Dataset Information

Active vaccination attenuates the psychostimulant effects of ?-PVP and MDPV in rats.

ABSTRACT: Recreational use of substituted cathinones continues to be an emerging public health problem in the United States; cathinone derivatives ?-pyrrolidinopentiophenone (?-PVP) and 3,4-methylenedioxypyrovalerone (MDPV), which have been linked to human fatalities and show high potential for abuse liability in animal models, are of particular concern. The objective of this study was to develop an immunotherapeutic strategy for attenuating the effects of ?-PVP and MDPV in rats, using drug-conjugate vaccines created to generate antibodies with neutralizing capacity. Immunoconjugates (?-PVP-KLH and MDPV-KLH) or the control carrier protein, keyhole limpet hemocyanin (KLH), were administered to groups (N = 12) of male Sprague-Dawley rats on Weeks 0, 2 and 4. Groups were administered ?-PVP or MDPV (0.0, 0.25, 0.5, 1.0, 5.0 mg/kg, i.p.) in acute drug challenges and tested for changes in wheel activity. Increased wheel activity produced by ?-PVP or MDPV in the controls was attenuated in the ?-PVP-KLH and MDPV-KLH vaccinated groups, respectively. Rectal temperature decreases produced by MDPV in the controls were reduced in duration in the MDPV-KLH vaccine group. A separate group (N = 19) was trained to intravenously self-administer ?-PVP (0.05, 0.1 mg/kg/inf) and vaccinated with KLH or ?-PVP-KLH, post-acquisition. Self-administration in ?-PVP-KLH rats was initially higher than in the KLH rats but then significantly decreased following a final vaccine booster, unlike the stable intake of KLH rats. The data demonstrate that active vaccination provides functional protection against the effects of ?-PVP and MDPV, in vivo, and recommend additional development of vaccines as potential therapeutics for mitigating the effects of designer cathinone derivatives.

SUBMITTER: Nguyen JD

PROVIDER: S-EPMC5385148 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Active vaccination attenuates the psychostimulant effects of α-PVP and MDPV in rats.

Nguyen Jacques D JD Bremer Paul T PT Ducime Alex A Creehan Kevin M KM Kisby Brent R BR Taffe Michael A MA Janda Kim D KD

Neuropharmacology 20161209

Recreational use of substituted cathinones continues to be an emerging public health problem in the United States; cathinone derivatives α-pyrrolidinopentiophenone (α-PVP) and 3,4-methylenedioxypyrovalerone (MDPV), which have been linked to human fatalities and show high potential for abuse liability in animal models, are of particular concern. The objective of this study was to develop an immunotherapeutic strategy for attenuating the effects of α-PVP and MDPV in rats, using drug-conjugate vacc ...[more]

PMID: 27956054

Similar Datasets

Project description:Drug-induced alterations in transcriptional regulation play a central role in establishing the persistent neuroplasticities that occur during drug addiction. Additionally, changes in gene expression associated with drug administration provide valuable insight into the molecular basis of drug abuse. The molecular mechanisms that underlie susceptibility to psychostimulant addiction remain unknown. Identifying the common gene transcriptional responses to psychostimulants can provide a mechanistic insight to elucidate the molecular nature of drug dependence. Male Wistar rats (4 weeks old) were acclimatized for a week to their housing conditions prior to experiments. Thereafter, they were divided into two groups: (cohort 1) 4 groups of rats (n=12 rats per group) given saline only (i.p., "drug-naive" rats); and (cohort 2): 3 groups of rats given either methamphetamine, amphetamine or methylphenidate (5 mg/kg,i.p., M-CM-"M-bM-^BM-,M-EM-^Sdrug-pretreated") for 7 days (2x daily) prior to behavioral assays. Conditioned place preference (CPP) tests were conducted a day after the final drug administration. Rats which showed CPP were evaluated for self-administration of the psychostimulants. [Cohort 1] A day after the final self-administration test, brains of 2-3 rats from each subgroups (i.e. those which showed the most robust self-administration), as well as 5 rats from the control group were removed for microarray analysis. The striatum (rostral part of the caudate putamen and the nucleus accumbens [NAc]) and the prefrontal cortex were dissected and immediately frozen at -70M-CM-^BM-BM-0C. Total RNA was isolated and gene expression profiling was conducted on independent pools of total RNA from 2-5 animals per group. [Cohort 2] A day after the final self-administration test, brains of 3 rats from each subgroups (i.e. those which showed the most robust self-administration), as well as 3 rats from the control group were removed for microarray analysis. The striatum (rostral part of the caudate putamen and the nucleus accumbens [NAc]) and the prefrontal cortex were dissected and immediately frozen at -70M-BM-0C. Total RNA was isolated and gene expression profiling was conducted on independent pools of total RNA from three animals per group.

Project description:Cholestasis is a hepatobiliary condition that manifests as acute or chronic and results from disruptions in the bile flow, formation, or secretion processes. The Farnesoid X receptor (FXR) is a vital target for the therapy of cholestasis since it regulates BA homeostasis. Despite the discovery of multiple active FXR agonists, there are still no effective treatments for cholestasis. Papaverine is identified as an FXR agonist.This study investigates papaverine's efficacy and probable mechanism in protecting against alpha naphthylisothiocyanate (ANIT) induced cholestasis. Thirty male albino rats were divided into three groups, each with ten rats. Group I (control) rats were administered 1 mL/kg corn oil 48 h before sacrifice; group II rats were orally administered 100 mg/kg ANIT. Group III received a 200 mg/kg dosage of papaverine over seven consecutive days. A single dose of ANIT at a concentration of 100 mg/kg was orally administered on the fifth day; group II and III animals were euthanized 48 h after inducing cholestasis, and serum concentrations of liver function tests and total bile acid (TBA) were measured. Besides measuring the inflammatory mediator's tumor necrosis factor-alpha (TNF-α) and interleukin 1 (IL-1β), antioxidant markers such as superoxide dismutase (SOD) and glutathione (GSH) were also assessed. The findings indicated the enhancement in the liver function test and total bile acids, as well as in liver histology; papaverine significantly lowered TNF-α and IL-1β while SOD and GSH significantly increased. Additionally, papaverine upregulates Fxr gene expression, bile salt export pump (Besp), small heterodimer partner (shp), hepatocyte nuclear factor 1α (Hnfα), nuclear factor erythroid 2-related factor (Nrf2), heme oxygenase (Ho-1), NAD(P)H quinone oxidoreductase 1 (Nqo1). Furthermore, papaverine increased protein expressions of Sirtuin1. (SIRT 1), FXR, HO-1, and BSEP levels in the rats' livers. The protective effects of papaverine may be attributed to the activation of FXR signaling pathways. These findings revealed that papaverine protects against ANIT-induced Cholestasis.

Project description:Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of substance use vary across individuals. Yet, when rats are allowed to self-administer drugs such as cocaine under short-access conditions, their behavior tends to be well-regulated and homogeneous in nature; though individual differences can emerge when rats are provided long- or intermittent-access to cocaine. In contrast to cocaine, significant individual differences emerge when rats are allowed to self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein ~30% of rats rapidly transition to high levels of drug-taking. This study assessed the SUD-like phenotypes of male and female Sprague Dawley rats self-administering MDPV (0.032 mg/kg/infusion) or cocaine (0.32 mg/kg/infusion) by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to test the hypotheses that: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administered cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long- and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. After short-access, rats that self-administered MDPV exhibited a more severe phenotype than rats that self-administered cocaine. Though long- and intermittent-access to cocaine and MDPV self-administration altered drug-taking patterns, manipulating access conditions did not systematically alter their SUD-like phenotype. Evidence from behavioral and quantitative autoradiography studies suggest that these differences are unlikely due to changes in expression levels of dopamine transporter, dopamine D2 or D3 receptors, or 5-HT1B, 5-HT2A, or 5-HT2C receptors, though these possibilities cannot be ruled out. These results show that the phenotype exhibited by rats self-administering MDPV differs from that observed for rats self-administering cocaine, and suggests that individuals that use MDPV and/or related cathinones may be at greater risk for developing a SUD, and that short-access MDPV self-administration may provide a useful method to understand the factors that mediate the transition to problematic or disordered substance use in humans.

Dataset Information

Active vaccination attenuates the psychostimulant effects of ?-PVP and MDPV in rats.

Publications

Active vaccination attenuates the psychostimulant effects of α-PVP and MDPV in rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets