Author ORCID Identifier

https://orcid.org/0000-0001-7862-1913

Defense Date

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Matthew L. Banks

Abstract

The increase in heroin use is one factor contributing to the current opioid epidemic in the United States. There are three Food and Drug Administration (FDA) approved medications for the treatment of opioid use disorder (OUD), and these include agonist (i.e. methadone and buprenorphine) and antagonist (i.e. naltrexone) therapies. Although these medications are effective for some patients, regulatory constraints for agonist therapies limit access and patient compliance for naltrexone is poor. The development of new therapies, such as immunopharmacotherapies, for the treatment of OUD is a priority for the National Institute of Drug Abuse. A heroin immunopharmacotherapy, or vaccine, produces heroin selective antibodies that bind to and sequester heroin in the periphery. One formulation of a heroin-tetanus toxoid (TT) conjugate vaccine has shown promise in preclinical studies in mice in monkeys but has not been fully assessed to determine independent variables that might impact vaccine effectiveness such as heroin route of administration, species of animal or abuse-related behavioral endpoints. Chapter II of this dissertation aimed to determine effectiveness and selectivity of the heroin-TT conjugate vaccine to alter the antinociceptive effects of subcutaneous and intravenous heroin in male and female rats. In addition, maximal vaccine effects were compared to effects of a positive control naltrexone. Vaccine effectiveness to reduce heroin antinociception was selective, but effectiveness did not depend on route of administration. Furthermore, maximum effects were less than those seen with a clinically meaningful dose of naltrexone. Combining the vaccine with naltrexone enhanced the effectiveness of naltrexone to block the antinociceptive effects of heroin. Chapter III determined vaccine effectiveness and selectivity to block heroin’s discriminative-stimulus effects in nonhuman primates and compared maximal effects produced by vaccine and naltrexone. The heroin vaccine weakly but selectively reduced the abuse-related subjective-like effects of heroin in one of two monkeys. However, chronic naltrexone treatment nonselectively antagonized the abuse-related effects of both heroin and fentanyl, and naltrexone effects were more robust than those of the vaccine. Chapter IV established a translational procedure to assess candidate medication effects on the reinforcing effectiveness of heroin in a heroin versus food choice procedure in rats. In the procedure, rats choose between a liquid food reinforcer and ascending doses of heroin in a 5-component choice procedure. Heroin versus food choice was found to be sensitive to an environmental manipulation of altering response requirement for both reinforcers. Chronic buprenorphine decreased heroin choice, consistent with its FDA-approved indication for treating OUD. Collectively, these data suggest that the current formulation of the heroin-TT conjugate vaccine may not be as effective as naltrexone at decreasing heroin use. However, one potential indication the vaccine may be useful for is as an adjunctive therapy to clinically available agonist or antagonist medications and a heroin versus food choice procedure in rodents would be one way to full assess this preclinically.

Rights

© Kathryn Schwienteck

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-1-2019

Available for download on Monday, April 29, 2024

Included in

Pharmacology Commons

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