Development and Preclinical Testing of a Vaccine for 3,4‐Methylenedioxypyrovalerone ((R,S)‐MDPV) Substance Use Disorders

Abstract

Synthetic cathinones like 3,4‐methylenedioxypyrovalerone ((R,S)‐MDPV) are medically dangerous psychoactive drugs which at high doses produce psychosis, cardiovascular toxicity, and death. The goal for these studies was to develop and test a vaccine for treating ((R,S)‐MDPV) substance use disorders. A racemic MDPV conjugate vaccine was developed from a hapten structure capable of generating antibodies that bind with high affinity to (R,S)‐MDPV and other potent synthetic cathinones. We hypothesized that treatment with an optimized MDPV vaccine could produce high affinity antibodies against (R,S)‐MDPV capable of mitigating the pharmacological effects of (R,S)‐MDPV. An (R,S)‐MDPV‐like hapten was conjugated to different carrier proteins, mixed with Sigma Adjuvant System, and used to immunize male Sprague Dawley rats (n=5/group). The immunochemical characteristics of the rats' immune response was then evaluated. The KD value as determined by radioimmunoassay for (R,S)‐MDPV binding was 2.5 ± 1.9 nM, which demonstrated production of high affinity antibodies. The KD value for the individual (R)‐ and (S)‐MDPV binding was 0.71 ± 0.8 nM and 2.8 ± 2.3 nM, respectively. These similar KD values for the MDPV enantiomers indicates antibodies for both enantiomers contribute to the high binding of (R,S)‐MDPV. The rat antisera also showed similar high affinity binding of (R,S)‐α‐pyrrolidinovalerophenone (α‐PVP). No significant cross reactivity was detected with over‐the‐counter medications like (+)‐pseudoephedrine, neurotransmitters (dopamine, norepinephrine, epinephrine, and serotonin), or non‐cathinone drugs of abuse (cocaine, morphine, phencyclidine, (+)‐methamphetamine, (+)‐MDMA, and (−)‐MDMA). Moreover, the vaccination protocol produced high serum antibody titers, determined by rapid equilibrium dialysis, from 5 weeks after the start of immunizations until termination of the rats 3 months later. Finally, locomotor studies of control and vaccinated rats were conducted to test the vaccine's efficacy using a series of increasing doses of (R,S)‐MDPV (0.3–5.6 mg/kg, sc, 2 days apart). The immunized rats displayed significantly (p<0.05) lower MDPV‐induced locomotor activity and a significantly shorter duration of action compared to controls. In conclusion, active vaccination with an (R,S)‐MDPV conjugate vaccine produced very high affinity antibodies against (R,S)‐MDPV; and the vaccinated rats showed significantly reduced (R,S)‐MDPV‐induced locomotor effects compared to controls.Support or Funding InformationFunded by NIDA grants DA039195 and T32 GM106999This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.