TL neuro

March 19, 2017

Vaccination against methamphetamine works in female rats

Filed under: Methamphetamine, Vaccines, Vape inhalation, Vapor Inhalation — mtaffe @ 9:32 am

We have shown that a vaccine designed to blunt the effects of methamphetamine works in male rats in two prior publications, summarized here and here. We have also had success showing that vaccines directed against the synthetic cathinones MDPV (“bathsalts”) and alpha-PVP (“flakka”) work to reduce the effects of those drugs. A brief video outlining the approach to generating vaccines that might be helpful for drug abused created by NIDA can be found here.

The following has recently been accepted for publication:

Nguyen, J.D., Bremer, P.T., Hwang, C.S., Vandewater, S.A., Collins, K.C., Creehan, K.M., Janda, K.D. and Taffe, M.A. Effective active vaccination against methamphetamine in female rats, Drug Alcohol Depend, 2017, 175:179-186. [Publisher Site] [PubMed]

In this study we show that an increase in the amount that female rats move around their cages after an injection of methamphetamine is reduced in the MH6-KLH vaccinated rats.

As you can see in the explainer video, the main principle of anti-drug vaccination is that antibodies can bind some of the drug molecules (methamphetamine in this case) in the bloodstream, thereby preventing them from getting into the brain. This capacity to retain methamphetamine is relatively fixed at a given point in the vaccine sequence, thus administering a sufficiently high dose can (should) overcome the protection.

In our data, the effects of the vaccine were dose dependent. This is Figure 4 from the paper which depicts locomotor activity rates (counts per minute) in the MH6-KLH and KLH groups in the first and second hours after injection of methamphetamine in three doses [Significant differences from the Vehicle and 0.25 mg/kg within Group and Hour are indicated by ยง, from Vehicle (only) by # and from the 0.5 mg/kg condition by &. ]. There is a dose-dependent increase in activity rate compared with the vehicle injection condition. With respect to the active vaccination group, complete protection was found at the 0.25 mg/kg dose and partial protection at 0.5 mg/kg compared with the KLH group; the two groups were about the same after 1.0 mg/kg was injected. This further enhances our ability to interpret these data as a specific effect of the vaccination and to determine where the threshold for effective protection may lie.

There was another finding in this study which was slightly disappointing in terms of the vaccine study but greatly enhanced our understanding of another thing that we have been working on, namely vapor inhalation techniques to deliver drugs to rats for various research purposes. Most specifically we showed that e-cigarette type vapor inhalation of methamphetamine (and MDPV and mephedrone) increases the activity of male rats to a similar extent as it does when injected (blogpost overview). We used this model in the present study as well and confirmed that just as with male rats, the female rats activity in the cage was increased after vapor inhalation of methamphetamine to about the same extent as after the injected doses. Therefore up to this point in time we were assuming that the dose delivered to the rat was approximately similar when similar behavioral results were produced.

Unfortunately there was no difference in the effects of inhaled methamphetamine across the vaccinated and control groups of rats. We originally interpreted this as potentially a difference in the rate of drug penetration into the brain which minimized the ability of the vaccine-generated antibodies to prevent locomotor effects.

Upon reviewer request we then examined the blood levels of methamphetamine after injection (0.25, 1.0 mg/kg, i.p.) and the inhalation condition in a different group of unvaccinated female rats. We found that methamphetamine was about ten times higher in the blood after inhalation versus injection in this new study. This of course explains why the vaccinated group was not protected, i.e., the dose under inhalation was far past the ability of the antibodies to sequester in the bloodstream.

The curious thing is still why a similar level of locomotor activity was produced at the 10-fold difference in methamphetamine levels. Very likely this is due to the rate at which drug is delivered to the animal- in our inhalation model this takes place over 30 minutes whereas an injection takes seconds. Obviously one of our next avenues of research is to better determine the way that drug levels increase in the blood during vapor inhalation.

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