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Angoa-Perez M.,Research and Development Service 11R | Angoa-Perez M.,Wayne State University | Kane M.J.,Research and Development Service 11R | Kane M.J.,Wayne State University | And 12 more authors.
Journal of Neurochemistry | Year: 2013

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its re-uptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20, or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (four injections of 2.5 or 5.0 mg/kg at 2 h intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT, and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and 3,4-methylenedioxymethamphetamine on DA nerve endings. In contrast, nomifensine protected against methamphetamine-induced neurotoxicity. As mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity. Mephedrone is a psychoactive component of 'bath salts'. Despite its remarkable structural similarity to the neurotoxic amphetamines, mephedrone is not neurotoxic. Mephedrone is often co-abused with amphetamines, and data presented here show that when combined with methamphetamine, amphetamine, or MDMA, mephedrone significantly increases the neurotoxicity of the latter drugs. These findings focus much needed attention on the dangers associated with this designer drug of abuse. © 2012 International Society for Neurochemistry. Source

Angoa-Perez M.,Research and Development Service 11R | Angoa-Perez M.,Wayne State University | Kane M.J.,Research and Development Service 11R | Kane M.J.,Wayne State University | And 10 more authors.
ACS Chemical Neuroscience | Year: 2014

Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Selective serotonin reuptake inhibitors (SSRIs) are the most common treatment for depression, and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and rate-limiting enzyme in the biosynthetic pathway of 5HT in the CNS, and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their antidepressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2-/- mice on the sucrose preference test, tail suspension test, and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2-/- mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2-/- mouse questions the role of 5HT in depression. Furthermore, the TPH2-/- mouse may serve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system. © 2014 American Chemical Society. Source

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