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dc.contributor.authorNorthrop, Nicole Alia Fazoen_US
dc.date.accessioned2015-08-05T00:57:18Z
dc.date.available2015-08-05T00:57:18Z
dc.date.issued2012
dc.date.submitted2012
dc.identifier.other(ALMA)contemp
dc.identifier.urihttps://hdl.handle.net/2144/12543
dc.descriptionThesis (Ph.D.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.en_US
dc.description.abstractMethamphetamine (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 β-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 β-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.en_US
dc.language.isoen_US
dc.publisherBoston Universityen_US
dc.titleThe role of neuroinflammation in stress & methamphetamine-induced damageen_US
dc.typeThesis/Dissertationen_US
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplinePharmacologyen_US
etd.degree.grantorBoston Universityen_US


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