Methamphetamine intoxication causes long-lasting damage to dopamine nerve endings in the striatum. The mechanisms underlying this neurotoxicity are not known but oxidative stress has been implicated. Microglia are the major antigen-presenting cells in brain and when activated, they secrete an array of factors that cause neuronal damage. Surprisingly, very little work has been directed at the study of microglial activation as part of the methamphetamine neurotoxic cascade. We report here that methamphetamine activates microglia in a dose-related manner and along a time course that is coincident with dopamine nerve ending damage. Prevention of methamphetamine toxicity by maintaining treated mice at low ambient temperature prevents drug-induced microglial activation. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which damages dopamine nerve endings and cell bodies, causes extensive microglial activation in striatum as well as in the substantia nigra. In contrast, methamphetamine causes neither microglial activation in the substantia nigra nor dopamine cell body damage. Dopamine transporter antagonists (cocaine, WIN 35,428 [(Ϫ)-2-␤-carbomethoxy-3-␤-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate], and nomifensine), selective D1 (SKF 82958 [(Ϯ)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide]), D2 (quinpirole), or mixed D1/D2 receptor agonists (apomorphine) do not mimic the effect of methamphetamine on microglia. Hyperthermia, a prominent and dangerous clinical response to methamphetamine intoxication, was also ruled out as the cause of microglial activation. Together, these data suggest that microglial activation represents an early step in methamphetamine-induced neurotoxicity. Other neurochemical effects resulting from methamphetamine-induced overflow of DA into the synapse, but which are not neurotoxic, do not play a role in this response.

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Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g., obsessive-compulsive disorder; OCD) and impulse-control (e.g., impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2−/−), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2−/− mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2−/− mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2−/− mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis.

The neurotransmitter dopamine (DA) has long been implicated as a participant in the neurotoxicity caused by methamphetamine (METH), yet, its mechanism of action in this regard is not fully understood. Treatment of mice with the tyrosine hydroxylase (TH) inhibitor α‐methyl‐p‐tyrosine (AMPT) lowers striatal cytoplasmic DA content by 55% and completely protects against METH‐induced damage to DA nerve terminals. Reserpine, by disrupting vesicle amine storage, depletes striatal DA by more than 95% and accentuates METH‐induced neurotoxicity. l‐DOPA reverses the protective effect of AMPT against METH and enhances neurotoxicity in animals with intact TH. Inhibition of MAO‐A by clorgyline increases pre‐synaptic DA content and enhances METH striatal neurotoxicity. In all conditions of altered pre‐synaptic DA homeostasis, increases or decreases in METH neurotoxicity paralleled changes in striatal microglial activation. Mice treated with AMPT, l‐DOPA, or clorgyline + METH developed hyperthermia to the same extent as animals treated with METH alone, whereas mice treated with reserpine + METH were hypothermic, suggesting that the effects of alterations in cytoplasmic DA on METH neurotoxicity were not strictly mediated by changes in core body temperature. Taken together, the present data reinforce the notion that METH‐induced release of DA from the newly synthesized pool of transmitter into the extracellular space plays an essential role in drug‐induced striatal neurotoxicity and microglial activation. Subtle alterations in intracellular DA content can lead to significant enhancement of METH neurotoxicity. Our results also suggest that reactants derived from METH‐induced oxidation of released DA may serve as neuronal signals that lead to microglial activation early in the neurotoxic process associated with METH.

Quinone derivatives of DOPA, dopamine, and N-acetyldopamine inactivate tyrosine hydroxylase, the initial and rate-limiting enzyme in the biosynthesis of the catecholamine neurotransmitters. The parent catechols are inert in this capacity. The effects of the catecholquinones on tyrosine hydroxylase are prevented by antioxidants and reducing reagents but not by scavengers of hydrogen peroxide, hydroxyl radicals, or superoxide radicals. Quinone modification of tyrosine hydroxylase modifies enzyme sulfhydryl groups and results in the formation of cysteinyl-catechols within the enzyme. Catecholquinones convert tyrosine hydroxylase to a redox-cycling quinoprotein. Quinotyrosine hydroxylase causes the reduction of the transition metals iron and copper and may therefore contribute to Fenton-like reactions and oxidative stress in neurons. The discovery that a phenotypic marker for catecholamine neurons can be converted into a redox-active species is highly relevant for neurodegenerative conditions such as Parkinson's disease.

An intensive case management intervention for homeless persons was evaluated by random assignment of 202 cases (involving 213 adults and 70 children) to the intervention or a control group. Full follow-up data (4 interviews: at baseline and at 6-, 12-, and 18-month follow-ups) were available on 98 cases (105 adults and 37 children). The follow-up rates for the 2 groups were not significantly different. Based on 13 repeated measures analyses, there were 3 statistically significant linear time effects (indicating overall change across the follow-up period) and 3 linear Time x Condition interactions (indicating differential change over time for intervention vs. control participants). Regardless of condition, adult participants improved in terms of their experience of homelessness, as well as on physical health symptoms and stressful life events. Condition x Time interactions indicating positive intervention impact were observed on the quality of housing environments, stressful life events, and interviewer ratings of psychopathology.

A computerized analysis of prognostic variables was performed in 96 proven cases of extrahepatic bile duct carcinoma treated over a 24-year period at UCLA. Forty-nine percent of the lesions were in the upper third of the bile ducts and 47% of these were resected, for an operative mortality rate of 23% and a maximum survival rate of 4.5 years. Palliative procedures in this region were associated with a 16% mortality rate and maximum survival rate of three years. The patients whose lesions were in the middle third suffered no operative mortality rate for resection or palliation and had a 12% five-year survival rate, with the longest survivor lasting 11 years. In the lower third lesions, 67% were resected by Whipple's procedures, for an 8% mortality rate and a five-year survival rate of 28% extending to nine years. Resection of these difficult carcinomas offers the best hope of survival but must be weighed against the high operative mortality risk in those lesions located in the hilar region.

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine with close structural analogy to substituted amphetamines and cathinone derivatives. Abuse of mephedrone has increased dramatically in recent years and has become a significant public health problem in the US and Europe. Unfortunately, very little information is available on the pharmacological and neurochemical actions of mephedrone. In light of the proven abuse potential of mephedrone and considering its similarity to methamphetamine and methcathinone, it is particularly important to know if mephedrone shares with these agents an ability to cause damage to dopamine nerve endings of the striatum. Accordingly, we treated mice with a binge-like regimen of mephedrone (4X 20 or 40 mg/kg) and examined the striatum for evidence of neurotoxicity 2 or 7 days after treatment. While mephedrone caused hyperthermia and locomotor stimulation, it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels. Taken together, these surprising results suggest that mephedrone, despite its numerous mechanistic overlaps with methamphetamine and the cathinone derivatives, does not cause neurotoxicity to dopamine nerve endings of the striatum.