Vaccination protects rats from methamphetamine-induced impairment of behavioral responding for food
Introduction
(+)-Methamphetamine (METH) abuse is a worldwide problem, causing deleterious effects in users and enormous costs to communities [1], [2]. While METH users report positive effects like increased energy, euphoria and appetite suppression [3], [4]; chronic use results in addiction, organ system dysfunction, weight loss and neurotoxicity [4], [5], [6]. Rather than affecting a single site of action or organ system, METH use interferes with a range of medically important functions [7], [8].
Because METH addiction is a root cause of most METH-associated health problems, a variety of addiction pharmacotherapies have been tested. Unfortunately no drug(s) have proven effective by United States FDA standards, but a few drugs are useful for acute supportive and symptomatic treatment [8]. The most successful addiction therapy is cognitive behavioral intervention, but even when patients successfully complete behavioral treatment, 36% use METH within 6 months and by 13 months 51% are back to METH use [9].
Combining behavioral treatments with medications to lessen the medical impact of METH use could potentially improve patient health and increase the chance of successful treatment [3], [10]. An antibody-based medication could be either anti-METH monoclonal antibody (mAb) [2], [11], [12], [13] or antibodies generated by active immunization with a METH conjugate vaccine [11], [13], [14], [15], [16].
Preclinical rodent studies show that active immunization with haptens (derived from drugs of abuse) conjugated to antigenic proteins can favorably alter behavioral and pharmacokinetic properties of addictive drugs like cocaine, heroin, METH, morphine, nicotine, and oxycodone [11], [17], [18], [19], [20]. Under optimal conditions active immunization can lead to high titer and high affinity immune responses [21], [22], [23], [24], decrease drug-induced locomotor activity [14], [15], [25], [26], [27], [28], prevent drug-induced reinstatement [11], [28] and alter (i.e., increase or decrease) drug self-administration in animal studies [11], [16], [29], [30], [31].
Importantly, studies in rats show METH use during the immunization period does not affect the affinity or titer of the immune response to a METH-conjugate vaccine (MCV) [10]. This is clinically important since many patients are likely to use drugs of abuse during the development of an immune response. While vaccination is a promising treatment, two clinical trials of a nicotine vaccine and one trial of a cocaine vaccine failed to meet their Phase II clinical endpoints [21], [23], [24], [32]. Two shared problems among all three vaccines were a large variation in response and less than optimal affinity for the drug of abuse.
The purpose of the present studies was to evaluate the efficacy and safety of a MCV [11], [13] in rats, and to better understand the potential for clinically approved aluminum-based adjuvants like Alhydrogel® to augment the immune response. Behavioral studies showed that a high METH dose substantially impaired the control rats’ ability to continue stable food maintained behavior, but did not affect the ability of MCV immunized rats to respond for food, or eat the earned food reinforcers, which demonstrated an effective health benefit of the MCV.
Section snippets
Drugs and chemicals
Reagents were purchased from Sigma Aldrich (St. Louis, MO) unless noted otherwise. (+)-Methamphetamine hydrochloride, (+)-amphetamine sulfate (AMP), and 3H-METH (23.5Ci/mmol) were obtained from the NIDA Drug Supply Program. Doses were calculated as the free base.
Vaccines
The METH-like hapten HSMO9 (Fig. 1) was covalently bound to immunocyanin to produce the MCV (ICKLH-SMO9) by the method of Carroll et al. [11]. Immunocyanin (ICKLH; Biosyn Corp., Carlsbad, CA) is derived from native keyhole limpet
Gel and Western blot analysis
While the initial electrophoresis step after maleimide activation of ICKLH did not separate the ∼360 and ∼390 kDa proteins (Fig. 2), the final ICKLH-Cys and ICKLH-SMO9 antigens showed two bands, with a significant and equal amount of METH hapten conjugated to both immunocyanin monomers.
Food maintained behavior performance testing and METH binding over time
Table 1 summarizes the food maintained behavior results before the assignment to immunization groups. Daily testing during the immunization period showed no differences between immunization groups for any measures
Discussion
These studies provide a preclinical efficacy and safety profile for a MCV designed to treat human METH addiction. We chose to use the ability of the animals to maintain stable food maintained behavior as an indication of efficacy, as well as a general measure of animal health. While this is not a standard test of vaccine protection from addiction behaviors, we hypothesized it could be an important measure since METH has significant negative health effects on eating behavior and body weight in
Conclusions
In conclusion, repeated immunization with a high dose of ICKLH-SMO9 produced no adverse effects on health, body weight or performance during food maintained behavioral testing. Even when rats were challenged with increasing METH doses over a two-week period, there were no apparent additive or synergistic interactions between the immunization and METH. Administration of 3.0 mg/kg METH dramatically impaired food maintained behavior in control, but not ICKLH-SMO9 immunized rats. Even though low
Acknowledgements
This work was supported by grants from the National Institute on Drug Abuse (U01 DA23900 and DA05477) and the National Center for Advancing Translational Sciences (UL1TR000039).
Conflict of interest statement: SMO has financial interests in and serves as Chief Scientific Officer for InterveXion Therapeutics LLC (Little Rock, AR), a pharmaceutical biotechnology company focused on treating human drug addiction with antibody-based therapy.
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