Repeated weekly exposure to MDMA, methamphetamine or their combination: Long-term behavioural and neurochemical effects in rats
Introduction
The recreational use of substituted amphetamines such as ‘ecstasy’ (3,4-methylenedioxymethamphetamine; MDMA) and methamphetamine (METH, ‘speed’, ‘ice’) is common across many cultures (United Nations Office on Drugs and Crime, 2003), and co-administration of MDMA and METH is frequently reported (Barrett et al., 2005, Degenhardt et al., 2005). In addition to intentional combined use, many ecstasy users may inadvertently consume MDMA and METH simultaneously through ingesting ‘ecstasy’ tablets that contain little or no MDMA, but rather a cheaper substitute such as METH (Kalasinsky et al., 2004, Quinn et al., 2004). These findings support the notion that polydrug use is the norm in party drug users, and that MDMA and METH are often used together.
Particular concern surrounds the possible adverse effects of mixing MDMA with METH. Both drugs have been independently linked with long-term behavioural and cognitive deficits in humans (Parrott, 2001, Meredith et al., 2005), and when regularly used together, combining MDMA with METH has been associated with more severe long-term cognitive, behavioural and neurological changes (Brecht and von Mayrhauser, 2002, Fox et al., 2002, Reneman et al., 2002). This notion has been supported through investigation of the long-term effects of combined MDMA/METH administration in laboratory animals. Results from our laboratory indicate that exposure to MDMA and METH in combination results in a more severe pattern of long-term behavioural and neurochemical alteration in rats than administering either drug alone (Clemens et al., 2004, Clemens et al., 2005).
Administration of moderate to high doses of MDMA or METH to rats produces long-term social anxiety, as well as marked serotonin (5-HT) and dopamine (DA) depletion, respectively (Clemens et al., 2004, Clemens et al., 2005). Administration of a MDMA/METH cocktail resulted in similar long-term decreases in social interaction, and this was also accompanied by increased anxiety on the emergence test and altered behaviour on the forced swim test of depression (Clemens et al., 2005). Lasting effects on the forced swim test are usually only seen with higher doses of MDMA when given alone (McGregor et al., 2003b, Thompson et al., 2004). Notably, the behavioural changes evident in the MDMA/METH group were paralleled by unique depletions of noradrenaline (NA), and significant DA and 5-HT depletion in MDMA/METH treated rats, in some brain regions beyond that in rats given MDMA or METH alone (Clemens et al., 2005).
While these results represent the effects of a single day of dosing, in the current study we wished to extend these findings to encompass the long-term behavioural and neurochemical effects of intermittent MDMA, METH or MDMA/METH administration once a week, for 16 weeks. The majority of MDMA or METH neurotoxicity studies examine depletion following a brief, 1- or 2-day exposure to relatively high levels of MDMA or METH, thus attempting to model the effects of ‘binge’ episodes of drug taking in humans (Green et al., 2003). While such studies are highly informative and valid, they may be restricted in their applicability to humans as the majority of party-drug takers report ‘infrequent’ consumption, using once every 1–3 months (Degenhardt et al., 2004, McCambridge et al., 2005). For this reason it is important to examine whether the robust effects obtained following a single, high dose administration of MDMA and METH are also obtained with a less rigorous, intermittent pattern of administration maintained over a much longer period of time.
Previous research addressing chronic exposure to MDMA has suggested that long-term sporadic administration may be less likely to produce neurochemical depletion than a single higher dose episode of exposure (O'Shea et al., 1998). It has been hypothesised that this difference is reliant on the additional time between administrations to allow sufficient recovery of the neurochemical processes affected by MDMA (O'Shea et al., 1998). While this spacing between drug administrations may well allow recovery of neurochemical levels, it is not clear how it will impact on the long-term adverse behavioural effects typically associated with this drug. This is especially pertinent when we consider that significant persistent MDMA-induced behavioural changes may sometimes occur in the absence of any detectable 5-HT depletion (Fone et al., 2002, McGregor et al., 2003a).
Similarly, the long-term neurochemical and behavioural consequences of intermittent METH administration have yet to be fully investigated. Results of shorter term studies indicate that deficits appear to be largely dependent on the route of administration, the dose and frequency of administration, as well as the amount of time in ‘withdrawal’ before neurochemical measures are taken (Suzuki et al., 1997, Segal et al., 2003, Broom and Yamamoto, 2005). Such neurochemical alterations detected in the next few days after withdrawal may no longer be evident weeks later (Segal et al., 2005), indicating a transient nature of neurochemical alteration, that may or may not be reflected in behaviour.
Therefore the aims of the current experiment were to explore the lasting effects of repeated, weekly administration of MDMA, METH and a MDMA/METH combination. We aimed to detect if long-term behavioural changes were evident after an extended period of abstinence following chronic administration and also to measure if this was reflected in long-term modification of NA, DA and 5-HT levels. Additional control groups were included to verify the neurochemical changes produced by a single dose of the drugs used.
Section snippets
Subjects
The subjects were 32 experimentally naïve female Albino Wistar rats weighing 238 ± 4 g at the beginning of the experiment. Our past research has indicated both male and female Albino rats respond similarly with regard to MDMA or METH effects (Clemens et al., 2004, Clemens et al., 2005), therefore it is unlikely that the results achieved here will be affected by sex differences.
Rats were housed in large plastic tubs, eight rats per tub, with food and water freely available. The colony room was
Body weight
Chronic drug treatment had no overall effect on body weight across the 16 weeks of drug-treatment.
Body temperature
As illustrated in Fig. 1, an overall effect of treatment in week 1 (F(3,16) = 4.91, p < 0.01) was reflected in significant hyperthermia in the MDMA and MDMA/METH groups as compared to controls. These effects were no longer evident in weeks 8 or 16. Repeated measures ANOVA for each treatment group across weeks 1, 8 and 16 indicated that although there was a trend towards increased body temperature in
Discussion
Previous research from our laboratory has demonstrated persistent behavioural and neurochemical changes following repeated moderate to high dose administration of MDMA or METH on a single day (Clemens et al., 2004, Clemens et al., 2005). This effect was markedly augmented following administration of MDMA/METH in combination. Here we extend this finding to show a similar pattern of social anxiety, but a much milder pattern of neurochemical depletion following weekly administration of 8 mg/kg of
Acknowledgement
This work was funded by a NH&MRC grant to I.S.M. and G.E.H.
References (53)
- et al.
Short toxic methamphetamine schedule impairs object recognition task in male rats
Brain Res
(2002) - et al.
Decreased social behaviour following 3,4-methylenedioxymethamphetamine (MDMA) is accompanied by changes in 5-HT (2A) receptor responsivity
Neuropharmacology
(2004) - et al.
MDMA (‘Ecstasy’) and methamphetamine combined: Order of administration influences hyperthermic and long-term adverse effects in female rats
Neuropharmacology
(2005) - et al.
The pre-clinical behavioural pharmacology of 3,4-methylenedioxymethamphetamine (MDMA)
Neurosci Biobehav Rev
(2003) Hyperthermia following MDMA administration in rats: effects of ambient temperature, water consumption, and chronic dosing
Physiol Behav
(1995)- et al.
Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment
Brain Res Brain Res Rev
(2001) - et al.
A review of the mechanisms involved in the acute MDMA (ecstasy)-induced hyperthermic response
Eur J Pharmacol
(2004) - et al.
The methamphetamine experience: a NIDA partnership
Neuropharmacology
(2004) - et al.
Prior exposure to methylenedioxyamphetamine (MDA) induces serotonergic loss and changes in spontaneous exploratory and amphetamine-induced behaviors in rats
Life Sci
(2001) - et al.
The role of hyperthermia and metabolism as mechanisms of tolerance to methamphetamine neurotoxicity
Eur J Pharmacol
(2003)
Role of brain norepinephrine in the behavioral response to stress
Prog Neuropsychopharmacol Biol Psychiatry
Increased anxiety and impaired memory in rats 3 months after administration of 3,4-methylenedioxymethamphetamine (“ecstasy”)
Eur J Pharmacol
The relationship between the degree of neurodegeneration of rat brain 5-HT nerve terminals and the dose and frequency of administration of MDMA (‘ecstasy’)
Neuropharmacology
Psychobiological problems in heavy ‘ecstasy’ (MDMA) polydrug users
Drug Alcohol Depend
Behavioural despair in rats: a new model sensitive to antidepressant treatments
Eur J Pharmacol
Tolerance to the neurotoxic effects of methamphetamine in young rats
Eur J Pharmacol
Effects of acute methamphetamine administration on spacing in paired rats: investigation with an automated video-analysis method
Prog Neuropsychopharmacol Biol Psychiatry
Acute and subchronic effects of methylenedioxymethamphetamine [(+/−)MDMA] on locomotion and serotonin syndrome behavior in the rat
Pharmacol Biochem Behav
Changes of behavior and monoamine metabolites in the rat brain after repeated methamphetamine administration: effects of duration of repeated administration
Prog Neuropsychopharmacol Biol Psychiatry
The acute effects of methylenedioxymethamphetamine on dopamine release in the awake-behaving rat
Eur J Pharmacol
Social interactions in rats: behavioral and neurochemical alterations in DSP-4-treated rats
Pharmacol Biochem Behav
History of the methamphetamine problem
J Psychoactive Drugs
Patterns of simultaneous polysubstance use in Canadian rave attendees
Subst Use Misuse
Anxiogenic and depressive-like effects, but no cognitive deficits, after repeated moderate tryptophan depletion in the rat
J Psychopharmacol
Differences between Ecstasy-using and nonusing methamphetamine users
J Psychoactive Drugs
Effects of subchronic methamphetamine exposure on basal dopamine and stress-induced dopamine release in the nucleus accumbens shell of rats
Psychopharmacology (Berlin)
Cited by (57)
Does chronic use of amphetamine-type stimulants impair interference control? – A meta-analysis
2023, Neuroscience and Biobehavioral ReviewsEthanol pre-exposure differentially impacts the rewarding and aversive effects of α-pyrrolidinopentiophenone (α-PVP): Implications for drug use and abuse
2021, Pharmacology Biochemistry and BehaviorCitation Excerpt :That said, some studies done with methylone and other drugs do address this. For example, Piper et al. (2005) found that adolescent exposure to MDMA in male SD rats reduced the subsequent effects of MDMA on body temperature compared to vehicle pre-exposed subjects (an effect that diminished with repeated testing, see Piper et al., 2005; see also Clemens et al., 2007; Rodsiri et al., 2011). Although not a study of drug pre-exposure, Shortall et al. (2015) examined body temperature changes in response to three short-term repeated mephedrone injections spaced 2 h apart in adult male Lister hooded rats and found that the hypothermic effects of mephedrone were attenuated with repeated dosing (see also Baumann et al., 2012 for hypothermic effects following repeated mephedrone administration and hyperthermic effects with repeated methylone and MDMA injections).
Effects of methamphetamine on alloparental behavior in male and female prairie voles
2019, Physiology and BehaviorDifferential effects of MDMA and cocaine on inhibitory avoidance and object recognition tests in rodents
2017, Neurobiology of Learning and MemoryNMDA receptor adjusted co-administration of ecstasy and cannabinoid receptor-1 agonist in the amygdala via stimulation of BDNF/Trk-B/CREB pathway in adult male rats
2017, Brain Research BulletinCitation Excerpt :MDMA is an indirect agonist of dopamine or serotonin and it could facilitate the serotonin and dopamine releases and subsequently increase the level of glutamate in the brain. Also, it has been claimed that increased levels of glutamate could intensify neural toxicity and cause cell injury in the brain (Clemens et al., 2006; Clemens et al., 2007). The endogenous cannabinoid system has a crucial role in memory and reward mechanism.