Enduring changes in brain and behavior produced by chronic amphetamine administration: A review and evaluation of animal models of amphetamine psychosis

The amphetamine derivative (±)-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a popular recreational drug among young people, particularly those involved in the dance culture. MDMA produces an acute, rapid enhancement in the release of both serotonin (5-HT) and dopamine from nerve endings in the brains of experimental animals. It produces increased locomotor activity and the serotonin behavioral syndrome in rats. Crucially, it produces dose-dependent hyperthermia that is potentially fatal in rodents, primates, and humans. Some recovery of 5-HT stores can be seen within 24 h of MDMA administration. However, cerebral 5-HT concentrations then decline due to specific neurotoxic damage to 5-HT nerve endings in the forebrain. This neurodegeneration, which has been demonstrated both biochemically and histologically, lasts for months in rats and years in primates. In general, other neurotransmitters appear unaffected. In contrast, MDMA produces a selective long-term loss of dopamine nerve endings in mice. Studies on the mechanisms involved in the neurotoxicity in both rats and mice implicate the formation of tissue-damaging free radicals. Increased free radical formation may result from the further breakdown of MDMA metabolic products. Evidence for the occurrence of MDMA-induced neurotoxic damage in human users remains equivocal, although some biochemical and functional data suggest that damage may occur in the brains of heavy users. There is also some evidence for long-term physiological and psychological changes occurring in human recreational users. However, such evidence is complicated by the lack of knowledge of doses ingested and the fact that many subjects studied are or have been poly-drug users.

The Pharmacology and Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”)

Parkinson's disease is a devastating neurological condition that affects at least four million people. A striking feature of this disorder is the preferential loss of dopamine-producing neurons in the midbrain. Several aetiological triggers have been linked to Parkinson's disease, including genetic mutations and environmental toxins, but the pathway that leads to cell death is unknown. Recent developments have shed light on the pathogenic mechanisms that underlie the degeneration of these cells. We propose that defective sequestration of dopamine into vesicles, leading to the generation of reactive oxygen species in the cytoplasm, is a key event in the demise of dopaminergic neurons in Parkinson's disease, and might represent a common pathway that underlies both genetic and sporadic forms of the disorder.

Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein.

Ascending projections from the dorsal raphe nucleus (DR) were examined in the rat by using the anterograde anatomical tracer, Phaseolus vulgaris leucoagglutinin (PHA-L). The majority of labeled fibers from the DR ascended through the forebrain within the medial forebrain bundle. DR fibers were found to terminate heavily in several subcortical as well as cortical sites. The following subcortical nuclei receive dense projections from the DR: ventral regions of the midbrain central gray including the 'supraoculomotor central gray' region, the ventral tegmental area, the substantia nigra-pars compacta, midline and intralaminar nuclei of the thalamus including the posterior paraventricular, the parafascicular, reuniens, rhomboid, intermediodorsal/mediodorsal, and central medial thalamic nuclei, the central, lateral and basolateral nuclei of the amygdala, posteromedial regions of the striatum, the bed nucleus of the stria terminalis, the lateral septal nucleus, the lateral preoptic area, the substantia innominata, the magnocellular preoptic nucleus, the endopiriform nucleus, and the ventral pallidum. The following subcortical nuclei receive moderately dense projections from the DR: the median raphe nucleus, the midbrain reticular formation, the cuneiform/pedunculopontine tegmental area, the retrorubral nucleus, the supramammillary nucleus, the lateral hypothalamus, the paracentral and central lateral intralaminar nuclei of the thalamus, the globus pallidus, the medial preoptic area, the vertical and horizontal limbs of the diagonal band nuclei, the claustrum, the nucleus accumbens, and the olfactory tubercle. The piriform, insular and frontal cortices receive dense projections from the DR; the occipital, entorhinal, perirhinal, frontal orbital, anterior cingulate, and infralimbic cortices, as well as the hippocampal formation, receive moderately dense projections from the DR. Some notable differences were observed in projections from the caudal DR and the rostral DR. For example, the hippocampal formation receives moderately dense projections from the caudal DR and essentially none from the rostral DR. On the other hand, virtually all neocortical regions receive significantly denser projections from the rostral than from the caudal DR. The present results demonstrate that dorsal raphe fibers project significantly throughout widespread regions of the midbrain and forebrain.

A PHA-L analysis of ascending projections of the dorsal raphe nucleus in the rat.

Amphetamine is a psychostimulant commonly used to treat several disorders, including attention deficit, narcolepsy, and obesity. Plasmalemmal and vesicular monoamine transporters, such as the neuronal dopamine transporter and the vesicular monoamine transporter-2, are two of its principal targets. This review focuses on new insights, obtained from both in vivo and in vitro studies, into the molecular mechanisms whereby amphetamine, and the closely related compounds methamphetamine and methylenedioxymethamphetamine, cause monoamine, and particularly dopamine, release. These mechanisms include amphetamine-induced exchange diffusion, reverse transport, and channel-like transport phenomena as well as the weak base properties of amphetamine. Additionally, amphetamine analogs may affect monoamine transporters through phosphorylation, transporter trafficking, and the production of reactive oxygen and nitrogen species. All of these mechanisms have potential implications for both amphetamine- and methamphetamine-induced neurotoxicity, as well as dopaminergic neurodegenerative diseases.

New insights into the mechanism of action of amphetamines.

(+/-)-3,4-Methylenedioxymethylamphetamine (MDMA) was administered s.c. to rats (10, 20 or 40 mg/kg b. wt.) and guinea pigs (20 mg/kg) twice a day for 4 days, 2 weeks before decapitation. Norepinephrine, dopamine and serotonin (5-HT) levels were assayed in the hippocampus, hypothalamus, striatum and neocortex. In rats, MDMA produced dose-dependent reductions in 5-HT in all brain regions examined. The highest dose also reduced norepinephrine and/or dopamine in some regions. The 20-mg/kg dose of MDMA depleted 5-HT in all regions of the guinea pig brain assayed. In both species, repeated administration of 20 mg/kg of MDMA reduced the Vmax but not the Km of 5-HT uptake 2 weeks after administration. A single 40-mg/kg injection of MDMA depleted 5-HT 2 and 8 weeks after administration to rats in all regions of the brain examined except the hypothalamus. Administration of 80 mg/kg of MDMA twice a day for 2 days to rats depleted striatal 5-HT and dopamine. Brain sections from rats injected with MDMA according to this dosage regimen were stained by the Fink-Heimer method. Degenerating axon terminals and cell bodies were observed in the striatum and somatosensory cortex, respectively. These findings suggest that MDMA is toxic to serotonergic and, to a lesser extent, catecholaminergic neurons. Some neurons that do not contain these transmitters (neocortical neurons) are also affected.

Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain.

We now report that 6-hydroxydopamine (0.39±0.31 nangrams/mg of tissue at 2 hr) is formed in the rat caudate nucleus after a single injection of methylamphetamine (100 mg/kg). The same dose of methylamphetamine causes approximately 50% depletion of caudate dopamine 2 weeks after the injection. We suggest that the formation of 6-hydroxydopamine from endogenous dopamine is responsible for the neurotoxicity to dopamine terminals seen after methylamphetamine administration.

Formation of 6-hydroxydopamine in caudate nucleus of the rat brain after a single large dose of methylamphetamine.

Dopamine uptake inhibitors block long-term neurotoxic effects of methamphetamine upon dopaminergic neurons

In summary, we have shown that MA is toxic to both 5-HT and DA cells and we have proposed a mechanism that would account for this response, namely, the conversion of the transmitters to neurotoxins. In addition, brain depletions of DA seem regionally specific with larger depletions occurring in some areas than in others. The depletions, however, do not seem to depend entirely on the nuclei of origin, that is, substantia nigra versus VTA. 5-HT was depleted by different amounts in the various regions examined and the 5-HT depletions, although proportional to the DA depletions, were consistently greater. The reasons for this differential sensitivity of the 5-HT and DA systems to the toxic effect of MA is speculative, but may be related to the differential formation of toxins due to the differing availability of oxygen and superoxides at serotonergic and dopaminergic synapses.

Georgetta Vosmer

Papers

Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain.

Formation of 6-hydroxydopamine in caudate nucleus of the rat brain after a single large dose of methylamphetamine.

Dopamine uptake inhibitors block long-term neurotoxic effects of methamphetamine upon dopaminergic neurons

Neurotoxicity in Dopamine and 5‐Hydroxytryptamine Terminal Fields: A Regional Analysis in Nigrostriatal and Mesolimbic Projections

5,6-dihydroxytryptamine, a serotonergic neutotoxin, is formed endogenously in the rat brain