice is more sensitive than that of CD-1 mice to drugs affecting the central noradrenergic system.     

Assessment of the discriminative stimulus effects of the optical isomers of ecstasy (3,4-methylenedioxymethamphetamine; MDMA)

The discriminative stimulus effects of the stereoisomers of 3,4-methylenedioxymethamphetamine (MDMA) were studied in rats trained to discriminate 1.25mg/kg of (+)-MDMA or 3.5mg/kg of (-)-MDMA from saline, in a two lever, water-reinforced, drug discrimination situation. The isomers of MDMA and 3,4-methylenedioxyamphetamine (MDA) substituted completely for both training drugs. The stimulants amphetamine and cocaine did not substitute for either MDMA isomer. The hallucinogens (+/-)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-lysergic acid diethylamide (LSD), and mescaline failed to substitute completely for (+)-MDMA. Similarly, DOM and mescaline did not substitute for (-)-MDMA; however, LSD did substitute for this isomer at a dose of 0.06mg/kg but not at higher doses. Substitution tests with 5-HT-releasing agents revealed that fenfluramine substituted partially for (+)-MDMA and completely for (-)-MDMA, while p-chloroamphetamine substituted completely for both isomers of MDMA. When given in combination with (+)-or (-)-MDMA, neither the 5-HT(2) antagonist pirenpirone nor the less selective 5-HT antagonist metergoline consistently blocked drug-appropriate responding. These results indicate that the stereoisomers of MDMA and MDA have similar discriminative stimulus properties. More importantly, the present findings suggest that 5-HT release may be important for the discriminative stimulus effects of (+)-and (-)-MDMA. Actions at 5-HT(2) receptors, however, do not appear to be critical.     

MDMA Elicits Behavioral and Neurochemical Sensitization in Rats

Rats were treated with repeated injections of saline or one of two doses of (±)3,4-methylenedioxymethamphetamine (MDMA; 5 or 20 mg/kg, SC). Rats pretreated with either of the two repeated MDMA treatment regimens demonstrated an augmented increase in motor activity to an injection of MDMA made 12 days after the last repeated injection compared with either the first MDMA injection or MDMA given to animals pretreated with repeated saline. Furthermore, animals pretreated with the highest dose of repeated MDMA revealed a greater behavioral response to cocaine (15 mg/kg, IP). Microdialysis was conducted in the nucleus accumbens and the capacity of MDMA (5 mg/kg, SC) to elevate extracellular dopamine content was augmented in rats pretreated with repeated MDMA compared with the animals pretreated with repeated saline. These data reveal repeated MDMA administration produces behavioral sensitization and enhanced dopamine transmission in the nucleus accumbens of rats.     

Light-dark variation in response to chronic nicotine treatment and the density of hypothalamic alpha-bungarotoxin receptors

Chronic nicotine administration increased locomotor activity during the light, but not the dark, in rats maintained on a 12:12-hr light/dark cycle, but the period and peak of the circadian rhythm (CR) were not affected. In Experiment I, 24 male rats were implanted with battery-operated telemeters and locomotor activity was continuously measured for 10 days before and 10 days after the implantation of osmotic mini-pumps which delivered 0, 0.5, 3.0 or 10 mg/kg/day of (+/-)-nicotine tartrate. Nicotine increased locomotor activity during the light in a dose-dependent manner. Tolerance to the stimulant effects of nicotine during the light occurred in 5-6 days. To determine if the stimulant properties of nicotine were associated with light as opposed to disruption by the environmental stimuli normally present during the day in our animal facility, a second experiment was conducted in which rats were treated with saline or 10 mg/kg/day (+/-)-nicotine di(+)hydrate tartrate and maintained on a reversed light/dark cycle. Again nicotine increased activity during the light (21:00-09:00) but not the dark (09:00-21:00). In a third experiment, the density of alpha-bungarotoxin binding sites was found to be significantly decreased when animals were sacrificed at 06:00 in comparison with animals sacrificed at 10:00 and 14:00.     

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") and its stereoisomers as reinforcers in rhesus monkeys: serotonergic involvement

RATIONALE: The reinforcing effects of MDMA and its enantiomers have not been extensively characterized in laboratory animals. OBJECTIVES: To investigate whether MDMA and its stereoisomers would be self-administered intravenously by rhesus monkeys ( Macaca mulatta), and to assess the effects of serotonin(2) receptor antagonists on MDMA-maintained responding. METHODS: Four adult male rhesus monkeys were maintained on a fixed ratio 10, time-out 60-s schedule for 0.01 mg/kg cocaine or saline injections. Racemic MDMA and its stereoisomers, and racemic methamphetamine were periodically substituted for cocaine or saline. In subsequent antagonist experiments, five adult rhesus monkeys (three male, two female) were maintained on a multiple dose fixed ratio 30, time-out 45-s schedule for cocaine or saline injections. Racemic MDMA and its enantiomers were periodically substituted for cocaine or saline, with or without a pre-session injection of the serotonin(2) receptor antagonists ketanserin or MDL100907. RESULTS: In the initial self-administration experiments, MDMA and its stereoisomers generated "inverted U"-shaped self-administration curves across the dose range tested. Racemic MDMA doses between 0.01 and 0.1 mg/kg per injection, S(+)-MDMA doses between 0.003 and 0.1 mg/kg per injection, and R(-)-MDMA doses between 0.01 and 0.1 mg/kg per injection engendered more responding than saline; however, no dose of any form of MDMA maintained as much behavior as cocaine or methamphetamine. In subsequent antagonist experiments, pretreatments with 0.1 or 0.3 mg/kg ketanserin or MDL100907 attenuated responding for S(+)-MDMA, and completely abolished responding for R(-)-MDMA, but did not affect cocaine-maintained behavior. CONCLUSIONS: MDMA and its stereoisomers serve as reinforcers in rhesus monkeys. We suggest that stimulation of 5-HT(2A) receptors is integral to the reinforcing effects of MDMA.     

Comparison of caffeine-induced locomotor activity between adolescent and adult rats

Caffeine is the psychostimulant drug most consumed in the world. This drug is present in food, beverages and medicines marketed for individuals of all ages. In spite of this, caffeine effects on adolescents are poorly understood. The aim of this study was to evaluate the differences on caffeine-induced locomotor stimulant or depressant effects in adolescent and adult rats. Adolescent (37-40 days old) or adult (70-74 days old) Wistar rats were tested for stimulant and depressant caffeine effects in two different experiments. The first was designed to evaluate the locomotor effect of caffeine in habituated rats. To this end, rats were previously habituated to test environment and had their locomotor activity registered following i.p. injections of vehicle or caffeine (3, 10, 30, 60 or 120 mg/kg). In the second experiment adolescent or adult rats were not habituated to the test environment and their locomotor activity was registered following i.p. injections of vehicle or caffeine (30, 60 or 120 mg/kg). In both experiments caffeine-induced a biphasic effect, with stimulation in small to moderate drug doses and no effect or locomotor depression in higher caffeine doses. Moreover, caffeine-induced locomotor stimulation was higher in adolescent than adult rats. Also, locomotor depression was only revealed in adult rats non-habituated to the test environment. These results suggest that adult and adolescent respond differently to caffeine indicating the need of more studies on the effects of caffeine in animals' models of adolescence.     

Effects of diurnal phase and pimozide on cholecystokinin-elicited hypoactivity in the hamster.

Locomotor activity in golden Syrian hamsters was measured following IP injections of cholecystokinin (CCK; 25 micrograms/kg) and pimozide (0.5 mg/kg), the dopamine receptor antagonist. In addition, animals were tested during either the dark or light phase of the diurnal cycle in either dark or light running wheel environments. Results indicated that CCK-elicited hypoactivity was blocked by pimozide and that the effect of CCK was evident only among animals tested during the light phase of the daily cycle. Ambient lighting conditions in the test environment did not modify the drug effects. Independently of any drug effect, locomotor activity was affected by diurnal phase and ambient lighting in the test environment. Animals were more active when tested during the dark phase than during the light phase and locomotor activity was higher under dark than under light ambient conditions. It is concluded that diurnal phase modulates CCK's effect on hamster locomotion and that CCK's effect on locomotion is mediated, in part, by dopaminergic mechanisms.     

Estimating the relative reinforcing strength of (±)-3,4-methylenedioxymethamphetamine (MDMA) and its isomers in rhesus monkeys: comparison to (+)-methamphetamine

Rationale (±)3,4-Methylenedioxymethamphetamine (MDMA) is an analog of methamphetamine (MA) and a drug of abuse. MA, MDMA, and its isomers release monoamine neurotransmitters with varying selectivities and would, therefore, be predicted to vary in their relative strength as reinforcers.Objectives This study compared self-administration of MA, MDMA, and its isomers using a progressive-ratio schedule in rhesus monkeys.Methods Rhesus monkeys [n = 6, MA and MDMA; n = 5, (+)-MDMA and (−)-MDMA] were prepared with chronic i.v. catheters and allowed to self-administer cocaine or saline in daily baseline sessions. When responding was stable, MA (0.006–0.1 mg/kg per injection), MDMA (0.025–0.8 mg/kg injection), (+)-MDMA (0.025–0.8 mg/kg per injection), or (−)-MDMA (0.05–0.8 mg/kg per injection) was made available in test sessions.Results MA, MDMA, and (+)-MDMA functioned as positive reinforcers in all monkeys with a potency relationship of MA > (+)-MDMA > (±)-MDMA. Two of five monkeys took (−)-MDMA above saline levels. Dose–response relationships were biphasic for MA and (±)-MDMA, and asymptotic for (+)-MDMA. In terms of maximum number of injection per session, a measure of relative reinforcing strength, the order was MA > (+)-MDMA = (±)-MDMA > (−)-MDMA.Conclusions MDMA and (+)-MDMA were consistent positive reinforcers, but weaker than MA, whereas (−)-MDMA was, at best, a weak reinforcer in some monkeys. The reinforcing strength of MDMA appears to derive primarily from (+)-MDMA. Because MDMA and its isomers have been shown to have relatively higher serotonin to dopamine releasing potency, these data support the hypothesis that increasing 5-HT releasing potency relative to DA is associated with weaker reinforcing effects.