A vaccine against methamphetamine attenuates its behavioral effects in mice
Introduction
Methamphetamine (MA) abuse has grown at alarming rates in the United States over the past two decades and is spreading across Southeast and East Asia (Gonzales et al., 2010, McKetin et al., 2008). Currently, there are no FDA approved medications for treating MA addiction. The highly addictive effects of MA likely relates to its known central and peripheral sympathomimetic effects (Darke et al., 2008, Fowler et al., 2007, Volkow et al., 2010) and to its ability to release multiple neurotransmitters, including dopamine (DA), norepinephrine (NE), serotonin (5-HT), histamine, and gamma-aminobutyric acid (GABA), from synaptic vesicles (Sulzer et al., 2005). Due to this multiplicity of effects, MA is much less likely than other drugs of abuse to be treated effectively with specific pharmacological antagonists or substitute agonists.
An increasing appealing approach to drug addiction treatment is to use conjugate drug vaccines to induce specific antibody blockade of abused drugs. Conjugate vaccines developed against cocaine and nicotine has progressed to clinical trials (Hatsukami et al., 2005, Martell et al., 2009). Data from these trials suggest that many patients may not produce a sufficient antibody response, but of those who do, drug use is reduced and abstinence rates can be quite good (Hatsukami et al., 2011, Martell et al., 2009, Maurer and Bachmann, 2007). An anti-MA vaccine could also be a viable treatment approach for this addiction. Several laboratories have been working on evaluating the best composition for an MA vaccine. For example, Janda's group has recently evaluated three MA-KLH conjugates vaccines that generated substantial antibody titers with good affinity (Moreno et al., 2011). There are several choices in vaccine construction, including hapten design, selection of the carrier protein, the chemical positioning of a linker between the target antigen and the carrier protein, and selection of the adjuvant (Byrnes-Blake et al., 2001, Moreno et al., 2011, Peterson et al., 2007).
In theory, an anti-MA vaccine would generate antibodies that bind to MA so that when MA is subsequently introduced into the bloodstream, those antibodies would bind to it and form antibody-MA complexes within the circulatory system. Such complexes should be too large to readily cross the blood–brain barrier and therefore would reduce the rate or amount of MA entry into the brain. Antibody-bound drug would then be slowly released from antibody binding in the equilibrium state as residual-free drug to be metabolized and eliminated. Reduction in either rate or amount of MA entering the brain should attenuate its behavioral effects, including its ability to be rewarding. Here, we report on the effects of one such construct, succinyl-methamphetamine-keyhole limpet hemocyanin (SMA-KLH), in mice.
We assessed the ability of SMA-KLH to generate antibodies in mice by measuring serum titers across a 35-week period. In addition, we tested the functional effects of SMA-KLH by examining whether vaccinated mice would show attenuated behaviors induced by MA administration. Two behavioral assays were chosen based on known actions of MA and other psychostimulants in mice and rats. These were locomotor activity and conditioned place preference (CPP). MA and other psychostimulants, such as cocaine, increase locomotor activity at moderate doses and can induce stereotypic responses, such as sniffing, head bobbing, and other in-place activities, at higher doses (Antoniou et al., 1998, Brien et al., 1978, Ellinwood and Balster, 1974, Kuczenski and Segal, 1989). However, at very low doses, cocaine and amphetamine can cause hypolocomotion in rats and mice (George, 1989, George, 1990) and we recently confirmed this observation with MA in mice (Kitahama and Valatx, 1979, Singh et al., 2012). CPP is a procedure that has been used to assess the rewarding properties of many drugs (Bardo and Bevins, 2000, Carr et al., 1989, Schechter and Calcagnetti, 1993, Tzschentke, 1998). In CPP, drug administrations are paired with a distinct context while vehicle is paired with a different context. After several conditioning trials, the animal is allowed access to both contexts and the degree to which it approaches and spends more time in the drug-paired context is thought to measure drug reward.
Section snippets
Animals and housing
Female BALB/c mice were bred in the Houston VAMC vivarium from mice originally purchased from Charles River Laboratories (Wilmington, MA). Mice were 8 weeks of age and weighed approximately 20 g at the start of the study. They were group-housed (5 per cage) under temperature- and humidity-controlled conditions with a 12:12 h light/dark cycle (lights on from 0600). Food and water were available ad libitum. Procedures were approved by the Institutional Animal Care and Use Committee in accordance
Serum anti-MA titers
Titers of MA antibodies induced by administration of SMA-KLH were assessed from pooled samples at several time points after the initial injection as seen in Fig. 2. The initial administration of the MA vaccine leads to a modest level of antibody production seen at 2 weeks. Higher titers of MA antibodies are generated after the first vaccine boost given at week 3. Titers are quite high at 4 weeks, peak at 6 weeks, and then decrease to lower levels seen through week 18. There is a stable titer of
Discussion
Results from this evaluation of a succinyl-methamphetamine-keyhole limpet hemocyanin (SMA-KLH) conjugate vaccine support its potential as an anti-MA vaccine. We have shown that the conjugate used in this study, composed of succinyl-methamphetamine molecules covalently linked to a carrier protein derived from the keyhole limpet hemocyanin (KLH) carrier protein and suspended in a monophosphoryl lipid A (MPL) adjuvant, generates MA antibodies in sera of mice. And, the vaccine has functional
Role of funding source
This research was supported by grants DP1DA033502 and U01023898 from The National Institute on Drug Abuse (NIDA). NIDA had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Drs. T.A. Kosten, T.R. Kosten, and Orson have received funding from the NIH and the Department of Veterans Affairs.
Contributors
All authors made significant contributions to the conduct of the study and the manuscript that reports on the results. Drs. Xiaoyun Shen and Therese A. Kosten contributed equally to the conduct of the research and preparation of this manuscript. Specific contributions are as follows: Dr. Shen developed and wrote the protocol, oversaw the conduct of the study, and managed the data sets. Dr. Therese Kosten wrote the manuscript, designed the behavioral studies, crafted the figures and performed
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgments
The authors thank Y. Wu and B. Mao for their excellent technical assistance.
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Contributed equally to the conduct of the research and preparation of the manuscript.