| Methamphetamine (Meth) is a widely abused psychostimulant that causes damage to monoamine nerve terminals, marked by long-term depletions of dopamine (DA) and serotonin (5-HT), but the exact mechanisms by which this damage occurs remain unclear. Drug abuse and stress are highly co-morbid in society and therefore, stress should be considered a co-factor in mediating the deleterious effects of Meth. In fact, recent studies illustrate that stress enhances Meth-induced toxicity to monoamine nerve terminals. As both chronic stress and Meth produce a pro-inflammatory state, the current studies examined the role of neuroinflammation in mediating the effects of chronic stress and/or Meth in rats. Exposure to 10 days of chronic unpredictable stress (CUS) increased proinflammatory transcripts and protein expression of the inflammatory mediator, cyclooxygenase (COX)-2. COX activity, in turn, mediated the stress and Meth-induced increases in the proinflammatory enzyme, matrix metalloproteinase-9 (MMP-9). COX and MMP-9, however, were not responsible for the depletions of 5-HT in the hippocampus observed after the serial exposure to CUS and Meth. In contrast, COX activity mediated the enhancement of Meth-induced striatal monoaminergic damage produced by CUS. In addition to damaging monoaminergic terminals, COX activity could mediate blood-brain barrier (BBB) disruption. Thus the effects of stress and Meth on the BBB were examined. Twenty-four hours after the administration of Meth, only rats pre-exposed to CUS showed evidence of BBB disruption reflected by decreases in occludin and claudin-5 and increases in truncation of beta-dystroglycan, FITC-dextran extravasation, and brain edema. Except for FITC-dextran extravasation, these effects were blocked by the inhibition of COX. All changes other than beta-dystroglycan and edema persisted 7 days later, were paralleled by increases in the inflammatory biomarker, glial fibrillary acidic protein, and were blocked by COX inhibition during and after Meth treatment. These results indicate that stress and Meth synergize to produce a persistent inflammatory state that damages striatal monoaminergic nerve terminals and creates a long-lasting structural and functional BBB disruption. Furthermore, these results suggest that stress can render non-toxic insults toxic through neuroinflammatory mechanisms and implicate the use of anti-inflammatory drugs in combating the neurotoxic effects of chronic stress and drug abuse. |
