Methamphetamine Administration Reduces Hippocampal Vesicular Monoamine Transporter-2 Uptake

Rau, Kristi S.; Birdsall, Elizabeth; Volz, Trent J.; Riordan, James A.; Baucum, Anthony J.; Adair, Brian P; Bitter, R; Gibb, James W.; Hanson, Glen R.; Fleckenstein, Annette E.

doi:10.1124/jpet.105.099200

Cited by 21 publications

(21 citation statements)

References 36 publications

(43 reference statements)

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“…The monoamine transporter, MAT, rapidly transports 5-HT into vesicles. We take the K m of the transporter to be 0.198 μ M as found in [65], which is consistent with the values in [66]. We choose the V max so that the concentration of cytosolic serotonin is very low.…”

Section: Methodsmentioning

confidence: 90%

Serotonin synthesis, release and reuptake in terminals: a mathematical model

Best

Nijhout

Reed

2010

Theor Biol Med Model

127

144

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BackgroundSerotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system.MethodsWe construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data.ResultsWe compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct in silico experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to experimental data. Finally, we study how the properties of the the serotonin transporter and the autoreceptors give rise to the time courses of extracellular serotonin in various projection regions after a dose of fluoxetine.ConclusionsSerotonergic systems must respond robustly to important biological signals, while at the same time maintaining homeostasis in the face of normal biological fluctuations in inputs, expression levels, and firing rates. This is accomplished through the cooperative effect of many different homeostatic mechanisms including special properties of the serotonin transporters and the serotonin autoreceptors. Many difficult questions remain in order to fully understand how serotonin biochemistry affects serotonin electrophysiology and vice versa, and how both are changed in the presence of selective serotonin reuptake inhibitors. Mathematical models are useful tools for investigating some of these questions.

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Section: Methodsmentioning

confidence: 90%

Serotonin synthesis, release and reuptake in terminals: a mathematical model

Best

Nijhout

Reed

2010

Theor Biol Med Model

127

144

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“…The hippocampus receives sparse input from DA afferents, but receives dense inputs from serotonergic afferents (Rau et al, 2006). Thus, it is likely in this region, the toxic effects of MDA adduction have little to do with the DA system and inhibition of ALDH-2 activity.…”

Section: Discussionmentioning

confidence: 99%

Widespread Increases in Malondialdehyde Immunoreactivity in Dopamine-Rich and Dopamine-Poor Regions of Rat Brain Following Multiple, High Doses of Methamphetamine

Horner¹,

Gilbert²,

Cline³

2011

Front. Syst. Neurosci.

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Treatment with multiple high doses of methamphetamine (METH) can induce oxidative damage, including dopamine (DA)-mediated reactive oxygen species (ROS) formation, which may contribute to the neurotoxic damage of monoamine neurons and long-term depletion of DA in the caudate putamen (CPu) and substantia nigra pars compacta (SNpc). Malondialdehyde (MDA), a product of lipid peroxidation by ROS, is commonly used as a marker of oxidative damage and treatment with multiple high doses of METH increases MDA reactivity in the CPu of humans and experimental animals. Recent data indicate that MDA itself may contribute to the destruction of DA neurons, as MDA causes the accumulation of toxic intermediates of DA metabolism via its chemical modification of the enzymes necessary for the breakdown of DA. However, it has been shown that in human METH abusers there is also increased MDA reactivity in the frontal cortex, which receives relatively fewer DA afferents than the CPu. These data suggest that METH may induce neuronal damage regardless of the regional density of DA or origin of DA input. The goal of the current study was to examine the modification of proteins by MDA in the DA-rich nigrostriatal and mesoaccumbal systems, as well as the less DA-dense cortex and hippocampus following a neurotoxic regimen of METH treatment. Animals were treated with METH (10 mg/kg) every 2 h for 6 h, sacrificed 1 week later, and examined using immunocytochemistry for changes in MDA-adducted proteins. Multiple, high doses of METH significantly increased MDA immunoreactivity (MDA-ir) in the CPu, SNpc, cortex, and hippocampus. Multiple METH administration also increased MDA-ir in the ventral tegmental area and nucleus accumbens. Our data indicate that multiple METH treatment can induce persistent and widespread neuronal damage that may not necessarily be limited to the nigrostriatal DA system.

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“…This decrease is likely associated with serotonergic nerve terminals. Since pretreatment with the 5HT reuptake inhibitor, fluoxetine, attenuates both the rapid effect on VMAT-2 and the decrease in 5HT content observed 7 d after METH treatment, the data suggest an association between METH-induced alterations in 5HT hippocampal vesicular uptake and the long-term hippocampal 5HT damage caused by the stimulant (Rau et al, 2006). …”

Section: Acute Effects Of Da Releasers On Vmat-2cmentioning

confidence: 95%