Dissertation/Thesis Abstract

Development and Preclinical Testing of a 3,4-Methylenedioxypyrovalerone-like Vaccine in Rats
by McClenahan, Samantha, Ph.D., University of Arkansas for Medical Sciences, 2019, 193; 13904838
Abstract (Summary)

The goal of these studies was to characterize a 3,4-methylenedioxypyrovalerone-like vaccine and evaluate its capacity to protect against the MDPV and α- pyrrolidinovalerophenone-induced behavioral and cardiovascular effects which may be relevant to drug abuse. The hypothesis was that active vaccination with an MDPV-like vaccine could significantly decrease the MDPV- and a-PVP-induced physiological and behavioral effects through alteration of the pharmacokinetics of the drugs.

The first series of studies aimed to characterize the polyclonal antibody response following active vaccination with the MDPV-like vaccine in Sprague-Dawley rats. The affinity and functional titers of the polyclonal antibodies for MDPV were determined. Antibody cross reactivity was also evaluated using other structurally similar synthetic cathinones as well as other endogenous and exogenous compounds. The MDPV-like vaccine was found to produce high affinity antibodies against racemic MDPV, its enantiomers and racemic a-PVP without significant cross-reactivity with other compounds. Preliminary studies of how the vaccine alters the locomotor and pharmacokinetic properties of MDPV and a-PVP revealed reduced locomotor stimulant effects and alterations in pharmacokinetics typical of drug-conjugate vaccines, supporting further evaluation of the vaccine.

The second series of studies aimed to evaluate MDPV-induced cardiovascular effects. The first experiment characterized the effect of rat sex on MDPV-induced cardiovascular effects. MDPV-induced cardiovascular effects were not dependent on sex; therefore, active vaccination was only carried out in male rats for the remainder of the studies. The second experiment in this aim characterized the effect of active vaccination on MDPV-induced cardiovascular effects. Active vaccination with an MDPV-like vaccine significantly decreased the MDPV-induced increase in heart rate and blood pressure in male rats.

The third series of studies aimed to investigate the capacity of the vaccine to alter the reinforcing effects of MDPV. Rats were trained to self-administer cocaine with MDPV substitution under a fixed-ratio (FR) schedule of reinforcement which transitioned to a progressive-ratio (PR) schedule of reinforcement. Following completion of dose- effect curves for both cocaine and MDPV under both schedules, responding was extinguished and cue- and drug-primed reinstatement evaluated for drug seeking behavior. Active vaccination with the MDPV-like vaccine shifted the MDPV dose-effect curve 2.5 to 5-fold to the right under FR and PR, but effectiveness of MDPV was unchanged. Consistent with the antibody specificity demonstrated in vitro (Chapter 2), active vaccination did not alter the reinforcing effects of cocaine under any schedule, but also failed to protect against MDPV-primed reinstatement.

The final study aimed to determine the pharmacokinetics of a-PVP with and without active vaccination in male rats after administration of three different doses of a- PVP. a-PVP exhibited linear serum pharmacokinetics in control rats, but vaccinated rats showed significant reductions in apparent clearance and apparent volume of distribution of a-PVP. Active vaccination with the MDPV-like vaccine significantly increased a- PVP area under the serum-time concentration curve and maximum serum concentration. Brain, heart and kidney tissue concentrations were also significantly reduced between f 0.5 h (heart) and 2 h (brain and kidney) after a-PVP administration.

In conclusion, active vaccination with the MDPV-like vaccine produced high affinity, long-lasing polyclonal antibody titers capable of reducing the physiological, behavioral, and reinforcing effects of MDPV with additional support of use for a-PVP abuse. Overall, these studies support the potential use of drug-conjugate vaccines as supplemental therapy for substance use disorders. However, future experiments should explore the use of a vaccine adjuvant producing more robust immune response and different carrier proteins to increase antibody titers.

Indexing (document details)
Advisor: Owens, Samuel M.
Commitee: Peterson, Eric C., Fantegrossi, William E., Rusch, Nancy, Ward, Keith W.
School: University of Arkansas for Medical Sciences
Department: Interdisciplinary Toxicology
School Location: United States -- Arkansas
Source: DAI-B 81/2(E), Dissertation Abstracts International
Subjects: Pharmacology
Keywords: 4-methylenedioxypyrovalerone, Rat, Vaccine, α-pyrrolidinovalerophenone
Publication Number: 13904838
ISBN: 9781085633802
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