Is brain gliosis a characteristic of chronic methamphetamine use in the human?

Animal data show that high doses of the stimulant drug methamphetamine can damage brain dopamine neurones; however, it is still uncertain whether methamphetamine, at any dose, is neurotoxic to human brain. Since gliosis is typically associated with brain damage and is observed in animal models of methamphetamine exposure, we measured protein levels (intact protein and fragments, if any) of markers of microgliosis (glucose transporter-5, human leukocyte antigens HLA-DRα [TAL.1B5] and HLA-DR/DQ/DPß [CR3/43]) and astrogliosis (glial fibrillary acidic protein, vimentin, and heat shock protein-27) in homogenates of autopsied brain of chronic methamphetamine users (n=20) and matched controls (n=23). Intact protein levels of all markers were, as expected, elevated (+28%-1270%, P<0.05) in putamen of patients with the neurodegenerative disorder multiple system atrophy (as a positive control) as were concentrations of fragments of glial fibrillary acidic protein, vimentin and heat shock protein-27 (+170%-4700%, P<0.005). In contrast, intact protein concentrations of the markers were normal in dopamine-rich striatum (caudate, putamen) and in the frontal cortex of the drug users. However, striatal levels of cleaved vimentin and heat shock protein-27 were increased (by 98%-211%, P<0.05), with positive correlations (r=0.41-0.60) observed between concentrations of truncated heat shock protein-27 and extent of dopamine loss (P=0.006) and levels of lipid peroxidation products 4-hydroxynonenal (P=0.046) and malondialdehyde (P=0.11). Our failure to detect increased intact protein levels of commonly used markers of microgliosis and astrogliosis could be explained by exposure to methamphetamine insufficient to cause a toxic process associated with overt gliosis; however, about half of the subjects had died of drug intoxication suggesting that "high" drug doses might have been used. Alternatively, drug tolerance to toxic effects might have occurred in the subjects, who were all chronic methamphetamine users. Nevertheless, the finding of above-normal levels of striatal vimentin and heat shock protein-27 fragments (which constituted 10-28% of the intact protein), for which changes in the latter correlated with those of several markers possibly suggestive of damage, does suggest that some astrocytic "disturbance" had occurred, which might in principle be related to methamphetamine neurotoxicity or to a neuroplastic remodeling process. Taken together, our neurochemical findings do not provide strong evidence for either marked microgliosis or astrogliosis in at least a subgroup of human recreational methamphetamine users who used the drug chronically and shortly before death. However, a logistically more difficult quantitative histopathological study is needed to confirm whether glial changes occur or do not occur in brain of human methamphetamine (and amphetamine) users.

Brain serotonin transporter in human methamphetamine users.

RATIONALE: Research on methamphetamine (MA) toxicity primarily focuses on the possibility that some of the behavioural problems in human MA users might be caused by damage to brain dopamine neurones. However, animal data also indicate that MA can damage brain serotonin neurones, and it has been suggested that cognitive problems and aggression in MA users might be explained by serotonergic damage. As information on the brain serotonin system in human MA users is fragmentary, our objective was to determine whether protein levels of serotonin transporter (SERT), a key marker of serotonin neurones, are decreased in brain of chronic MA users. METHODS: SERT immunoreactivity was measured using an immunoblotting procedure in autopsied brain of 16 chronic MA users testing positive for the drug in blood and brain and matched controls. RESULTS: SERT levels were non-significantly decreased (-14% to -33%) in caudate, putamen and thalamus (normal in hippocampus), and, unlike the robust striatal dopamine reduction, there was marked overlap between control and MA user ranges. Concentrations of SERT were significantly decreased (-23% to -39%) in orbitofrontal and occipital cortices (normal in frontopolar and temporal cortices). CONCLUSIONS: Our data suggest that MA might modestly damage brain serotonin neurones and/or inhibit SERT protein expression, with cerebral cortex being more affected than sub-cortical regions. The SERT reduction in orbitofrontal cortex complements other data suggesting involvement of this area in MA-related behaviour. Decreased brain SERT could also be related to the clinical finding that treatment with a selective serotonin re-uptake inhibitor might increase relapse to MA.

Why is parkinsonism not a feature of human methamphetamine users?

For more than 50 years, methamphetamine has been a widely used stimulant drug taken to maintain wakefulness and performance and, in high doses, to cause intense euphoria. Animal studies show that methamphetamine can cause short-term and even persistent depletion of brain levels of the neurotransmitter dopamine. However, the clinical features of Parkinson's disease, a dopamine deficiency disorder of the brain, do not appear to be characteristic of human methamphetamine users. We compared dopamine levels in autopsied brain tissue of chronic methamphetamine users with those in patients with Parkinson's disease and in a control group. Mean dopamine levels in the methamphetamine users were reduced more in the caudate (-61%) than in the putamen (-50%), a pattern opposite to that of Parkinson's disease. Some methamphetamine users had severely decreased dopamine levels, within the parkinsonian range, in the caudate (up to 97% dopamine loss) but not in the putamen. As the putamen and caudate subserve aspects of motor and cognitive function, respectively, our data suggest that methamphetamine users are not parkinsonian because dopamine levels are not sufficiently decreased in the motor component of the striatum. However, the near-total reduction in the caudate could explain reports of cognitive disturbances, sometimes disabling, in some drug users, and suggests that treatment with dopamine substitution medication (e.g. levodopa) during drug rehabilitation might be helpful.

Decreased striatal dopamine D1 receptor-stimulated adenylyl cyclase activity in human methamphetamine users.

OBJECTIVE: It has been assumed that some behavioral changes associated with repeated exposure to dopaminergic psychostimulant drugs might be explained by changes in activity of dopamine receptors, including the dopamine D(1) receptor, which is linked by a stimulatory G protein to the effector enzyme adenylyl cyclase. To establish whether dopamine D(1) receptor function might be altered in human methamphetamine users, the authors measured dopamine-stimulated adenylyl cyclase activity in the brain of chronic human users of the drug. METHOD: Adenylyl cyclase activity stimulated by dopamine and by guanylyl-imidodiphosphate (to assess G protein and adenylyl cyclase coupling) was determined in the postmortem brain tissue of 16 methamphetamine users who had used the drug both recently and chronically (i.e., at least 1 year) as well as 21 matched comparison subjects. RESULTS: A 25%-30% decrease in the maximal extent of dopamine stimulation of adenylyl cyclase activity was seen in the striatum (nucleus accumbens, caudate, and putamen) of the methamphetamine users. No changes were found in basal or guanylyl-imidodiphosphate-stimulated enzyme activity. CONCLUSIONS: These data suggest that dopamine receptor function linked to adenylyl cyclase is partially desensitized in the striatum of human methamphetamine users. Decreased dopamine D(1) receptor function might underlie part of the known (drug withdrawal syndrome) or expected (drug tolerance) consequences of methamphetamine exposure in humans.

Asphyxial deaths caused by automobile exhaust inhalation not attributable to carbon monoxide toxicity: study of 2 cases.

The authors report two suicides that resulted from the intentional inhalation of automobile exhaust gases in which death occurred without the formation of physiologically significant amounts of carboxyhemoglobin. These circumstances are correlated with measurements of the involved vehicles' exhaust gases, which showed reduced concentrations of carbon monoxide present, reflecting improvements in automobile engine technology. In the absence of carbon monoxide toxicity, the authors attribute death in these cases to asphyxia caused by carbon dioxide intoxication and diminished atmospheric oxygen concentrations.

Decreased activity of brain phospholipid metabolic enzymes in human users of cocaine and methamphetamine.

Phospholipids are essential components of cell membranes which may also function to mediate some of the behavioural effects of dopamine receptor stimulation caused by psychostimulant drugs. Neuroimaging and pharmacological data suggest that abnormal brain metabolism of phospholipids might explain some of the consequences of chronic exposure to drugs of abuse including drug craving. We previously reported decreased activity of calcium-stimulated phospholipase A(2) (Ca-PLA(2)) in autopsied putamen of human cocaine users. To establish the specificity of this change in phospholipid metabolism and whether decreased Ca-PLA(2) might be a general feature of all abused drugs which enhance dopaminergic neurotransmission, we measured activity of 11 major phospholipid metabolic enzymes in dopamine-rich (putamen) and poor brain areas of chronic users of cocaine and of methamphetamine. Enzyme changes were restricted to the putamen which showed decreased (-21%, as compared with the control subjects) Ca-PLA(2) activity in users of methamphetamine and reduced (-31%) activity of phosphocholine cytidylyltransferase (PCCT), the rate-limiting enzyme of phosphatidylcholine synthesis, in the cocaine users. We suggest that chronic exposure to psychostimulant drugs might cause a compensatory downregulation of Ca-PLA(2) in dopamine-rich brain areas due to excessive dopamine-related stimulation of the enzyme. Decreased striatal Ca-PLA(2) and/or PCCT activity in cocaine users might also help to explain why CDP choline, which enhances phospholipid synthesis, reduces craving in some users of the drug cocaine.