No abstract

1 The pharmacology of the acute hyperthermia that follows 3,4-methylenedioxymethamphetamine (MDMA,`ecstasy') administration to rats has been investigated. 2 MDMA (12.5 mg kg 71 i.p.) produced acute hyperthermia (measured rectally). The tail skin temperature did not increase, suggesting that MDMA may impair heat dissipation.

1 Administration of 3,4-methylenedioxymethamphetamine (MDMA,`ecstasy') to mice produces acute hyperthermia and long-term degeneration of striatal dopamine nerve terminals. Attenuation of the hyperthermia decreases the neurodegeneration. We have investigated the mechanisms involved in producing the neurotoxic loss of striatal dopamine. 2 MDMA produced a dose-dependent loss in striatal dopamine concentration 7 days later with 3 doses of 25 mg kg 71 (3 h apart) producing a 70% loss. ) increased 2,3-dihydroxybenzoic acid formation from salicylic acid perfused through a microdialysis tube implanted in the striatum, indicating increased free radical formation. This increase was prevented by AR-R17477AR administration. Since AR-R17477AR was also found to have no radical trapping activity this result suggests that MDMA-induced neurotoxicity results from MDMA or dopamine metabolites producing radicals that combine with NO to form tissuedamaging peroxynitrites.

A large body of data indicates that (7)3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') can damage brain serotonin neurons in animals. However, the relevance of these preclinical data to humans is uncertain, because doses and routes of administration used in animals have generally differed from those used by humans. Here, we examined the pharmacokinetic profile of MDMA in squirrel monkeys after different routes of administration, and explored the relationship between acute plasma MDMA concentrations after repeated oral dosing and subsequent brain serotonin deficits. Oral MDMA administration engendered a plasma profile of MDMA in squirrel monkeys resembling that seen in humans, although the half-life of MDMA in monkeys is shorter (3 vs 6-9 h). MDMA was biotransformed into MDA, and the plasma ratio of MDA to MDMA was 3-5/100, similar to that in humans. MDMA accumulation in squirrel monkeys was nonlinear, and plasma levels were highly correlated with regional brain serotonin deficits observed 2 weeks later. The present results indicate that plasma concentrations of MDMA shown here to produce lasting serotonergic deficits in squirrel monkeys overlap those reported by other laboratories in some recreational 'ecstasy' consumers, and are two to three times higher than those found in humans administered a single 100-150 mg dose of MDMA in a controlled setting. Additional studies are needed on the relative sensitivity of brain serotonin neurons to MDMA toxicity in humans and non-human primates, the pharmacokinetic parameter(s) of MDMA most closely linked to the neurotoxic process, and metabolites other than MDA that may play a role.

The behavioural consequences of a single neurotoxic dose of MDMA can be demonstrated over 2 months after administration of the compound, thereby indicating that long-term adaptive changes occur within the brain following the neurodegeneration of 5-HT neurones produced by this recreationally used drug.

While the high level of anxiety-like behaviour of DA rats versus SD rats could prove useful in future ethological studies on anxiety, the fact that acute handling decreased the anxiety-like behaviour on the elevated plus maze may limit the value of this strain for the study of putative anxiolytic drugs.

Pharmacotherapy with amphetamine is effective in the management of attention-deficit/hyperactivity disorder (ADHD), now recognized in adults as well as in children and adolescents. Here we demonstrate that amphetamine treatment, similar to that used clinically for adult ADHD, damages dopaminergic nerve endings in the striatum of adult nonhuman primates. Furthermore, plasma concentrations of amphetamine associated with dopaminergic neurotoxicity in nonhuman primates are on the order of those reported in young patients receiving amphetamine for the management of ADHD. These findings may have implications for the pathophysiology and treatment of ADHD. Further preclinical and clinical studies are needed to evaluate the dopaminergic neurotoxic potential of therapeutic doses of amphetamine in children as well as adults.Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neuropsychiatric illness, afflicting 3 to 9% of school-age children and 1 to 5% of adults worldwide (Leung and Lemay, 2003;Biederman and Faraone, 2004;Wilens et al., 2004). For years, psychomotor stimulant drugs have been the mainstay of ADHD treatment (Greenhill et al., 2002;Fone and Nutt, 2005), and in the last decade, their use has increased substantially (Olfson et al., 2003;Robison et al., 2004). Of the various stimulant drugs used in the treatment of ADHD, amphetamine is among the most often prescribed (Greenhill et al., 2002;Fone and Nutt, 2005), both in children and adults (Wilens et al., 2004;Dodson, 2005).As the use of amphetamine in the treatment of ADHD has increased, a large body of preclinical data has accrued indicating that amphetamine has the potential to damage brain dopamine-containing neurons in experimental animals. In particular, animals treated with amphetamine develop lasting reductions in striatal dopamine, its major metabolite dihydroxyphenylacetic acid (DOPAC), its rate-limiting enzyme tyrosine hydroxylase, its membrane transporter (DAT), and its vesicular transporter (VMAT 2 ) (Gibb et al., 1994;McCann and Ricaurte, 2004). Anatomic studies indicate that lasting dopaminergic deficits after amphetamine are due to damage of dopaminergic nerve endings in the striatum, with sparing of dopaminergic nerve cell bodies in the substantia nigra.Despite these preclinical data and growing awareness of potential long-term adverse effects of stimulant ADHD medications (Volkow and Insel, 2003;Fone and Nutt, 2005), there has been little expressed concern over possible dopaminergic neurotoxicity in humans receiving amphetamine for the treatment of ADHD. In large measure, this appears to be due to the fact that, as noted by various authors (Vitiello, 2001a,b;Greenhill et al., 2002;Fone and Nutt, 2005), doses, routes, and regimens of administration used in amphetamine neurotoxicity studies in animals differ significantly from those used in the treatment of ADHD.The purpose of the present study was to determine whether amphetamine treatment, similar to that used clini-

A neurotoxic dose of MDMA resulted in impaired thermoregulation when rats were exposed to high ambient temperature. 5-HT1A receptor mechanisms were unaltered. Impaired serotonergic function following MDMA presumably alters the neurotransmitter balance, thereby compromising thermoregulation. Heavy recreational users of MDMA may also have impaired thermoregulation and thus be at greater risk of an acute adverse response to MDMA in a hot crowded dance environment.