TL neuro

December 9, 2016

Vaccination against the effects of MDPV (“bathsalts”) and alpha-PVP (“flakka”)

Filed under: alpha-PVP, Cathinones, MDPV, Vaccines — mtaffe @ 10:10 am

The substituted cathinone stimulants 3,4-methylenedioxypyrovalerone (MDPV) and alpha-pyrrolidinopentiophenone(alpha-PVP) have emerged as significant public health concerns in recent years. These drugs turned out to be monoamine transporter inhibitors with high selectivity for the dopamine transporter. These two compounds lack the monoamine releasing properties of methamphetamine, MDMA and other recently popular cathinone derivatives such as mephedrone and methylone. As we’ve shown, both MDPV and alpha-PVP are highly reinforcing in the rat self-administration paradigm and increase locomotor behavior when injected non-contingently or inhaled with e-cig technology. Although these drugs are still in the early stages of market penetration, the data from our lab as well as several other labs suggest that these will have high abuse liability. Effective countermeasures are therefore likely to be needed in the future.

One method to counteract effects of psychoactive drugs that has been attempted is vaccination; an explainer video from NIDA is available here. In this strategy a drug-like chemical structure is attached to a large protein that generates an immune response. When successful, this immune response creates antibodies that circulate in the blood with the capacity to recognize and bind to the target drug molecule. If this is done to effective levels, the administration of a given dose of drug leads to a reduced response, due to part of the drug dose being bound to antibodies in the bloodstream which prevents from entering the brain.

A paper describing an initial effort to develop a vaccine to provide protection against the effects of MDPV and alpha-PVP has recently been accepted for publication. As with all of our vaccine work to date, this was conducted in collaboration with the Janda laboratory at TSRI.

Nguyen, J.D., Bremer, P.T., Ducime, Creehan, K.M., Kisby, B.R., Taffe, M.A. and Janda, K.D. Active vaccination attenuates the psychostimulant effects of α-PVP and MDPV in rats, Neuropharmacology, 2017, 116:1-8. [PubMed][Publisher Site]

In this study, Paul Bremer and Alex Ducime created vaccine candidates designed to generate antibodies against MDPV and alpha-PVP, respectively. Initially, three groups of male rats were vaccinated to evaluate the MDPV-specific, alpha-PVP-specific vaccines against a group vaccinated with the immunogenic protein (keyhole limpet hemocyanin; KLH). The antibodies in the MDPV-vaccinated group showed high affinity for MDPV but not for alpha-PVP or methamphetamine. Likewise, the antibodies in the alpha-PVP group were selective for alpha-PVP over MDPV or methampetamine.

Brent Kisby, an undergraduate on an extended internship, in combination with Kevin Creehan and Jacques Nguyen first determined if these rats would exhibit functional protection against drug exposure. We selected a wheel-activity response to drug injection (see Huang et al, 2012) because this had proved effective at screening anti-methamphetamine candidate vaccines in our prior study (Miller et al, 2013).
nguyen17-alphavaccfig3-wheel This figure (click to enlarge) shows wheel activity (quarter revolutions) in the four hours following injection with four doses of alpha-PVP (Panels A, B) or four doses of MDPV (Panels C, D). The left hand panels depict the effects of drug in the KLH-only control groups while the right hand panels depict the effects of drug in the respective alpha-PVP-KLH and MDPV-KLH vaccine groups. The asterix indicates a significant change of activity relative to the vehicle (saline) injection condition. The takeaway message here is that doses of alpha-PVP (0.5, 1.0 mg/kg, i.p.) and MDPV (1.0 mg/kg, i.p.) which increase wheel activity in the control group do not do so in the respective vaccine group. The vaccine can be partially surmounted since the 5 mg/kg dose of each drug increased activity in the vaccinated rats, although this increase was numerically lower and lasted less long in the MDPV-KLH and alpha-PVP-KLH animals compared with the control group.

This promising result led to the design of an intravenous self-administration study to test the ability of alpha-PVP-KLH vaccination to alter the course of self-administration. Jacques Nguyen and Kevin Creehan headed up this study.
A group of rats were first trained to self-administer alpha-PVP, prior to any vaccination. This is only the second study to publish the acquisition of alpha-PVP self-administration in an animal model (see Aarde et al, 2015) and we found that a 0.1 mg/kg/infusion dose was required to produce good acquisition in Sprague-Dawley male rats. Thereafter the rats were placed on hiatus from drug self-administration and given a 5 week protocol of three immunizations, divided into two groups- one receiving KLH only and the other receiving alpha-PVP-KLH vaccine. We showed first that on return to self-administration at a reduced per-infusion dose of 0.025 mg/kg/infusion the alpha-PVP-KLH vaccinated animals self-administered more drug. This result is consistent with the circulating antibodies producing partial reduction of the dose as it was self-administered and the corresponding behavioral compensation to produce similar brain levels of drug.
nguyen17-fig7-prepostAfter three weeks the animals were given a booster immunization which resulted in about a doubling of the circulating antibody level (titer). This resulted in no change in the KLH-only animals’ drug intake, however the alpha-PVP-KLH animals changed from a mean of 17-20 infusions per session to a mean of about 4-5 infusions per session, a significant reduction in self administration. This lasted for 15 sessions and is depicted in the figure (click to enlarge) as Post4-Post8 bins of three sequential sessions.

As discussed in the paper this is an initial feasibility study but it shows the potential of the anti-drug immunotherapy strategy to be effective against the effects of both MDPV and alpha-PVP. This should encourage additional work to determine the extent and nature of the protection against these substituted cathinone stimulants that can be achieved with vaccines.

These studies were funded by USPHS grants DA024705, DA042211 and DA037709.
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Additional Reading: A list of our cathinone-related publications can be found here.

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