Elsevier

Vaccine

Volume 31, Issue 41, 23 September 2013, Pages 4596-4602
Vaccine

Vaccination protects rats from methamphetamine-induced impairment of behavioral responding for food

https://doi.org/10.1016/j.vaccine.2013.07.038Get rights and content

Highlights

  • A vaccine (ICKLH-SMO9) for treatment of methamphetamine abuse was tested in rats.

  • Repeated immunization with ICKLH-SMO9 caused no apparent adverse effect.

  • ICKLH-SMO9 protects from methamphetamine-induced reductions in responding for food.

  • METH serum concentrations substantially increased due to anti-METH antibody binding.

  • These studies suggest the vaccine is effective and safe.

Abstract

(+)-Methamphetamine (METH) addiction is a chronic disease that interferes with fundamental brain-mediated behaviors and biological functions like eating. These studies present preclinical efficacy and safety profiles for a METH conjugate vaccine (ICKLH-SMO9) designed to treat METH abuse. ICKLH-SMO9 efficacy and safety were assessed over a 16-week period by monitoring general health and stability of responding in a food maintained behavioral paradigm. Male Sprague–Dawley rats were trained to lever press for food reinforcers until stable behavior was established. Rats (n = 9/group) were then immunized with 100 μg of a control antigenic carrier protein (ICKLH-Cys) or ICKLH-SMO9 in Alhydrogel® adjuvant, with booster immunizations at 4, 8 and 12 weeks. Health, immunization site and behavior were assessed daily. No adverse effects were found. During weeks 14–16, when antibody titers and METH affinity (Kd = 13.9 ± 1.7 nM) were maximal, all rats received progressively higher METH doses (0.3–3.0 mg/kg) every 3–4 days, followed by behavioral testing. Even though the lower METH doses from 0.3 to 1.0 mg/kg produced no impairment in food maintained behavior, 3.0-mg/kg in control rats showed significantly (p < 0.05) reduced response rates and number of reinforcers earned, as well as reduced food intake. In sharp contrast, the ICKLH-SMO9 group showed no changes in food maintained behavior at any METH dose, even though METH serum concentrations showed profound increases due to anti-METH antibody binding. These findings suggest the ICKLH-SMO9 vaccine is effective and safe at reducing adverse METH-induced effects, even at high METH doses.

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.

References (43)

  • T. Akera et al.

    A simple method for the determination of affinity and binding site concentration in receptor binding studies

    Biochim Biophys Acta

    (1977)
  • A. Milesi-Hallé et al.

    Sex differences in (+)-amphetamine- and (+)-methamphetamine-induced behavioral response in male and female Sprague–Dawley rats

    Pharmacol Biochem Behav

    (2007)
  • W.B. Gentry et al.

    (+)-Methamphetamine-induced spontaneous behavior in rats depends on route of (+)METH administration

    Pharmacol Biochem Behav

    (2004)
  • V.V. Pinto et al.

    The effect of adjuvants on the immune response induced by a DBL4varepsilon-ID4 VAR2CSA based Plasmodium falciparum vaccine against placental malaria

    Vaccine

    (2012)
  • N. Nicosia et al.

    The Economic Cost of Methamphetamine Use in the United States, 2005

    (2009)
  • S. Owens et al.

    Monoclonal antibodies as pharmacokinetic antagonists for the treatment of (+)-methamphetamine addiction

    CNS Neurol Disord-DR

    (2011)
  • W.B. Gentry et al.

    Anti-(+)-methamphetamine monoclonal antibody antagonists designed to prevent the progression of human diseases of addiction

    Clin Pharmacol Ther

    (2010)
  • A.K. Cho

    Ice: a new dosage form of an old drug

    Science

    (1990)
  • N.D. Volkow et al.

    Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence

    J Neurosci

    (2001)
  • Y. Sekine et al.

    Brain serotonin transporter density and aggression in abstinent methamphetamine abusers

    Arch Gen Psychiatry

    (2006)
  • J.R. Richards et al.

    Methamphetamine abuse and emergency department utilization

    West J Med

    (1999)
  • Cited by (0)

    View full text