Pharmacokinetic, Cardiovascular and Locomotor Effects of alpha‐Pyrrolidinopentiophenone (alpha‐PVP) in Male Sprague Dawley Rats after Active Vaccination

Abstract

Alpha‐pyrrolidinopentiophenone (alpha‐PVP) is a psychoactive synthetic cathinone that elicits pharmacological effects similar to methamphetamine and cocaine and at high doses can produce psychosis, cardiovascular toxicity, and death. The goal for these studies was to characterize the pharmacokinetics (PK) of alpha‐PVP and test an active vaccine for treating alpha‐PVP‐induced effects. The hapten‐protein conjugate vaccine was developed from an alpha‐PVP/MDPV‐like hapten structure capable of generating high affinity antibodies that significantly cross react with both alpha‐PVP and 3,4‐methylenedioxypyrovalerone (MDPV). Previous studies showed the bi‐specific vaccine could significantly reduce locomotor effects of MDPV. For the current studies, we hypothesized that treatment with this vaccine could stimulate production of high affinity antibodies against alpha‐PVP capable of altering the PK disposition and attenuating the cardiovascular and locomotor effects of alpha‐PVP. The hapten was conjugated to immunocyanin monomers of keyhole limpet hemocyanin, mixed with Sigma Adjuvant System, and used to immunize male Sprague Dawley rats (n=6/group) at 0, 3, and 9 weeks. Pharmacological testing occurred between 12–26 weeks from the start of immunizations. For the PK studies, three doses of alpha‐PVP (0.56, 1, and 3 mg/kg) were administered subcutaneously (sc) to control and vaccinated rats (n=6/group/dose); and tail vein blood samples were collected over time. PK values of alpha‐PVP showed linear PK with a half‐life of 1.7 h in controls and a significant (p<0.05) treatment‐dependent difference in the area under the alpha‐PVP concentration time curve between control and vaccinated rats. In a separate group of rats (n=5–6/group), cardiovascular parameters recorded by radiotelemetry showed a significantly lower area under the heart rate and blood pressure time curves after 0.56, 1 and 3 mg/kg alpha‐PVP in vaccinated rats compared to controls. Finally, locomotor studies of control and vaccinated rats (n=6/group) were conducted using a series of increasing doses of alpha‐PVP (0.3–5.6 mg/kg, sc, 2 days apart). The immunized rats displayed significantly lower alpha‐PVP‐induced locomotor activity and a significantly shorter duration of action compared to controls. In conclusion, alpha‐PVP has linear PK in control rats, and active vaccination with a bi‐specific conjugate vaccine significantly increased the binding of alpha‐PVP in the serum and reduced alpha‐PVP‐induced cardiovascular and locomotor effects compared to controls.Support or Funding InformationFunded by NIDA grants DA039195 and F31 DA046121, and T32 GM106999This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.