A vaccine against methamphetamine attenuates its behavioral effects in mice

Abstract

BACKGROUND Vaccines have treatment potential for methamphetamine (MA) addiction. We tested whether a conjugate vaccine against MA (succinyl-methamphetamine–keyhole limpet hemocyanin carrier protein; SMA-KLH) would generate MA antibodies and alter MA-induced behaviors. METHODS Mice were injected with SMA-KLH and received booster administrations 3-and 20-weeks later. Serum antibody titers reached peak levels by 4–6 weeks, remained at a modest level through 18-weeks, peaked again at 22-wks after the second boost, and were still elevated at 35-weeks. At 7 weeks, groups of vaccinated and non-vaccinated mice were administered one of three MA doses (1, 2, or 3 mg/kg) to assess locomotor activity. RESULTS Non-vaccinated mice showed dose-dependent effects of MA with hypolocomotion at the lowest dose and elevated activity levels at the highest dose. Both dose effects were reduced in SMA-KLH groups, particularly low dose-induced hypolocomotion at later times post MA administration. Separate groups of vaccinated and non-vaccinated mice were trained in MA place conditioning at 30-weeks with either 0 (vehicle) or 0.5 mg/kg MA. Although times spent in the MA-paired side did not differ between groups on Test vs. Baseline sessions, SMA-KLH mice conditioned with MA showed reduced conditioned approach behaviors and decreased conditioned activity levels compared to control groups. CONCLUSION These data suggest SMA-KLH attenuates the ability of MA to support place conditioning and reduces or delays its locomotor effects. Overall, results support SMA-KLH as a candidate MA vaccine.

Altered methamphetamine place conditioning in mice vaccinated with a succinyl-methamphetamine-tetanus-toxoid vaccine

“…25 In our previous study, we tested an anti-MA vaccine in mice that was made by attaching the hapten succinyl-methamphetamine (SMA) to KLH and administering it in combination with monophosphoryl lipid A (MPL) as the adjuvant. 6 Although we found that this vaccine generated antibodies, it only marginally attenuated some conditioned effects of MA when assessed in acquisition of place conditioning procedure.…”

“…[3][4][5] An alternative treatment approach for SUDs is immunotherapy that has better compliance since treatments may involve fewer adverse events and only a few injections instead of daily medication dosing. [6][7][8] A number of SUD vaccines are in preclinical development, and some have been tested in humans. [9][10][11][12][13][14][15][16] Overall, preclinical and clinical studies emphasize the importance of generating high antibody levels against the target drug to prevent its entry into the central nervous system (CNS) and thereby reduce relapse.…”

Biologics to treat substance use disorders: Current status and new directions

“…40,42,43,[74][75][76]93 To develop vaccines for treatment of methamphetamine abuse, for which no therapies exist, immunogens containing either native or dimer KLH, or TT, showed promising pre-clinical efficacy in blocking distribution of methamphetamine to the brain and blocking a variety of methamphetamine-induced behaviors, including intravenous self-administration. [94][95][96][97][98] Other carrier proteins have adjuvant-like properties, such as the well-characterized CRM 197 . 99 A cocaine hapten conjugated to the TLR5 agonist flagellin elicited greater cocaine-specific Ab concentrations than the same hapten conjugated to KLH.…”

Treatment with a Monoclonal Antibody against Methamphetamine and Amphetamine Reduces Maternal and Fetal Rat Brain Concentrations in Late Pregnancy

“…Keyler et al (2003Keyler et al ( , 2005 report that immunization with a nicotine vaccine or administration of anti-nicotine antibodies can reduce nicotine concentrations in maternal and fetal rat brains. Preclinical studies of active vaccines for METH suggest this therapeutic approach does not appear to generate the high and controllable levels of antibody concentrations needed to sustain neuroprotection (Miller et al, 2013;Rüedi-Bettschen et al, 2013;Shen et al, 2013). Our data show that a murine anti-phencyclidine (PCP) mAb [mAb6B5 equilibrium dissociation rate constant (K D ) = 1.3 nM] can safely protect pregnant rats and fetuses from PCP-induced adverse health effects even after repeated i.v.…”