Neuropharmacology and Neurotoxicity of 3,4-Methylenedioxymethamphetamine - Drugs of Abuse: Neurological Reviews and Protocols - page 54

Recently, MDMA also has been shown to increase the release of acetylcho-
line in striatal slices and in the cortex and hippocampus in vivo (14-16) .
Although the MDMA-induced release of acetylcholine in the striatum involves
histaminergic mechanisms (14) , the neurotransmitter interactions underlying
the ability of MDMA to enhance cholinergic function in the cortex and
hippocampus are unknown at present.
The excessive release of dopamine and 5-HT induced by MDMA is thought
to mediate many of the physiological and behavioral effects of the drug. MDMA
produces a 5-HT 2 receptor-dependent increase in the serum concentrations
of the hormones prolactin and corticosterone (17) . MDMA also produces a
marked increase in core body temperature, and evidence supports the view that
activation of 5-HT 2 receptors contributes to this response (17 , 18) . Motor func-
tion also is enhanced by MDMA. A characteristic 5-HT behavioral syndrome is
produced by MDMA (19 , 20) , and low doses of MDMA induce hyperlocomotion
that is mediated, in part, by activation of 5-HT 1B/1D receptors (21) .
Recently, the acute effects of MDMA on social function in rats have been
investigated. Morley and McGregor (22) report that MDMA can elicit both
anxiogenic and anxiolytic effects that are dependent on the test situation
employed. MDMA elicits anxiogenic effects in the elevated plus maze and
the emergence test. Anxiolytic effects of acute MDMA administration are
evident in the reduction of aggressive behavior and increase in the duration
of social interaction (22) .
2. Long-Term Effects of MDMA: 5-HT Neurotoxicity
The single or repeated administration of MDMA consistently has been
shown to result in long-term reductions in (1) 5-HT concentrations in multiple
brain regions of the rat and nonhuman primate (23 , 24) , (2) the density of 5-HT
uptake sites (25) , (3) the activity of tryptophan hydroxylase (26) , and (4) the
density of fi ne axons of 5-HT neurons (27) . The monoamine-depleting effect of
MDMA is selective for 5-HT. Dopamine and norepinephrine concentrations are
unaffected by MDMA; an exception is the mouse, in which MDMA depletes
dopamine (28 , 29) . In nonhuman primates and humans exposed to MDMA,
data from positron emission tomography and single photon emission computed
tomography studies are indicative of MDMA-induced reductions in the density
of 5-HT transporters (30 , 31) .
The effect of MDMA on brain concentrations of 5-HT is biphasic and can be
divided into early and late or long-lasting phases. An early, reversible phase of
5-HT depletion occurs within 3-6 h after its administration, after which 5-HT
concentrations return to normal values (23) . A long-lasting depletion of
5-HT occurs 2-3 d after drug treatment, and this depletion of 5-HT is evident