Effects of active anti-methamphetamine vaccination on intravenous self-administration in rats
Introduction
d-Methamphetamine (METH) abuse and addiction continues to be a serious public health concern for which successful treatment remains elusive (SAMHSA, 2010). Behavioral therapy shows moderate success (Roll et al., 2006), but maintaining long-term abstinence is a challenge for recovering addicts. Pharmacotherapies also have limited efficacy for treating METH addiction (Karila et al., 2010, Vocci and Appel, 2007), and additional approaches are needed. Immunopharmacotherapy has shown promise as a treatment for drug addiction in recent years (Gentry et al., 2009, Janda and Treweek, 2012, LeSage et al., 2006b, Moreno and Janda, 2009, Shen et al., 2013). In outline, conjugate vaccines stimulate drug-specific antibodies that sequester drug molecules in the blood stream, thereby reducing distribution to the brain.
Clinical trials for vaccines against cocaine (Haney et al., 2010, Kosten et al., 2002, Martell et al., 2009) and nicotine (Cornuz et al., 2008, Hatsukami et al., 2011) were advanced due to promising pharmacokinetic and behavioral results from preclinical studies. Anti-nicotine vaccines generate nicotine-specific antibodies (Cerny et al., 2002, de Villiers et al., 2004, Pentel et al., 2000), reduce brain nicotine concentrations (de Villiers et al., 2004, Pentel et al., 2000), and delay nicotine elimination (Keyler et al., 1999, Keyler et al., 2005). Similar pharmacokinetic results exist for anti-cocaine vaccines (Carrera et al., 1995). Behavioral effects of drugs such as cocaine (Carrera et al., 1995, Carrera et al., 2001, Carrera et al., 2000, Kantak et al., 2001, Kantak et al., 2000, Wee et al., 2012) and nicotine (Carrera et al., 2004, LeSage et al., 2006a, Lindblom et al., 2002, Roiko et al., 2008) are likewise attenuated by vaccination. Kantak et al. (2001) reported that vaccination decreased cocaine intravenous self-administration (IVSA) in rats by about 30%. Wee et al. (2012) showed that vaccination reduced cocaine IVSA in rats across several phases of the self-administration procedure, including a dose–response assessment, progressive ratio schedule, extinction and reinstatement. (LeSage et al. 2006a) reported that 70% of controls while only 36% of vaccinated rats acquired nicotine IVSA, and that by the end of the study vaccination reduced the amount of nicotine self-administered by 38%. Collectively, these successes prompted the development of vaccines capable of opposing the actions of METH.
An initial study found no effect of an active anti-METH vaccine on METH-induced locomotor activity (Byrnes-Blake et al., 2001) but recent findings show that active vaccination with the MH6-KLH conjugate vaccine (Moreno et al., 2011) blocks METH-induced locomotor and thermoregulatory disruptions in rats (Miller et al., 2013), and another vaccine alters METH-induced locomotion in mice (Shen et al., 2013). Lastly, active vaccination altered METH IVSA in rats; that is, vaccinated rats initially self-administered more METH than controls, but then self-administration decreased to a level indistinguishable from controls as the response requirement progressively increased across sessions (Duryee et al., 2009).
The current study investigated the effects of an anti-METH vaccine on METH IVSA, with a primary focus on the acquisition of self-administration. Since drug dependence is a minority outcome for most humans who sample a given drug (Anthony et al., 1994, Schramm-Sapyta et al., 2009), prevention of the establishment of a compulsive use pattern is important to model pre-clinically. Although anti-drug vaccine investigators frequently assume that broad spectrum vaccination of, e.g., adolescents is unimaginable, the approval and acceptance of a vaccine against human papilloma virus (Constantine et al., 2007, Shi et al., 2007) shows such views are unduly pessimistic. Preclinical investigators should determine what is biologically possible rather than fail to do so based on suppositions about what might be approved as an eventual treatment. We have previously shown that the MH6-KLH conjugate vaccine is capable of sequestering METH in the blood compartment of the rat while decreasing brain levels and that actively vaccinated rats are protected from thermoregulatory and locomotor effects of METH (Miller et al., 2013). Consequently, rats were not lever trained prior to self-administration sessions, the response requirement remained constant throughout the study, and two different training doses were used (unlike the Duryee et al. study). Effect of vaccination across a range of METH doses during the maintenance phase of self-administration was investigated, along with an assessment of antibody titers and plasma METH concentrations at the end of the study.
Section snippets
Animals
Male Sprague-Dawley rats (Experiment 1: N = 24; Experiment 2: N = 18; Charles River, NY, USA) weighing ∼250 g on arrival were group housed in clear shoebox cages in a vivarium with a 12:12 reverse light-dark cycle. Food pellets and water were available ad libitum in the vivarium. All studies were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and under protocols approved by the Institutional Animal Care and Use Committee (IACUC) of The Scripps Research
Acquisition
The percentage of rats reaching self-administration criterion by session 13 was lower for the MH6-KLH group (66%) than the KLH group (100%; Fig. 1A). A Wilcoxon survival analysis confirmed a significant group difference (p < 0.05). Similarly, there was a main effect of group on the number of days until acquisition criteria were met (t(22) = −2.216; p < 0.05; Fig. 1B) with KLH-control rats reaching acquisition a mean of 3 days earlier than MH6-KLH-vaccinated rats.
The number of METH infusions increased
Discussion
This study is the first to show that active immunopharmacotherapy attenuated the rate of the acquisition of d-methamphetamine (METH) intravenous self-administration (IVSA) in rats by using the MH6-KLH conjugate vaccine previously shown to attenuate locomotor and thermoregulatory effects of METH, as well as to reduce METH entry to the brain (Miller et al., 2013, Moreno et al., 2011). The delay in acquisition was substantial, with less than 17% of the vaccinated group reaching acquisition
Role of funding source
The study was conducted under the support of USPHS grant DA024705 (MAT). The NIH/NIDA had no role in study design, collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.
Contributors
MAT designed the study with significant input from MLM and SMA. KMC, SMA and MLM collected and organized the in vivo data, and completed initial data analyses. AYM and KDJ designed and created the MH6 conjugate vaccine and AYM performed antibody titer assessments. MLM and SMA conducted literature searches and provided summaries of previous related work. MAT undertook the statistical analysis and MAT, SMA and MLM created figures and drafted the manuscript. All authors contributed to and have
Conflict of interest
The authors have no conflicts of interest to report for this study.
Acknowledgement
This is manuscript #21938 from The Scripps Research Institute.
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