Active vaccination attenuates the psychostimulant effects of α-PVP and MDPV in rats

Abstract

Recreational use of substituted cathinones continues to be an emerging public health problem in the United States; cathinone derivatives α-pyrrolidinopentiophenone (α-PVP) and 3,4-methylenedioxypyrovalerone (MDPV), which have been linked to human fatalities and show high potential for abuse liability in animal models, are of particular concern. The objective of this study was to develop an immunotherapeutic strategy for attenuating the effects of α-PVP and MDPV in rats, using drug-conjugate vaccines created to generate antibodies with neutralizing capacity. Immunoconjugates (α-PVP-KLH and MDPV-KLH) or the control carrier protein, keyhole limpet hemocyanin (KLH), were administered to groups (N=12) of male Sprague-Dawley rats on Weeks 0, 2 and 4. Groups were administered α-PVP or MDPV (0.0, 0.25, 0.5, 1.0, 5.0 mg/kg, i.p.) in acute drug challenges and tested for changes in wheel activity. Increased wheel activity produced by α-PVP or MDPV in the controls was attenuated in the α-PVP-KLH and MDPV-KLH vaccinated groups, respectively. Rectal temperature decreases produced by MDPV in the controls were reduced in duration in the MDPV-KLH vaccine group. A separate group (N=19) was trained to intravenously self-administer α-PVP (0.05, 0.1 mg/kg/inf) and vaccinated with KLH or α-PVP-KLH, post-acquisition. Self-administration in α-PVP-KLH rats was initially higher than in the KLH rats but then significantly decreased following a final vaccine booster, unlike the stable intake of KLH rats. The data demonstrate that active vaccination provides functional protection against the effects of α-PVP and MDPV, in vivo, and recommend additional development of vaccines as potential therapeutics for mitigating the effects of designer cathinone derivatives.

Δ9-tetrahydrocannabinol attenuates oxycodone self-administration under extended access conditions

“…Oxy-TT (1.0 mg/ml in PBS) or control TT (1.0 mg/ml in PBS), CpG ODN 1826 (5 mg/ml in PBS), and Alhydrogel ® (alum, 10 mg/ml, InvivoGen) and administered intraperitoneally. Rats were administered the conjugate vaccine (Oxy-TT; N=12) or tetanus toxoid only (TT; N=10) on Weeks 0, 2, and 4, adapted from a vaccination protocol previously reported (Nguyen et al, 2016c;Nguyen et al, 2017a). Rats were prepared with chronic intravenous catheters on week 7 of the vaccination protocol and allowed one week of recovery prior to the start of self-administration experiments.…”

Conjugate Vaccine Immunotherapy for Substance Use Disorder

“…5), which consisted of the corresponding hapten-KLH conjugates formulated with alum and CpG ODN. In rats these vaccines could attenuate cathinone-induced hyperlocomotor activity, and the aPVP vaccine reduced self-administration of aPVP (Nguyen et al, 2017a).…”

“…Furthermore, antigen processing of hapten-protein conjugates results in hapten-peptide fragments, and the peptidic portion of these fragments is essential for anchoring the hapten to the MHCII (Avci et al, 2011), which may explain why peptidic linkers can influence hapten immunogenicity. Interestingly, in a recent study of (Stowe et al, 2011;Bremer et al, 2017); oxy/hydrocodone (Kimishima et al, 2017); fentanyl (Bremer et al, 2016); methamphetamine (MH6/ COOH haptens) (Moreno et al, 2011;Collins et al, 2016); cocaine (GNC hapten) (Carrera et al, 1995); nicotine (NIC hapten) (Isomura et al, 2001); and cathinones (Nguyen et al, 2017a).…”

Withdrawal-induced escalated oxycodone self-administration is mediated by kappa opioid receptor function

“…Rats were anesthetized with an isoflurane/oxygen vapor mixture (isoflurane 5% induction, 1-3% maintenance) and prepared with chronic indwelling intravenous catheters as described previously (34)(35)(36). Catheter patency was assessed once a week after the last session of the week, and if catheter patency failure was detected, data that were collected after the previous passing of this test were excluded from analysis.…”