Elsevier

Neuroscience

Volume 122, Issue 2, 2003, Pages 499-513
Neuroscience

Methamphetamine-induced deficits of brain monoaminergic neuronal markers: distal axotomy or neuronal plasticity

https://doi.org/10.1016/S0306-4522(03)00476-7Get rights and content

Abstract

We examined the effects of methamphetamine (METH) on monoaminergic (i.e. dopamine and serotonin) axonal markers and glial cell activation in the rat brain. Our findings indicate that the loss of dopamine transporters (DAT), serotonin transporters (5-HTT), vesicular monoamine transporter type-2 (VMAT-2) and glial cell activation induced by METH in the striatum and in the central gray are consistent with a degenerative process. Our novel finding of METH effects on monoaminergic neurons in the central gray may have important implications on METH-induced hyperthermia. In other brain regions examined, DAT and 5-HTT deficits after METH administration were present in the absence of lasting changes in VMAT-2 levels or glial cell activation. Brain regions exhibiting protracted deficits in DAT and/or 5-HTT and VMAT-2 levels also expressed increased levels of [3H]-R-PK11195 binding to peripheral benzodiazepine receptors, a quantitative marker of glial cell activation. Immunohistochemical assessment of microglia and astrocytes confirmed the PBR results. Microglia activation was more pronounced than astrocytosis in affected regions in most METH-exposed brains with the exception of a small number of rats that were most severely affected by METH based on loss of body weight. In these rats, both microglia and astrocytes were highly activated and expressed a distinct regional pattern suggestive of widespread brain injury. The reason for the pattern of glial cell activation in this group of rats is not currently known but it may be associated with METH-induced hyperthermia.

In summary, our findings suggest two neurotoxic endpoints in the brain of METH-exposed animals. Brain regions exhibiting DAT and 5-HTT deficits that co-localize with decreased VMAT-2 levels and glial cell activation may represent monoaminergic terminal degeneration. However, the DAT and 5-HTT deficits in brain regions lacking a deficit in VMAT-2 and glial cell activation may reflect drug-induced modulation of these plasma membrane proteins.

Section snippets

Animal protocol and drug treatment

Adult male Sprague-Dawley rats (225–250 g; Harlan, Indianapolis, IN, USA) were used in all experiments. Animals were individually housed in wire-bottom cages at 22 °C under a 12-h light/dark cycle. METH was dissolved in saline and administered according to the following schedule. Animals were given four i.p. injections of either METH (15 mg/kg as free base) or 0.9% saline vehicle at 2 h intervals. METH was generously supplied and administered to rats in Dr. George Ricaurte's laboratory (Johns

Binding of [3H]-paroxetine to 5-HTT

5-HTT levels were measured using [3H]-paroxetine quantitative autoradiography at 3, 5, and 14 days after METH administration. Due to the widespread distribution of 5-HTT in the CNS, three different levels of the brain were sampled. Brain sections at the level of the striatum, hippocampus and dorsal raphe were selected to examine 5-HTT expression on serotonergic terminal fields and cell bodies. Fig. 1

    Abbreviations used in the figures and tables

    ACg

    anterior cingulate cortex

    Aq

    cerebral aqueduct

    BLA

    basal lateral amygdaloid nucleus

    C

    control

    CG

Discussion

The major findings of this study are: 1) a METH exposure protocol that produces global and lasting deficits in the levels of the plasma membrane transporters DAT and 5-HTT in the rat brain, fails to produce similar global reductions in VMAT-2 levels or marked activation of microglia and astrocytes. The striatum and central gray are brain regions, among those examined, exhibiting significant deficits in DAT and/or 5-HTT and also in VMAT-2 levels and glial cell activation. However, deficits in

Acknowledgements

This work was supported by grants from the National Institute of Environmental Health Sciences (ES07062 to TRG and NIEHS Center grant ES03819). The authors wish to thank Dr. Jim O'Callaghan for reviewing the manuscript and Dr. Brian Schoefield for assistance with microscopy and imaging.

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