THE EFFECTS OF METHYLENEDIOXYMETHAMPHETAMINE (MDMA, “ECSTASY”) ON MONOAMINERGIC NEUROTRANSMISSION IN THE CENTRAL NERVOUS SYSTEM
Section snippets
INTRODUCTION
Methylenedioxymethamphetamine (MDMA, “Ecstasy”) is a legally restricted amphetamine derivative (Fig. 1) that has become increasingly popular in Europe and North America over the last 10 years because of its euphoria-inducing and mild stimulant properties (Cregg and Tracey, 1993; Cuomo et al., 1994; Green et al., 1995; McKenna and Peroutka, 1990; Steele et al., 1994). MDMA (Ecstasy) is used primarily by young people in large dance and music settings, but sometimes it is used in small social
Monoamine Release and Re-Uptake In Vitro
Nichols et al. (1982)first demonstrated that bath application of MDMA induced release of [3H]5HT from synaptosomes prepared from whole rat brain. This observation was confirmed subsequently by several laboratories and extended to DA release (Schmidt et al., 1987; McKenna et al., 1991), although MDMA is a more potent releaser of 5HT than DA in vitro. MDMA released 5HT from striatal slices at concentrations about 10-fold lower than those that were required to stimulate DA release (Schmidt et al.,
REPEATED MDMA, NEUROCHEMICAL CHANGES
Repeated systemic administration of MDMA to laboratory rats, guinea-pigs or monkeys produces long-lasting decreases in neurochemical and histological indices of serotonin function in the forebrain. MDMA reduces forebrain tissue levels of 5HT and its metabolite 5-hydroxyindolacetic acid (5HIAA) and depresses the activity of tryptophan hydroxylase, the synthetic enzyme for 5HT (Schmidt et al., 1987; Stone et al., 1988). These deficits can persist from weeks to more than a year following multiple
BEHAVIORAL EFFECTS OF MDMA
Ecstasy is rewarding to laboratory animals as well as humans; monkeys will press levers to self-administer MDMA (Beardsley et al., 1986; Lamb and Griffiths, 1987). In addition to its rewarding properties, MDMA produces locomotor hyperactivity, hyperthermia, head-weaving and other components of the “serotonin syndrome” in laboratory animals (Green et al., 1995). Systemic injection of single or multiple doses of MDMA increases locomotor activity in laboratory rats (Gold et al., 1988; Matthews et
ACUTE MDMA EFFECTS ON NEURONAL EXCITABILITY IN BRAIN REGIONS IMPLICATED IN THE REWARDING PROPERTIES OF ABUSED DRUGS
There is some evidence to suggest that MDMA might have direct postsynaptic effects on neuronal excitability as well as indirect effects that are mediated by monoamine release. MDMA binds with similar, relatively high affinities to 5HT2 receptors, α2-adrenoreceptors and M-1 muscarinic cholinergic receptors as to 5HT uptake sites in homogenates of frontal cortex and striatum (Battaglia et al., 1988). Since 5HT2 receptors, α2-adrenoreceptors and M-1 muscarinic receptors are located
REPEATED MDMA EXPOSURE, EFFECTS ON NEURONAL FIRING IN THE NUCLEUS ACCUMBENS
The neurotoxic effects that repeated MDMA has on 5HT-containing axons in the forebrain of laboratory animals are long-lasting. Levels of 5HT are reduced and 5HT immunoreactive fibers are diminished for several months or longer after the last administration of MDMA in some brain regions, including the striatum and nucleus accumbens (Fischer et al., 1995; Scanzello et al., 1993). It is highly likely, therefore, that toxic doses of MDMA would produce long-term changes in serotonergic and perhaps
CONCLUDING REMARKS
A major mechanism by which MDMA produces euphoric effects is undoubtedly by increasing extracellular levels of DA and 5HT in the nucleus accumbens, a property that it has in common with many other abused drugs such as cocaine, alcohol and opiates. However, the potential ways in which this increased extracellular DA and 5HT might interact with presynaptic and postsynaptic receptors to alter neurotransmission in the nucleus accumbens and in brain regions that project to the nucleus accumbens are
Acknowledgements
This research was supported in part by NIH grant DA-08116 to SRW. The authors thank NIDA (MDMA), Janssen Pharmaceuticals (Ketanserin), Eli Lilly Co. (fluoxetine) and Wyeth Research (WAY100135) for gifts of drugs.
References (220)
- et al.
Intracellular recordings from serotonergic dorsal raphe neurons: pacemaker potentials and the effects of LSD
Brain Res.
(1982) - et al.
Effects of haloperidol and sulpiride on dopamine-induced inhibition of nucleus accumbens neurons
Life Sci.
(1983) - et al.
Autoradiographic localization of dopamine D1 and D2 receptors in the rat nucleus accumbens: resistance to differential rearing conditions
Neuroscience
(1991) - et al.
Characterisation and autoradiographic localisation of 5-HT3 receptor recognition sites identified with [3H]-(S)-zacopride in the forebrain of the rat
Neuropharmacology
(1990) - et al.
Pharmacologic profile of MDMA (3,4-methylene-dioxymethamphetamine) at various brain recognition sites
Eur. J. Pharmacol.
(1988) - et al.
Self-administration of methylenedioxymethamphetamine (MDMA) by rhesus monkeys
Drug Alc. Dep.
(1986) - et al.
Facilitation of dopamine release in vivo by serotonin agonists: studies with microdialysis
Eur. J. Pharmacol.
(1991) - et al.
The substituted amphetamines 3,4-methylenedioxymethamphetamine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine
Eur. J. Pharmacol.
(1992) - et al.
Paired-pulse facilitation in the nucleus accumbens following stimulation of subicular inputs in the rat
Neuroscience
(1990) - et al.
In vitro microdialysis: a novel technique for stimulated neurotransmitter release measurements
J. Neurosci. Meth.
(1991)