MDMA pretreatment leads to mild chronic unpredictable stress-induced impairments in spatial learning.

3,4-Methylenedioxymethamphetamine (MDMA) is a drug of abuse worldwide and a selective serotonin (5-HT) neurotoxin. An important factor in the risk of drug abuse and relapse is stress. Although multiple parallels exist between MDMA abuse and stress, including effects on 5-HTergic neurotransmission, few studies have investigated the consequences of combined exposure to MDMA and chronic stress. Therefore, rats were pretreated with MDMA and exposed 7 days later to 10 days of mild chronic unpredictable stress (CUS). MDMA pretreatment was hypothesized to enhance the effects of CUS leading to enhanced 5-HT transporter (SERT) depletion in the hippocampus and increased anxiety and cognitive impairment. Whereas MDMA alone increased anxiety-like behavior on the elevated plus maze, CUS alone or in combination with MDMA pretreatment did not increase anxiety-like behavior. In contrast, MDMA pretreatment led to CUS-induced learning impairment in the Morris water maze but not an enhanced depletion of hippocampal SERT protein. These results show that prior exposure to MDMA leads to stress-induced impairments in learning behavior that is not otherwise observed with stress alone and appear unrelated to an enhanced depletion of SERT.

The role of oxidative stress, metabolic compromise, and inflammation in neuronal injury produced by amphetamine-related drugs of abuse.

Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are amphetamine derivatives with high abuse liability. These amphetamine-related drugs of abuse mediate their effects through the acute activation of both dopaminergic and serotonergic neurons. Long-term abuse of these amphetamine derivatives, however, results in damage to both dopaminergic and serotonergic terminals throughout the brain. This toxicity is mediated in part by oxidative stress, metabolic compromise, and inflammation. The overall objective of this review is to highlight experimental evidence that METH and MDMA increase oxidative stress, produce mitochondrial dysfunction, and increase inflammation that converge and culminate in the long-term toxicity to dopaminergic and serotonergic neurons.

Augmentation of methamphetamine-induced toxicity in the rat striatum by unpredictable stress: contribution of enhanced hyperthermia.

Stress is known to enhance the abuse of various drugs. Although the effects of chronic stress and the neurotoxicity of methamphetamine (METH) are influenced, in part, by hyperthermia, the role of hyperthermia in the hypothesized stress-induced enhancement of METH-induced dopamine (DA) and serotonin depletions and decreases in vesicular monoamine transporter 2 (VMAT-2) immunoreactivity is unknown. Rats were exposed to 10 days of unpredictable stress and then challenged with METH (7.5 mg/kg, i.p., once every 2 hx4 injections). There were no differences in the extracellular DA concentrations of stressed and non-stressed rats administered METH. Prior exposure to chronic unpredictable stress augmented the acute METH-induced hyperthermia, the decreases in VMAT-2 immunoreactivity, and the depletions of striatal DA and serotonin content. Prevention of enhanced hyperthermia through cooling of chronically stressed rats to levels exhibited by non-stressed but METH-exposed rats blocked the enhanced depletions. This study reports the novel finding that chronic stress enhances METH toxicity through enhanced hyperthermia and suggests that this effect may be mediated by early METH-induced decreases in VMAT-2 immunoreactivity.

Haloperidol treatment after high-dose methamphetamine administration is excitotoxic to GABA cells in the substantia nigra pars reticulata.

The therapeutic management of methamphetamine (METH)-induced psychoses often involves treatment with the typical antipsychotic drug and dopamine D2 receptor antagonist haloperidol. We report here that subchronic haloperidol administration after a high-dose regimen of METH produces a heretofore unrecognized toxicity to GABAergic cells, as reflected by GAD67 mRNA expression histochemistry, in the rat substantia nigra pars reticulata (SNr) through an acute and persistent augmentation of glutamate release, NMDA receptor activation, and DNA fragmentation. The dopaminergic cells in the substantia nigra pars compacta were unaffected by METH or haloperidol alone or the combination of METH and haloperidol. These findings suggest that the current therapeutic management of METH-induced psychoses with haloperidol may be contraindicated because of a resultant GABAergic cell death in the SNr, which may predispose some individuals to the development of hyperkinetic movement disorders and seizures.

Effects of chronic unpredictable stress and methamphetamine on hippocampal glutamate function.

Although stress and methamphetamine (Meth) can independently and acutely affect glutamate transmission in the hippocampus, no studies have examined how chronic unpredictable stress modulates glutamate function and alters glutamate responsiveness to Meth. Therefore, the effects of chronic unpredictable stress on markers of glutamate function and subsequent Meth-induced increases in extracellular glutamate in the dorsal hippocampus were examined. Ten days of chronic unpredictable stress increased the plasmalemmal glial-glutamate transporter 2 (EAAT2) and increased vesicular glutamate transporter-1 (VGLUT1) immunoreactivity in a vesicle associated fraction. In addition, a 2-fold increase in vesicular glutamate content was observed. Chronic stress also enhanced Meth-induced increases in extracellular glutamate in the dorsal hippocampus in a TTX dependent manner. Overall, the finding that chronic stress resulted in an upregulation of glutamate function and an enhanced glutamate response to Meth may have implications for glutamate responsiveness in chronically stressed animals exposed to other challenges or stressors.