Abstract: Methamphetamine is a drug that is often consumed at dance parties or nightclubs where the ambient temperature is high. The present study determined whether such high ambient temperatures alter intravenous methamphetamine self-administration in the rat. Male Hooded Wistar rats were trained to self-administer intravenous methamphetamine (0.1 mg/kg/infusion) under a fixed ratio 1 (FR1) or progressive ratio (PR) schedule of reinforcement at an ambient temperature of 23 +/- 1 degrees C. They were then given their daily self-administration session at a raised ambient temperature of 30 +/- 1 degrees C. Methamphetamine self-administration was increased at 30 degrees C under both FR1 and PR reinforcement schedules, with the latter effect indicating that heat enhances the motivation to obtain methamphetamine. High temperatures did not alter self-administration of the D1 receptor agonist SKF 82958 in methamphetamine-experienced rats suggesting some specificity in the methamphetamine effect. When rats were given access to drink isotonic saline solution during methamphetamine self-administration sessions they drank much more solution at 30 degrees C than 23 degrees C. However, availability of isotonic saline to drink did not alter the heat-induced facilitation of methamphetamine self-administration (PR schedule) indicating that the heat effect does not simply reflect increased motivation for intravenous fluids. Hyperthermia was evident in rats self-administering methamphetamine at high ambient temperatures and fluid consumption did not prevent this effect. Heat did not affect blood levels of methamphetamine, or its principal metabolite amphetamine indicating that the facilitatory effect of heat did not reflect altered methamphetamine pharmacokinetics. Overall, these results show that high ambient temperatures increase the reinforcing efficacy of methamphetamine and encourage higher levels of drug intake.

Abstract: Rats were trained to self-administer cocaine in a distinctive context (context A). They were then extinguished in a second context (context B) prior to test for cocaine-seeking in the original training context, context A (group ABA), context B (group ABB) or no test (group AB0). Group ABA showed renewal of extinguished cocaine-seeking associated with c-Fos induction in basolateral amygdala, lateral hypothalamus, and infralimbic prefrontal cortex. Groups ABA and ABB showed test-associated c-Fos induction in prelimbic prefrontal cortex, nucleus accumbens (core, shell, rostral pole), striatum, lateral amygdala, perifornical hypothalamus, and ventral tegmental area. Double immunofluorescence revealed that renewal-associated c-Fos was expressed in orexin-negative lateral hypothalamic neurons whereas test-associated c-Fos was expressed in orexin-positive perifornical hypothalamic neurons. Retrograde tracing from lateral hypothalamus with cholera toxin revealed only sparse dual-labeled neurons in basolateral amygdala and infralimbic prefrontal cortex, suggesting that these regions contribute to renewal of cocaine-seeking independently of their projections to lateral hypothalamus. Retrograde tracing from the ventral tegmental area suggested that hypothalamic contributions to cocaine-seeking are likewise independent of projections to the midbrain. These results suggest that renewal of cocaine-seeking depends critically on basolateral amygdala, lateral hypothalamus, and infralimbic prefrontal cortex. Whereas basolateral amygdala and lateral hypothalamus contributions may be common to renewal of extinguished cocaine-, alcohol-, and sucrose-seeking, infralimbic prefrontal cortex contributions appear unique to renewal of cocaine-seeking and may reflect the habitual nature of relapse to cocaine.

Abstract: In recent work we have documented lasting adverse neurochemical and behavioural effects in rats given short-term 'binge' dosing with methylenedioxymethamphetamine (MDMA, Ecstasy), methamphetamine (METH) or their combination. Here we investigated whether similar effects persist in rats given 16 weekly injections followed by a 10 week period of abstinence. Female rats received MDMA (8 mg/kg, i.p.), METH (8 mg/kg), or a MDMA/METH combination (4 mg/kg MDMA + 4 mg/kg METH), once a week for 16 weeks, with locomotor activity and body temperature measured on weeks 1, 8 and 16. The MDMA and MDMA/METH groups showed acute drug-induced hyperthermia on week 1 only. MDMA-treated rats demonstrated an acute hyperactivity while METH and MDMA/METH treated rats showed pronounced stereotypy. Seven weeks after drug-treatment concluded, a decrease in social interaction was observed in all chronically drug-treated rats. No group differences were evident on the emergence, object recognition or forced swim tests. Neurochemical analysis revealed modest noradrenaline and serotonin depletion in chronically treated rats that was not evident following a single equivalent administration. These results indicate that although chronic, intermittent exposure to MDMA, METH or their combination, may not lead to significant long-term monoamine depletion, lasting adverse behavioural effects may persist, especially those related to social behaviour.

Abstract: The substituted amphetamines 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and methamphetamine (METH, 'ice', 'speed') are increasingly popular drugs amongst party-drug users. Studies with humans have investigated the acute and possible long-term adverse effects of these drugs, yet outcomes of such studies are often ambiguous due to a variety of confounding factors. Studies employing animal models have value in determining the acute and long-term effects of MDMA and METH on brain and behaviour. Self-administration studies show that intravenous METH is a particularly potent reinforcer in rats and other species. In contrast, MDMA appears to have powerful effects in enhancing social behaviour in laboratory animals. Brief exposure to MDMA or METH may produce long-term reductions in dopamine, serotonin and noradrenaline in the brain and alterations in the density of various receptor and transporter proteins. However it is still unclear, particularly in the case of MDMA, whether this reflects a 'neurotoxic' effect of the drug. Lasting alterations in social behaviour, anxiety, depressive symptoms and memory have been demonstrated in laboratory rats given MDMA or METH and this matches long-term changes reported in some human studies. Recent laboratory studies suggest that MDMA/METH combinations may produce greater adverse neurochemical and behavioural effects than either drug alone. This is of some concern given recent evidence that party drug users may be frequently exposed to this combination of drugs.

Abstract: The combined use of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') with methamphetamine (METH) by recreational drug users is of particular concern due to their similar pharmacological and toxic profiles. In the current study we sought to elucidate why combining these particular drugs is such a popular choice among party-drug users. This was investigated through characterisation of the possible interactive effects of MDMA on METH intravenous self-administration. The first experiment involved characterisation of the METH dose-response curve for intravenous self-administration. Male Hooded-Wistar rats were trained to self-administer intravenous METH (0.01-0.3 mg/kg/infusion) and an inverted-U dose-response curve was obtained. In Experiment 2, a second squad of rats self-administered 0.01, 0.03 or 0.1 mg/kg/infusion METH and had small amounts of MDMA (0.001-0.03 mg/kg) then introduced into the infusion solution. Addition of MDMA to the METH infusion solution resulted in a dose independent reduction in responding. In Experiment 3, a third squad of rats was treated 20 min pre-session with an intraperitoneal injection of saline, 1.25 or 2.5 mg/kg of MDMA or METH to evaluate whether the reduction in responding evident in Experiment 2 was due to an MDMA-induced decrease in locomotor activity. Pre-treatment with intraperitoneal MDMA or METH had no effect on METH self-administration nor activity. We hypothesise that the reduction in METH self-administration caused by MDMA may reflect inhibitory effects of MDMA-induced 5-HT release on dopaminergic mechanisms.

Abstract: RATIONALE: The combined administration of heroin and cocaine ('speedball') is common among intravenous drug users. Dopamine receptors in the nucleus accumbens play a key role in cocaine self-administration; however, their role in speedball self-administration is unknown, as is the role of opiate receptors in this region. OBJECTIVES: The effect of blocking dopamine D1, D2, mu-opiate or delta-opiate receptors in the nucleus accumbens on the intravenous self-administration of combined heroin and cocaine was examined in rats. METHODS: Rats with bilateral cannulae implanted into the nucleus accumbens were trained to self-administer intravenous speedball (ratio of cocaine/heroin, 17:1) under a progressive ratio (PR) schedule. Prior to their self-administration session, rats were then microinjected with the dopamine D1 receptor antagonist SCH 23390 (1 and 6 nmol side(-1)), the D2 receptor antagonist raclopride (3 and 10 nmol side(-1)), the mu-opiate receptor antagonist CTOP (0.1, 0.3 and 1.0 nmol side(-1)), the delta-opiate receptor antagonist naltrindole (1.0, 3.0 and 10 nmol side(-1)) or a cocktail of SCH 23390 (1 nmol side(-1)) and CTOP (0.1 nmol side(-1)) into the nucleus accumbens. RESULTS: Microinjection of SCH 23390, raclopride or CTOP into the nucleus accumbens produced dose-dependent decreases in breakpoints under the PR schedule, while naltrindole was without effect. The highest dose of SCH 23390 also significantly reduced locomotor activity measured during speedball self-administration. The combination of SCH 23390 and CTOP significantly reduced breakpoints, while not affecting locomotor activity. CONCLUSIONS: These results indicate that dopamine and mu-opiate receptors, but not delta-opiate receptors, in the nucleus accumbens are involved in the reinforcing effects of speedball. Combined administration of D1 and mu-opiate receptor antagonists may be more selective at reducing the reinforcing effects of speedball self-administration than either drug alone.

Abstract: The acute and long-term dangers of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') and methamphetamine (METH) are well described individually, but their effect in combination is largely unknown. Here groups of female rats were given four MDMA or METH injections within a single session with each injection separated by 2h. Treatments included MDMA only, METH only, MDMA and METH in a cocktail (MDMA/METH), MDMA (two injections) followed by METH (two injections) (MDMA-->METH), or METH followed by MDMA (METH-->MDMA). Each injection involved 4mg/kg of total drug. Drug administration occurred at a high ambient temperature of 28 degrees C. All treatments produced hyperactivity while the treatments where MDMA was administered first (MDMA, MDMA-->METH and MDMA/METH) produced hyperthermia. All treatments involving METH caused significant head weaving. Six weeks after drug treatment all groups showed reduced social interaction relative to controls. MDMA/METH treatment was associated with reduced swimming in the forced swim test. MDMA given alone caused 5-HT depletion in several brain regions while METH given alone caused dopamine depletion in the striatum. The three treatments involving MDMA and METH combinations caused significant depletion of serotonin, dopamine and noradrenaline in several brain regions. Interestingly, the MDMA-->METH treatment produced greater hippocampal and cortical 5-HT depletion than the METH-->MDMA treatment suggesting an effect of order. These results extend our recent findings of additive toxic effects when METH is combined with MDMA. This has potentially important implications for party drug users who appear to frequently use this combination.

Abstract: RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) are illicit drugs that are increasingly used in combination. The acute and long-term effects of MDMA/METH combinations are largely uncharacterised. OBJECTIVES: The current study investigated the behavioural, thermal and neurotoxic effects of MDMA and METH when given alone or in combined low doses. METHODS: Male rats received four injections, one every 2 h, of vehicle, MDMA (2.5 or 5 mg/kg per injection), METH (2.5 or 5 mg/kg per injection) or combined MDMA/METH (1.25+1.25 mg/kg per injection or 2+2 mg/kg per injection). Drugs were given at an ambient temperature of 28 degrees C to simulate hot nightclub conditions. Body temperature, locomotor activity and head-weaving were assessed during acute drug administration while social interaction, anxiety-related behavior on the emergence test and neurochemical parameters were assessed 4-7 weeks later. RESULTS: All treatments acutely increased locomotor activity, while pronounced head-weaving was seen with both MDMA/METH treatments and the higher dose METH treatment. Acute hyperthermia was greatest with the higher dose MDMA/METH treatment and was also seen with MDMA but not METH treatment. Several weeks after drug administration, both MDMA/METH groups, both METH groups and the higher dose MDMA group showed decreased social interaction relative to controls, while both MDMA/METH groups and the lower dose MDMA group showed increased anxiety-like behaviour on the emergence test. MDMA treatment caused 5-HT and 5-HIAA depletion in several brain regions, while METH treatment reduced dopamine in the prefrontal cortex. Combined MDMA/METH treatment caused 5-HT and 5-HIAA depletion in several brain regions and a unique depletion of dopamine and DOPAC in the striatum. CONCLUSIONS: These results suggest that MDMA and METH in combination may have greater adverse acute effects (head-weaving, body temperature) and long-term effects (decreased social interaction, increased emergence anxiety, dopamine depletion) than equivalent doses of either drug alone.

Abstract: Use of the drug 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') can have long-term adverse effects on emotion in both humans and laboratory animals. The present study examined whether chronic treatment with the antidepressant drug fluoxetine could reverse such effects. Male Wistar rats were briefly exposed to MDMA (4 x 5 mg/kg over 4 h) or vehicle on 2 consecutive days. Approximately 9-12 weeks later, half of the rats received a dose of approximately 6 mg/kg/day fluoxetine in their drinking water for a 5-week period. Fluoxetine administration reduced fluid intake and body weight in MDMA and vehicle pretreated rats. After several weeks of fluoxetine treatment, rats were assessed on the social interaction test, the emergence test of anxiety and the forced swim model of depression. MDMA pretreated rats showed reduced social interaction, increased anxiety on the emergence test, and increased immobility and decreased active responses in the forced swim test. Fluoxetine treatment reversed MDMA-induced anxiety in the emergence test and depressive-like effects in the forced swim test, yet exhibited no effects on the social interaction test. MDMA pretreated rats had decreased 5-HT and 5-HIAA levels in limbic and cortical regions, and decreased density of serotonin transporter sites in the cortex. Fluoxetine treatment did not greatly affect 5-HT levels in MDMA pretreated rats, but significantly decreased 5-HIAA levels in all brain sites examined. Postmortem blood serum levels of fluoxetine and norfluoxetine did not differ in MDMA and vehicle pretreated rats. These results indicate that fluoxetine may provide a treatment option for some of the deleterious long-term effects resulting from MDMA exposure.

Abstract: Male Wistar rats were treated with 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") using either a high dose (4 x 5 mg/kg over 4 h) or low dose (1 x 5 mg/kg over 4 h) regimen on each of 2 consecutive days. After 10 weeks, rats were tested in the social interaction and emergence tests of anxiety. Rats previously given either of the MDMA dose regimens were significantly more anxious on both tests. After behavioral testing, and 3 months after the MDMA treatment, the rats were killed and their brains examined. Rats given the high-, but not the low-, dose MDMA treatment regimen exhibited significant loss of 5-hydroxytryptamine (5-HT) and 5-HIAA in the amygdala, hippocampus, striatum, and cortex. Quantitative autoradiography showed loss of SERT binding in cortical, hippocampal, thalamic, and hypothalamic sites with the high-dose MDMA regime, while low-dose MDMA only produced significant loss in the medial hypothalamus. Neither high- nor low-dose MDMA affected 5HT(1A) receptor density. High-dose MDMA increased 5HT(1B) receptor density in the nucleus accumbens and lateral septum but decreased binding in the globus pallidus, insular cortex and medial thalamus. Low-dose MDMA decreased 5HT(1B) receptor density in the hippocampus, globus pallidus, and medial thalamus. High-dose MDMA caused dramatic decreases in cortical, striatal, thalamic, and hypothalamic 5HT(2A)/(2C) receptor density, while low-dose MDMA tended to produce similar effects but only significantly in the piriform cortex. These data suggest that even brief, relatively low-dose MDMA exposure can produce significant, long-term changes in 5-HT receptor and transporter function and associated emotional behavior. Interestingly, long-term 5-HT depletion may not be necessary to produce lasting effects on anxiety-like behavior after low-dose MDMA.

Abstract: RATIONALE: There is some uncertainty whether the acute hyperthermia caused by MDMA (ecstasy) plays a significant role in determining the long-term neurotoxic effects on brain 5-HT systems and associated changes in mood and behaviour. OBJECTIVE: The present study assessed whether long-term behavioural and cognitive changes seen in MDMA-treated rats are affected by hyperthermia at the time of drug administration. METHOD: Male Wistar rats were treated with MDMA (4x5 mg/kg i.p. over 4 h on 2 consecutive days) or vehicle at either a high ambient temperature (28 degrees C) or a low ambient temperature (16 degrees C). Eight to 18 weeks later, rats were tested in behavioural measures of anxiety (social interaction and emergence tests), a test of cognition (object recognition test) and the forced swim test of depression. At the conclusion of behavioural testing the rats were killed and their brains analysed using HPLC. RESULTS: MDMA treatment caused a clear and consistent hyperthermia at 28 degrees C and hypothermia at 16 degrees C. Months later, rats pre-treated with MDMA at either 16 or 28 degrees C displayed increased anxiety in the social interaction and emergence tests and reduced escape attempts and increased immobility in the forced swim test. MDMA pre-treatment was also associated with poorer memory on the object recognition test, but only in rats given the drug at 28 degrees C. Rats pre-treated with MDMA showed loss of 5-HT in the hippocampus, striatum, amygdala and cortex, regardless of body temperature at the time of dosing. However, 5-HIAA loss in the amygdala and hippocampus was greater in rats pre-treated at 28 degrees C. Dopamine in the striatum was also depleted in rats given MDMA. CONCLUSIONS: These results indicate that hyperthermia at the time of dosing with MDMA is not necessary to produce subsequent 5-HT depletion and anxiety in rats. They also extend previous findings of long-term effects of brief exposure to MDMA in rats to include apparent "depressive" symptoms in the forced swim model.