Modulatory effects of low-dose MDMA on cocaine-induced locomotor activity and place conditioning in rats

Methylenedioxymethamphetamine (MDMA; “Ecstasy”) is commonly abused by humans in environments such as nightclubs and rave parties where other drugs of abuse are readily available. Despite the popularity of polysubstance abuse among recreational MDMA users, relatively few controlled experimental studies have documented the neurobehavioral effects of MDMA in combination with other abused substances. This study employed conditioned place preference procedures (CPP) to assess the locomotor activating and place conditioning effects of acute concurrent administration of MDMA (1.5 or 3.0 mg/kg) and cocaine (10 or 20 mg/kg) in rats. Results indicate that low dose MDMA can enhance the locomotor and conditioned rewarding effects of cocaine. These findings may have important implications for understanding the contribution of serotonergic-dopaminergic interactions in the abuse liability of MDMA when used in combination with cocaine or other psychostimulant drugs.     

Combined effects of ethanol and MK 801 on locomotor activity in the rat.

The present study examined the effects of ethanol (0.75 g/kg IP) alone and in combination with the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK 801 (0.1 mg/kg SC) on the locomotor activity of rats. Sixteen rats were treated with vehicle plus saline, MK 801 plus saline, vehicle plus ethanol, and MK 801 plus ethanol. Locomotor activity was quantified for a period of 12 hours following drug administration. Ethanol was found to significantly decrease locomotor activity whereas MK 801 significantly increased locomotion during the first 2 hours postdrug. In addition, there was a significant additive interaction between ethanol and MK 801 during this time period. Two to four hours postdrug, MK 801 was observed to significantly decrease locomotion. Four to six hours postdrug, ethanol-treated rats had significantly increased locomotor activity whereas MK 801-treated rats displayed significantly decreased locomotion. No significant interaction was found between ethanol and MK 801 4 to 6 hours postdrug. No significant effects of any of the drugs on locomotor activity were observed from 6 to 12 hours postdrug. These results suggest that ethanol and MK 801 produce a pattern of effects on locomotor activity which depend on the time elapsed following drug administration.     

The effects of MDMA pretreatment on the behavioural effects of other drugs of abuse in the rat elevated plus-maze test

Few preclinical studies have found long-term behavioural consequences of the serotonergic neurotoxicity produced by 3,4-methylenedioxymethamphetamine (MDMA). This study investigated whether pretreatment with MDMA altered the behavioural effects of other drugs of abuse. Adult male Lister hooded rats (n=10/group) were pretreated with 10 mg/kg MDMA or 1 ml/kg saline vehicle intraperitoneally every 2 h for 6 h. Fourteen days later, the behavioural effects of d-amphetamine (2 mg/kg), cocaine (10 mg/kg), ethanol (2.0 g/kg), heroin (0.5 mg/kg), or MDMA (10 mg/kg) were assessed in the elevated plus-maze test. MDMA pretreatment produced approximately 20-25% decrease in hippocampal 5-HT and 5-HIAA concentrations, and [(3)H]paroxetine binding when analysed 2 weeks later. Despite inducing neurotoxicity, this regimen had no effect upon the plus-maze behaviour induced by ethanol, heroin, and MDMA. Acutely, and independent of neurotoxic pretreatment, MDMA produced a clear anxiogenic-like behavioural profile with a reduction of open arm entries and suppression of explorative behaviours. Despite being acutely anxiogenic, pretreatment with a neurotoxic regimen of MDMA has little effect on the anxiety-related effects of other drugs of abuse. It is possible that extended time points would produce significant changes, although the available evidence suggests that the plus-maze may not be a suitable model for detection of behavioural dysfunction after neurotoxic MDMA.     

Interactions between ethanol and cocaine,amphetamine, or MDMA in the rat: thermoregulatory and locomotor effects

Rationale (±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is often taken recreationally with ethanol (EtOH). In rats, EtOH may potentiate MDMA-induced hyperactivity, but attenuate hyperthermia. Objective Experiment 1 compared the interactions between EtOH (1.5 g/kg) and MDMA (6.6 mg/kg) with EtOH + cocaine (COCA; 10 mg/kg) and EtOH + amphetamine (AMPH; 1 mg/kg) on locomotor activity and thermoregulation. Experiment 2 used a weaker dose of MDMA (3.3 mg/kg) and larger doses of COCA (20 mg/kg) and AMPH (2 mg/kg). Materials and methods Drug treatments were administered on four occasions (2, 5, and 2 days apart, respectively; experiment 1) or two (2 days apart; experiment 2). Results All psychostimulants increased activity, and EtOH markedly increased the effect of MDMA. AMPH alone-related hyperactivity showed modest sensitization across treatment days, while MDMA + EtOH activity showed marked sensitization. AMPH, COCA, and MDMA induced hyperthermia of comparable amplitude (+1 to +1.5°C). Co-treatment with EtOH and AMPH (1 mg/kg) or COCA (10 mg/kg) produced hypothermia greater than that produced by EtOH alone. Conversely, EtOH attenuated MDMA-related hyperthermia, an effect increasing across treatment days. These results demonstrate that the interaction between MDMA and EtOH may be different from the interaction between EtOH and AMPH or COCA. Conclusion Because of potential health-related consequences of such polydrug misuse, it is worth identifying the mechanisms underlying these interactions, especially between EtOH and MDMA. Given the different affinity profiles of the three drugs for serotonin, dopamine, and norepinephrine transporters, our results appear compatible with the possibility of an important role of serotonin in at least the EtOH-induced potentiation of MDMA-induced hyperlocomotion.     

The effect of gamma-butyrolactone on locomotor activity in the rat

The effect of -butyrolactone (GBL) on locomotor activity in the rat was studied. Low doses of GBL (100 and 200 mg/kg) had a biphasic effect on activity. Initially, the activity of the rats was reduced, and this reduction was then followed by a period of hyperactivity. The effect of -flupenthixol (50 g/kg -FPT), atropine (10 mg/kg), benztropine (25 mg/kg), protriptyline (15 mg/kg), and clomipramine (25 mg/kg) was investigated on this biphasic effect. -FPT reduced the hyperactivity while benztropine potentiated it; atropine, clomipramine, and protriptyline had little effect. It is concluded that the increase in activity could be due to a release of dopamine.     

Prenatal cocaine exposure: effects on locomotor activity in rat offspring

This study examines the developmental effects of prenatal exposure to cocaine in the rat, evaluated during the first month of life through open-field behavior. The offspring of Wistar dams that received 60 mg/kg of cocaine, from gestational day 8 to 22, were examined in the open-field during the second, third and fourth weeks of postnatal life in three consecutive 15-min daily sessions, starting on postnatal day (PND) 14, (PND 14–16), PND 21 (PND 21–23) and PND 28 (PND 28–30). Results show that prenatal exposure to cocaine increased total activity and rearing behavior on PND 22 and PND 29. Also, on PND 14, cocaine-exposed animals reared significantly more than control rats. There were no significant differences in the frequency of center and peripheral ambulation, nor in the defecation rate. The present results evidence alterations in the emotional behavior of rats prenatally exposed to cocaine. The delayed onset of exploration in the open-field observed in cocaine-exposed animals suggests that they take more time to become habituated to a novel and open environment.     

The effects of nicotine on locomotor activity in non-tolerant and tolerant rats.

1--Rats were tested for locomotor activity in photocell cages, for 80 min starting immediately after subcutaneous injection of (-)-nicotine bitartrate or 0.9% w/v NaCl solution (saline). In non-tolerant subjects, nicotine (0.1 to 0.4 mg/kg base) depressed activity and induced ataxia in the first 20 min, but increased activity later in the session; these actions were dose-dependent. 2--Tolerance was studied by comparing rats given nicotine (0.4 mg/kg s.c.) every day with control rats given saline instead. Each week, every subject was tested once with nicotine (0.4 mg/kg) and once with saline. With daily or even weekly injections of nicotine, the initial depressant action of the drug was replaced by a dose-dependent stimulant action which occurred throughout the session. In these tolerant animals, little ataxia was seen except when a larger dose of 0.8 mg/kg was given. Tolerance to the depressant action of nicotine persisted for at least 3 weeks. 3--In non-tolerant subjects, mecamylamine (0.5, 1.0 mg/kg s.c.) prevented the initial depressant action of nicotine (0.4 mg/kg). In tolerant rats, the locomotor stimulant action of nicotine (0.4 mg/kg) was prevented by mecamylamine (0.1, 0.32, 1.0 mg/kg s.c.) in a dose-related way; the quaternary ganglion blocker, hexamethonium (0.2, 1.0, 5.0 mg/kg s.c.) had little or no such effect. Neither mecamylamine nor hexamethonium altered activity when given alone. 4--It is suggested that a few treatments with nicotine can unmask a stimulant action of the drug, probably of central origin, which possibly reflects a stimulation of nicotine receptors.     

Caffeine-phenacetin interaction in the rat: effects on absorption,metabolism and locomotor activity

The interactive effects of caffeine and phenacetin on the locomotor activity of the DA rat involved changes in absorption and metabolism as well as effects possibly exerted at the cns level. Phenacetin initially retarded the absorption of caffeine when coadministered by gavage but not when caffeine was given intraperitoneally and phenacetin orally. Phenacetin also increased the time for the plasma/caffeine concentration to peak, increased its peak concentration and prolonged its presence in the plasma. Urinary excretion patterns, suggested a blockade of the N-demethylation of caffeine by phenacetin. In contrast, caffeine had only a minor influence on the absorption and metabolism of phenacetin. The locomotor effects of the caffeine-phenacetin combination reflected the absorptive and metabolic interactions which occurred. Caffeine-induced hyperactivity was initially masked by phenacetin in a dose-dependent manner but after 2 h, when the plasma phenacetin concentrations were much lower, its retarding influence on caffeine metabolism became apparent and hyperactivity consequent upon an elevated plasma caffeine concentration was seen. Phenacetin also antagonized the hyperactive effects of theophylline and of (+)-amphetamine.     

The subjective effects of MDMA and mCPP in moderate MDMA users.

The present study is part of a research program designed to better understand the neurochemical mechanisms underlying the abuse liability of 3,4-methylenedioxymethamphetamine (MDMA) in humans. In these studies, MDMA will be compared to prototypical dopamine (D-amphetamine) and serotonin (meta-chlorophenylpiperazine, mCPP) releasing agents on a variety of measures related to dependence. In order to determine an acceptable dose range (safe but active) of MDMA and mCPP for these studies, moderate MDMA users were administered escalating doses of MDMA (75, 110 and 145 mg/70 kg) and mCPP (17.5, 35 and 52.5 mg/70 kg). Each participant received a single dose under controlled laboratory conditions, i.e. this was a six-group design with a separate group for each dose. There were five participants tested in each group. MDMA increased blood pressure and heart rate whereas mCPP had no effect on these physiological measures. MDMA produced increases in subjective effects indicative of both stimulant (increases in POMS Elation, ARCI Amphetamine, VAS High and Stimulated scale scores) and hallucinogenic effects (increases on five of the six scales of the Hallucinogenic Rating Scale). mCPP produced similar stimulant effects (e.g. increases on POMS Elation, VAS High and Stimulated), as well as hallucinogenic effects (four of the six scales of the Hallucinogenic Rating Scale), which has not been observed in previous studies.     

Phencyclidine during pregnancy in the rat: effects on locomotor activity in the offspring

Either 5 or 10 mg/kg of phencyclidine hydrochloride (PCP) was administered by gastric intubation to gravid rats during the last two weeks of gestation. Intubation controls received the vehicle and all offspring were fostered to untreated controls at birth. PCP produced a decrement in maternal weight gain and a small but nonsignificant reduction in birth weight that was no longer evident at weaning. There were no maternal deaths nor were resorptions or stillbirths increased by PCP exposure. Offspring were tested for differences in locomotor activity from birth to weaning at 30 days of age and during adulthood. No behavioral differences were found among the preweanling or adult offspring. Results are compared with other prenatal studies of PCP toxicity and teratogenicity.     

Typical and atypical antidepressant drug effects on locomotor activity after intra-accumbens injections in the rat

Changes in spontaneous or drug-induced locomotor activity in rats were studied after injection of antidepressants in the nucleus accumbens. Antidepressant drugs, either alone or in combination with ergometrine, were injected bilaterally via fixed guide cannulas into the nucleus accumbens and locomotor activity was recorded during a period of 5 h. The after-effect, a long-lasting change in ergometrine-induced locomotor activity after priming with an antidepressant drug was also studied. It was concluded that: (a) The nucleus accumbens is a target site for antidepressant drugs in the rat. (b) Antidepressant drugs with mainly dopaminergic, noradrenergic or serotonergic features each show different effects in the test battery. (c) Typical as well as atypical antidepressants show common features.     

The effects of repeated administration of MDMA on the expression of sexual behavior in the male rat.

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a potent neurotoxin which preferentially produces 5-HT nerve terminal degeneration in the CNS in both rodents and primates. Timely research on the behavioral effects of acute and long term treatment of MDMA is critical due to the neuropathological effects of MDMA and its abuse liability. Presently, there are no published reports that have systematically examined the effects of acute or chronic treatment of MDMA on animal sexual behavior. Accordingly, the effects of repeated systemic administration of MDMA on a variety of parameters of male sexual behavior in sexually vigorous male rats were studied. Treatment consisted of subcutaneous injections of MDMA (40 mg/kg) or saline (1 ml/kg) every 12 hours for 4 consecutive days. In addition, neurochemical assessments of brain 5-HT and 5-HIAA depletion following repeated MDMA treatment were also conducted using reverse phase liquid chromatography. The results of this study revealed that repeated systemic administration of MDMA to sexually vigorous male rats produced a transient disruption of the expression of male copulatory behavior. In addition, in MDMA-treated males that did display copulatory behavior, both the ejaculation latency and postejaculatory interval were dramatically lengthened when compared to saline injected controls. Surprisingly, one week after the first behavioral test, copulatory behavior in MDMA treated rats appeared unaffected despite a marked depletion of 5-HT and 5-HIAA content in the striatum, and hippocampus.     

Comparative effects of estradiol stereoisomers on pimozide-induced catalepsy, locomotor activity and body-weight in the rat

The effects of 17-alpha and 17-beta estradiol were compared at three dose levels on locomotor activity, pimozide-induced catalepsy, and changes in body weight. At 10 micrograms/kg/day they increased locomotor activity to a similar degree but at 5 and 1 microgram/kg/day the beta form was mor effective. However the alpha isomer failed to potentiate catalepsy, or reduce body weight, even at the highest dose whereas 17-beta estradiol did both. From these and other results it is suggested that estradiol might act on intracellular receptors and not by changing catecholamine metabolism.     

Effects of MDMA, MDA and MDEA on blood pressure, heart rate, locomotor activity and body temperature in the rat involve alpha-adrenoceptors

The effects of injection of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and N-ethyl-3,4-methylenedioxyamphetamine (MDEA) (all 20 mg kg(-1)) on blood pressure, heart rate, core body temperature and locomotor activity in conscious rats were investigated using radiotelemetry. MDMA and MDA produced a prolonged increase in both systolic and diastolic pressures, with MDA causing the most marked rise. MDEA produced a transient but nonsignificant fall in diastolic pressure. The pressor response produced by MDA was accompanied by bradycardia. All three amphetamine derivatives caused an initial hypothermic response; however, MDA also produced a subsequent hyperthermia, and the speed of recovery from hypothermia was MDA>MDMA>MDEA. The alpha2A-adrenoceptor antagonist 2-((4,5-dihydro-1H-imidazol-2-yl)methyl)-2,3-dihydro-1-methyl-1H-isoindole (BRL 44408) (1 mg kg(-1)) prolonged the hypothermic response to MDMA. Only MDA induced locomotor activity when given alone, but in the presence of BRL 44408, MDMA produced increased locomotor activity. The order of potency for producing isometric contractions of rat aorta (alpha1D) and vas deferens (alpha1A) was MDA>MDMA>MDEA, with MDEA acting as an alpha1-adrenoceptor antagonist with a pK(B) of 4.79+/-0.12 (n = 4) in aorta. The order of potency for prejunctional inhibition of stimulation-evoked contractions in rat vas deferens (alpha2A-adrenoceptor mediated) was MDA>MDMA>MDEA. Blood pressure actions of the three amphetamine derivatives may be at least partly due to alpha1-adrenoceptor agonism or antagonism. The reversal of the hypothermic actions are at least partly due to alpha2A-adrenoceptor agonism since the hypothermic response was more prolonged with MDEA which exhibits low alpha2A-adrenoceptor potency, and effects of MDMA after alpha2A-adrenoceptor antagonism were similar to those of MDEA.     

A behavioral analysis of the effects of amphetamine on play and locomotor activity in the post-weaning rat

Amphetamine has been shown to canalize or direct the activity of a young rat towards ethologically relevant stimuli. In the five-day-old, amphetamine increases the speed of approach to the nipple of an anesthetized dam; in the 15-day-old, amphetamine increases motor activity and directs it toward an anesthetized adult, however, in the juvenile rat amphetamine reportedly disrupts species-specific behaviors such as huddling and play. The present experiments further assessed the effects of amphetamine in the post-weaning rat by measuring drug-induced behaviors in the presence of an alert and anesthetized companion. In Experiment 1, subjects were videotaped in the presence of an alert non-treated, same-age rat and components of play, a predominant behavior of the post-weaning rat, were recorded. Results confirmed previous reports that low doses of amphetamine (0.5 mg/kg) disrupt play behavior, however, in the present experiment higher doses of amphetamine (1.0 mg/kg) did not disrupt the percentage of time spent in play. Further analysis of drug-induced behavior revealed that the 1.0 mg/kg amphetamine-injected rat engaged in play with the companion, although the drug-treated animal did exhibit marked alterations in the flexibility of its motor patterns. The second experiment confirmed that amphetamine did not disrupt the amount of time a juvenile rat spent with an anesthetized age-mate. In fact, amphetamine-induced activity was directed towards the anesthesized same-age rat. Following amphetamine treatment, all subjects were active nearly 100% of the observation period whether they were tested alone or in the presence of an anesthetized same-age rat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Multiple 5-HT receptors are involved in the effects of acute MDMA treatment: studies on locomotor activity and responding for conditioned reinforcement

RATIONALE: Responding for conditioned reinforcement is increased by the dopamine releasing agent amphetamine, but reduced by drugs that enhance serotonin (5-HT) function. The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) releases both monoamines. OBJECTIVES: The primary purpose of this study was to examine the effects of MDMA on responding for conditioned reinforcement as well as on locomotor activity. The roles of several 5-HT receptor sub-types in mediating these behavioural effects of MDMA were also examined. METHODS: Locomotion was measured in photocell activity monitors. For conditioned reinforcement experiments thirsty rats learned to associate a conditioned stimulus (CS) with water in operant chambers. Subsequently, two response levers were available; responding on one lever delivered the CS, while responding on the second lever had no consequences. Drug effects on this operant response were measured. RESULTS: MDMA dose-dependently increased locomotion but reduced responding for conditioned reinforcement. This latter effect differs from that induced by amphetamine, which potentiates conditioned reinforcement responding. The stimulant effect of MDMA was attenuated by GR127935 and ketanserin, indicating facilitatory roles of 5-HT(1B) and 5-HT(2A) receptors in mediating this effect. The 5-HT(2C) antagonist SB242084 enhanced the stimulant effect of MDMA. Only SB242084 attenuated the suppressant effect of MDMA on responding for conditioned reinforcement. CONCLUSIONS: The results show that 5-HT(2A) and 5-HT(1B/1D) receptors play a facilitatory role in mediating the stimulant effect of MDMA, whereas 5-HT(2C) receptors are inhibitory. Activation of 5-HT(2C) receptors also contributes to the deficit in operant responding. Multiple 5-HT receptor sub-types appear to contribute to the behavioural effects of MDMA.     

The antinociceptive effects of 3,4-methylenedioxymethamphetamine (MDMA) in the rat

The antinociceptive effects of MDMA and morphine were examined in rats using the tail-flick and hot-plate analgesiometric tests. MDMA, in the dose range of 1.5-6.0 mg/kg IP, produced a dose-dependent elevation in hot-plate latency, but did not elevate tail-flick latency. In contrast, morphine (2-8 mg/kg, IP) produced analgesia on both the tail-flick and hot-plate tests in a dose-dependent manner. Neither the opiate antagonist naltrexone nor the adrenoceptor antagonist phentolamine effectively attenuated MDMA-induced analgesia. Conversely, the serotonin antagonist methysergide significantly reversed the analgesic effects of MDMA on the hot-plate test. These findings suggest that the antinociceptive effects of MDMA are serotonergically mediated. Furthermore, the results verify earlier findings describing the test-specific effects of serotonin-induced pain modulation.