Defense Date

2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Patrick Beardsley

Abstract

Methamphetamine is a psychomotor stimulant that produces hyperactivity and euphoria and can lead to drug-seeking and abuse. An estimate from 2005 put the cost of methamphetamine abuse to society at an estimated 23.4 billion dollars. One of methamphetamine's effects is activation of glial cells and associated neuroinflammatory activity in the periphery and CNS. Glia are responsible for maintaining calcium homeostasis, neuroplasticity, immune activity, and cell signaling. Activation of glia and neuroinflammation are becoming recognized as links in drug abuse-related behavior. The goal of the present work was to assess the ability of ibudilast, AV1013, and minocycline, three glial cell modulating compounds, to attenuate responding in rodent procedures that model different aspects of methamphetamine abuse-related behavior. First, Ibudilast (1.8, 7.5, 13 mg/kg) and AV1013 (10, 30, 56 mg/kg) were examined for their effects on methamphetamine-induced (3 mg/kg) locomotor activity and sensitization in mice, the latter thought to involve neurocircuitry common with drug relapse. Ibudilast and AV1013 dose-dependently attenuated methamphetamine-induced locomotor activity and its sensitization. Second, ibudilast (1, 7.5, 10 mg/kg), AV1013 (1, 10, 30 mg/kg), and minocycline (10, 30, 60 mg/kg) were examined for their effects on methamphetamine self-administration (0.001, 0.03, and 0.1 mg/kg/inf) in rats. All three compounds significantly reduced methamphetamine (0.03 mg/kg/inf) self-administration. Results suggested baseline self-administration rate as a possible determinant of these effects; however, follow-up tests with ibudilast while controlling for baseline response rate dismissed this possibility. Additional follow-up tests identified whether the attenuation of operant response rates was specific to methamphetamine-maintained behavior. Using a behavioral economic approach, all three test compounds were determined to also affect non-nutritive banana pellet-maintained responding when the baseline strengths maintained by methamphetamine and banana pellet delivery were matched. Finally, ibudilast was evaluated for its effects on methamphetamine discrimination in rats, a procedure thought to model clinical subjective effects. Ibudilast (1, 7.5, 10 mg/kg) did not significantly modify methamphetamine’s discriminative stimulus effects when trained at either 1 or 0.56 mg/kg. These results support the hypothesis that attenuation of glial cell activity and neuroinflammation may be linked to some abuse-related behaviors of methamphetamine, reinforcing their examination as novel targets for treating methamphetamine abuse.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

May 2014

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