TL neuro

June 22, 2018

An oxycodone vaccine prevents the acquisition of self-administration

Filed under: Opiates, Vaccines — mtaffe @ 2:59 pm

A paper from the laboratory has recently been accepted for publication .

Nguyen*, J.D., Hwang*, C.S., Grant, Y., Janda, K.D.. and Taffe, M.A. Prophylactic vaccination protects against the development of oxycodone self-administration.  Neuropharmacology, 2018, 138:292-303. [ Publisher Link ][ Free Author Share ]

This paper reflects joint effort with members of the Janda laboratory in our ongoing collaboration [ related posts ] to evaluate their anti-drug vaccines for efficacy in rat models of drug exposure and abuse. In this study we focused on a vaccine that induced antibodies that bind to oxycodone and evaluated the efficacy of this active vaccine (Oxy-TT) versus the carrier protein tetanus toxoid (TT). Our primary goal was to examine the intravenous self-administration of oxycodone in the rats.

This reorganization of Figure 2 from the paper depicts one of the key findings. The right panel shows the average number of infusions of oxycodone (0.06 mg/kg/infusion) obtained by subgroups of the Oxy-TT and TT rats. This median split analysis divides the Upper from Lower halves of the distribution based on average oxycodone responding across the 18 session acquisition interval. The distribution for the Oxy-TT group was more bimodal compared with the TT control group, indicating that some Oxy-TT rats took very little oxycodone across the acquisition period and some self-administered more. We defined successful acquisition as an average of 7 or more infusions obtained across two sequential days and the left panel reflects the proportion of the entire distributions of TT versus Oxy-TT that met this standard. Combined, we can infer that about 40% of the Oxy-TT animals essentially failed to acquire stable self-administration behavioral whereas all of the TT group did under these conditions. While it may seem disappointing to some eyes that the vaccine “worked” to prevent the establishment of stable self-administration in only 40% of the animals, this needs to be viewed in the context of human substance abuse. Only minorities of the individuals who try a given drug will go on to develop a habitual use pattern. This can be observed (cross-sectionally) in the Monitoring the Future data [vol 1 adolescents; vol 2 adults], in Schramm-Sapyta et al 2009 and in Anthony et al, 1994. The best way to reduce harm from repetitive use problems with drugs is to prevent it from progressing to this stage in the first place. Our study shows that the Oxy-TT vaccine is potentially capable of protecting a substantial subset of those individuals who sample a drug enough to become habitual users.

These panels from Figure 5 of the paper show that there was basic biological efficacy of the vaccine. These data show the plasma (left panel) and brain (right panel) amounts of oxycodone in the two vaccine groups after administration of 1.0 or 2.0 mg/kg subcutaneously. This shows that considerably more oxycodone is in the plasma of the Oxy-TT groups (as is expected since the antibodies should retain drug in the bloodstream and not let it get into other tissues. Lesser amounts of oxycodone were in the brains of the Oxy-TT group as well which is again consistent with the anticipated effects of successful anti-drug vaccination.

The second major behavioral finding is a bit more subtle. As you can see from the first figure, above, the Oxy-TT rats that did acquire self-administration responded for more drug than did the TT control animals. This is consistent with the second figure, i.e., that less of each infusion of drug was reaching the brain. Thus, assuming the rats on average seek the same approximate amount of drug in their brain, the vaccine resulted in an increase in self-administration behavior. In order to probe the extent to which the rats prefer to self-administer oxycodone we increased the workload. In training the rats only had to make one lever response for each infusion of drug, known as a Fixed Ratio 1 (FR1) contingency. But the Progressive Ratio procedure makes each successive infusion within the daily session cost more. When we did that, the Oxy-TT animals decreased their intake to a greater extent than did the TT rats. This figure is from a second cohort of rat groups that were trained to self-administer a

higher per-infusion dose (0.15 mg/kg/inf) of oxycodone. Under these conditions the Lower half of the Oxy-TT group self-administered about the same amount of drug as the entire TT group and the Upper half self-administered more. The figure depicts mean intake, post-acquisition, in four different workload conditions, starting and ending with the FR1 training condition. The two middle bars depict the oxycodone intake under two PR schedules which differ in steepness of the incrementing workload. There was a change for the TT group only in the hardest PR condition but this did not reach statistical significance. In contrast the overall number of infusions in a session that were obtained by the Oxy-TT animals (this is for the entire group) were reduced when it took more responses to obtain successive infusions. This shows that despite self-administering slightly more oxycodone when it is easy to get (FR1), the Oxy-TT animals are more likely to reduce their intake when the conditions are made slightly more difficult. Making drugs more difficult to obtain is, of course, one of the population level strategies we use to combat drug addiction. This is reflected in taxes and the regulation of sales of alcohol and tobacco that have been proven to reduce problematic use of these legal substances. Parents routinely use different strategies to make it more difficult for their teenagers to access drugs of all types. Many therapeutic interventions for drug abusers involve lifestyle changes that make getting access to drug more laborious. Thus, a strategy that makes an individual more liable to reduce their drug use when the costs increase has the potential for success in reducing drug use harms.

This last finding also has important implications for the design of human clinical trials that attempt to test the efficacy of anti-drug vaccines. The default approach has been to use measures of drug use as the measure of “success” of the trial. These data suggest that vaccinated people could use the same or even slightly more drug and still be getting a protective effect. That is, they might become more susceptible to other interventions which, for example, raise the cost or effort of getting drug.

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*authors contributed equally

Funding for this work provided by USPHS Grants R01 DA035281, R01 DA024705, UH3 DA041146 (K.D.J.) and F32 AI126628 (C.S.W.).

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