Defense Date

2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Patrick M. Beardsley

Abstract

Abuse of prescription opioids has become epidemic and oxycodone is among the most frequently abused of these drugs. Opioid misuse is a risk factor for HIV infection and its chronic use by HIV-infected individuals can be accompanied by worsened progression to AIDS, cellular damage, and behavioral deficits collectively termed “neuroAIDS”. This toxicity is likely attributable, in part, to the interaction of opioids with the neurotoxic HIV-1 Tat protein. The ultimate objective of this dissertation was to characterize the interaction of HIV-1 Tat expression with the abuse-related effects of oxycodone. Physical dependence, drug self-administration, and sensitization are three classes of phenomena observed in laboratory animals suggested to have relevance to opioid dependency. There have been few reports of oxycodone's physical dependence, self-administration, or its sensitization effects in mice; therefore, the initial objective of the present studies was to establish methodologies in the mouse to characterize these effects. Subsequently, these methodologies would be applied to examine the effects of HIV-1 Tat expression on these abuse-related phenomena. A novel escalating dosing regimen (9-33 mg/kg, s.c.) of oxycodone was developed to induce physical dependence in which naloxone dose-dependently (0.1-10 mg/kg, s.c.) increased somatic signs of withdrawal. In other mice administered a similar regimen, precipitated withdrawal effects were observed using the acoustic startle response and its related measure, habituation. These oxycodone regimens also produced evidence of locomotor sensitization. Using a novel oral operant self-administration procedure, C57BL/6J mice volitionally consumed oxycodone solutions (0.056-1.0 mg/ml) under post-prandial conditions to behaviorally-active levels (i.e., produced hyperlocomotion and Straub tail). Subsequently, HIV-1 Tat-expressing mice were examined under these behavioral conditions. HIV-1 Tat-expressing mice showed altered oxycodone abuse-related effects relative to non-expressing mice in that they: (i) increased oral oxycodone self-administration, (ii) had attenuated oxycodone physical dependence-related effects as measured by acoustic startle and habituation, and (iii) had blunted expression of oxycodone locomotor sensitization. Together, these effects are consistent with previous findings of reduced morphine efficacy and dependence in Tat-expressing mice, and suggest that opioid sensitivity is reduced by HIV-1 Tat. Further studies are needed to determine the rate at which opioid sensitivity is altered by HIV-1 Tat expression.

Rights

© Rachel Enga

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-4-2017

Available for download on Friday, May 04, 2018

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