Increased anxiety and impaired memory in rats 3 months after administration of 3,4-methylenedioxymethamphetamine (“Ecstasy”)
Introduction
3,4-Methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) is an increasingly popular recreational drug in many countries of the world. Concern continues to mount about the long-term neurotoxic effects of the drug and its possible deleterious effects in humans (Boot et al., 2000). In animals, MDMA markedly decreases regional brain serotonin (5-HT) content and produces 5-HT nerve terminal degeneration in forebrain areas of rats Battaglia et al., 1987, Molliver et al., 1990, Ricaurte et al., 1992 and primates (Fischer et al., 1995). Human MDMA users also show several possible markers of 5-HT depletion such as blunted endocrine responses to d-fenfluramine challenges, decreased cerebrospinal 5-hydroxy-indolacetic acid (5-HIAA) concentrations and a reduced density of brain 5-HT transporter sites Gerra et al., 2000, McCann et al., 1999, Semple et al., 1999.
Recent studies suggest that heavy MDMA users may suffer from both long-term cognitive deficits Reneman et al., 2000, Verkes et al., 2001, Wareing et al., 2000 and a number of psychiatric sequale such as anxiety and depression Parrott et al., 2000, Verkes et al., 2001, Wareing et al., 2000. Although these studies provide increasing evidence of clinical problems associated with long-term ecstasy use, they suffer from certain difficulties of interpretation (Boot et al., 2000). It is not possible for such studies to control for the amount of MDMA used, the purity of the MDMA consumed and the polydrug use of human subjects. In addition, pre-existing abnormalities in 5-HT systems and in cognitive and emotional function cannot be ruled out in human MDMA users. It is therefore likely that preclinical studies will be useful in allowing a definitive account of the long-term behavioural and emotional effects of MDMA.
Surprisingly, there has been a relative paucity of such preclinical studies particularly in relation to anxiety and memory. Slikker et al. (1989) found a trend towards increased anxiety-like behaviours in rats given neurotoxic doses of MDMA 2–4 weeks previously. With respect to memory, Marston et al. (1999) documented impairment in a delayed matching to position working memory task in rats at up to 19 days following MDMA treatment. However, Ricaurte et al. (1993) found that the choice accuracy of rats in a T-maze delayed alternation task was generally unaffected following exposure to neurotoxic doses of MDMA.
The present study aimed to further investigate the long-term effects of MDMA on anxiety and memory in rats using a range of behavioural paradigms. A battery of three different anxiety tests were employed for the first paradigm (see Morley and McGregor, 2000), which are thought to reflect different anxiety states in humans (File, 1995). These consisted of: the emergence test (Crawley and Goodwin, 1980), the elevated plus-maze test (Pellow et al., 1985) and the social interaction test (File, 1980). To assess memory, the novel object recognition test was used. This model is thought to measure non-spatial working memory in rats Blanchard et al., 1970, Aggleton, 1985, Aggleton, 1993.
In addition to a vehicle control group, the present study also utilized a control group given d-amphetamine. Although d-amphetamine has a similar chemical structure to MDMA and similar stimulant and hyperthermic properties, it is not generally thought to be neurotoxic except at very high doses (e.g. Linder et al., 1995, Ryan et al., 1990). Thus, use of this treatment group therefore allowed additional control for any long-term effects of stimulant administration on behaviour (cf. Robinson and Becker, 1986) that are unrelated to neurotoxicity.
Section snippets
Subjects
A total of 64 inbred male albino Wistar rats (Concord Hospital, Sydney, Australia) were used in the experiments, aged between 75 and 95 days. The rats weighed an average of 273 g at the start of treatment and 360 g at the start of behavioural testing 12 weeks later. The rats were housed in large plastic tubs in groups of 8 per cage in a temperature-controlled environment (average temperature 22 °C). A 12-h reversed light cycle was in operation (lights off at 8:30 a.m.) and all testing took
Temperature
Body temperatures on the 2 days of drug administration are depicted in Fig. 1. For day 1, ANOVA showed no significant group effect for h 0 (F<1), or h 1 (F(3, 60)=2.69, P=0.054), but revealed a significant group difference for h 2 (F(3, 60)=6.45, P<0.001), h 3 (F(3, 60)=20.00, P<0.0001) and h 4 (F(3, 60)=38.64, P<0.0001). For day 2, ANOVA showed no significant effect for h 0 (F<1), but revealed significant differences for h 1 (F(3, 60)=3.26, P<0.05), h 2 (F(3, 60)=8.80, P<0.0001), h 3 (F(3,
Discussion
The results of the present study indicate that exposure to MDMA can produce pronounced long-term effects on anxiety-like behaviours, social interaction and memory in rats. No long lasting effects were seen after exposure with another chemically similar stimulant d-amphetamine, suggesting that these behavioural effects are relatively specific to MDMA.
Acute hyperactivity was observed in both MDMA and d-amphetamine groups, as previously demonstrated Gold et al., 1989, Callaway et al., 1990,
Acknowledgements
Supported by a National Health and Medical Research Council grant to ISM and GEH. Kirsten Morley is the recipient of an Australian Postgraduate Award.
References (53)
- et al.
Aniracetam restores object recognition impaired by age, scopolamine, and nucleus basalis lesions
Pharmacol., Biochem. Behav.
(1996) - et al.
Historical effects of stimulus exposure; Readiness to eat and object exploration
Learn. Mot.
(1970) - et al.
MDMA (Ecstasy) neurotoxicity: assessing and communicating the risks
Lancet
(2000) - et al.
Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines
Pharmacol., Biochem. Behav.
(1980) Hyperthermia following MDMA administration in rats: effects of ambient temperature, water consumption, and chronic dosing
Physiol. Behav.
(1995)The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs
J. Neurosci. Methods
(1980)- et al.
Long-lasting effects of (+/−)3,4-methylene-dioxymethamphetamine (ecstasy) on serotonin system function in humans
Biol. Psychiatry
(2000) - et al.
Effects of 3,4-methylenedioxymethamphetamine on autonomic thermoregulatory responses of the rat
Pharmacol., Biochem. Behav.
(1991) - et al.
A new approach to the light/dark test procedure in mice
Pharmacol., Biochem. Behav.
(1998) - et al.
Electron microscopic evidence for neurotoxicity in the basal ganglia
Neurochem. Int.
(1995)
Ethologically-based animal models of anxiety disorders
Pharmacol. Ther.
(+/−)-3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) increases social interaction in rats
Eur. J. Pharmacol.
TMT, a predator odor, elevates mesoprefrontal dopamine metabolic activity and disrupts short-term working memory in the rat
Brain Res. Bull.
Psychobiological problems in heavy ‘ecstasy’ (MDMA) polydrug users
Drug Alcohol Depend.
Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat
J. Neurosci. Methods
Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis
Brain Res.
Histological and ultrastructural evidence that d-amphetamine causes degeneration in neostriatum and frontal cortex of rats
Brain Res.
The distribution of 3,4-methylenedioxymethamphetamine “Ecstasy”-induced c-fos expression in rat brain
Neuroscience
Ecstasy use in Australia: patterns of use and associated harm
Drug Alcohol Depend.
One-trial object-recognition by rats
Q. J. Exp. Psychol.
Behavioral tests for the recognition of non-spatial information by rats
3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites
J. Pharmacol. Exp. Ther.
Sexual behavior induction of c-Fos in the nucleus accumbens and amphetamine-stimulated locomotor activity are sensitized by previous sexual experience in female Syrian hamsters
J. Neurosci.
Serotonin release contributes to the locomotor stimulant effects of 3,4-methylenedioxymethamphetamine in rats
J. Pharmacol. Exp. Ther.
Time course of brain temperature and caudate/putamen microdialysate levels of amphetamine and dopamine in rats after multiple doses of d-amphetamine
Ann. N. Y. Acad. Sci.
Amphetamine levels in brain microdialysate, caudate/putamen, substantia nigra and plasma after dosage that produces either behavioral or neurotoxic effects
J. Pharmacol. Exp. Ther.
Cited by (113)
The role of serotonin in declarative memory: A systematic review of animal and human research
2022, Neuroscience and Biobehavioral ReviewsThe role of serotonin in learning and memory: a rich pallet of experimental studies
2020, Handbook of Behavioral NeuroscienceObject Novelty Recognition Memory
2018, Handbook of Behavioral NeuroscienceDifferential effects of MDMA and cocaine on inhibitory avoidance and object recognition tests in rodents
2017, Neurobiology of Learning and MemoryThe neurotoxicity of amphetamines during the adolescent period
2015, International Journal of Developmental NeuroscienceCitation Excerpt :The results suggest that MDMA exposure during adolescence can alter subsequent cognitive and affective function, in the absence of severe damage to the serotonergic system, since only mild decreases were found in 5-HT binding at PND 70 (Piper and Meyer, 2004). Administration of MDMA also showed the ability to produce deficits in working memory and promote anxiety-related responses in adult rats (Gurtman et al., 2002; Mechan et al., 2002; Morley et al., 2001). Moreover, exposure to MDMA (5, 10, or 20 mg/kg, s.c., twice daily) promoted changes in the learning and memory ability (Broening et al., 2001).
Serotonergic pharmacology in animal models: From behavioral disorders to dyskinesia
2014, Neuropharmacology