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Effects of a methamphetamine vaccine, IXT-v100, on methamphetamine-related behaviors

  • Courtney M KellerEmail author
  • Allyson L Spence
  • Misty W Stevens
  • S. Michael Owens
  • Glenn F Guerin
  • Nicholas E Goeders
Original Investigation
  • 43 Downloads

Abstract

Rationale:

Vaccines have been developed as a potential treatment for methamphetamine (meth) use disorder (MUD). Immunization with the meth vaccine IXT-v100 has previously been shown to elicit antibodies with high affinity for meth and thus may be an effective treatment for MUD.

Objectives:

These studies were designed to determine the efficacy of IXT-v100 on meth-taking and meth-seeking behaviors in rats.

Methods:

In the acquisition and maintenance study, male and female rats were trained to self-administer meth (0.06 mg/kg/infusion) over an 8-week period following vaccination. In the last 4 weeks, the dose of meth was increased or decreased each week. To assess meth-seeking behavior, the meth-primed reactivity model was used. Rats were trained to self-administer meth for 5 weeks, followed by a 5-week or 11-week forced abstinence period during which the animals were vaccinated. Rats were then placed back into the self-administration chamber immediately after being injected with meth (1 mg/kg, i.p.) but did not receive meth during the session. Responses were recorded and used as a measure of meth seeking.

Results:

Results from the acquisition and maintenance study in Wistar rats show that vaccination with IXT-v100 adjuvanted with glucopyranosyl lipid A stable emulsion decreases the percentage of animals that will self-administer a moderate level of meth. In the meth-primed reactivity studies, results from males showed that vaccination significantly attenuates meth-seeking behavior.

Conclusion:

Together, these results suggest vaccination with IXT-v100 may be effective at decreasing meth-taking and meth-seeking behaviors in humans suffering with MUD.

Keywords

Methamphetamine Self-administration Meth-primed reactivity Acquisition Therapeutic vaccine 

Notes

Funding information

This work was supported by the National Institute on Drug Abuse of the National Institutes of Health (grant number U01DA035511). The grant was awarded to InterveXion Therapeutic with MWS and SMO as co-PD/PI.

Compliance with ethical standards

Disclaimer

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest

SMO has financial and fiduciary interests in InterveXion Therapeutic LLC (Little Rock, AR), a pharmaceutical company. UAMS has licensed intellectual property developed by SMO to InterveXion Therapeutics LLC. MWS is Chief Operating Officer of InterveXion Therapeutics which had a role in the study design, interpretation, and review of the manuscript. CMK, ALS, GFG, and NEG have no conflicts of interest to declare.

References

  1. Anton B, Leff P (2006) A novel bivalent morphine/heroin vaccine that prevents relapse to heroin addiction in rodents. Vaccine 24:3232–3240PubMedCrossRefPubMedCentralGoogle Scholar
  2. Arora R, Haile CN, Kosten TA, Wu Y, Ramakrishnan M, Hawkins LD, Orson FM, Kosten TR (2019) Preclinical efficacy of an anti-methamphetamine vaccine using E6020 adjuvant. Am J Addict 28:119–126PubMedCrossRefGoogle Scholar
  3. Berkowitz B, Spector S (1972) Evidence for active immunity to morphine in mice. Science 178:1290–1292PubMedCrossRefPubMedCentralGoogle Scholar
  4. Bonese KF, Wainer BH, Fitch FW, Rothberg RM, Schuster CR (1974) Changes in heroin self-administration by a rhesus monkey after morphine immunisation. Nature 252:708–710PubMedCrossRefPubMedCentralGoogle Scholar
  5. Byrnes-Blake KA, Carroll FI, Abraham P, Owens SM (2001) Generation of anti-(+)methamphetamine antibodies is not impeded by (+)methamphetamine administration during active immunization of rats. Int Immunopharmacol 1:329–338PubMedCrossRefPubMedCentralGoogle Scholar
  6. Cho AK, Melega WP, Kuczenski R, Segal DS (2001) Relevance of pharmacokinetic parameters in animal models of methamphetamine abuse. Synapse 39:161–166PubMedCrossRefPubMedCentralGoogle Scholar
  7. Coler RN, Baldwin SL, Shaverdian N, Bertholet S, Reed SJ, Raman VS, Lu X, DeVos J, Hancock K, Katz JM, Vedvick TS, Duthie MS, Clegg CH, Van Hoeven N, Reed SG (2010) A synthetic adjuvant to enhance and expand immune responses to influenza vaccines. PLoS One 5:e13677PubMedPubMedCentralCrossRefGoogle Scholar
  8. Coler RN, Day TA, Ellis R, Piazza FM, Beckmann AM, Vergara J, Rolf T, Lu L, Alter G, Hokey D, Jayashankar L, Walker R, Snowden MA, Evans T, Ginsberg A, Reed SG, Team T-S (2018) The TLR-4 agonist adjuvant, GLA-SE, improves magnitude and quality of immune responses elicited by the ID93 tuberculosis vaccine: first-in-human trial. NPJ Vaccines 3:34PubMedPubMedCentralCrossRefGoogle Scholar
  9. Cox BM, Young AB, See RE, Reichel CM (2013) Sex differences in methamphetamine seeking in rats: impact of oxytocin. Psychoneuroendocrinology 38:2343–2353PubMedPubMedCentralCrossRefGoogle Scholar
  10. Cruickshank CC, Dyer KR (2009) A review of the clinical pharmacology of methamphetamine. Addiction 104:1085–1099PubMedCrossRefPubMedCentralGoogle Scholar
  11. De La Garza R, Shoptaw S, Newton TF (2008) Evaluation of the cardiovascular and subjective effects of rivastigmine in combination with methamphetamine in methamphetamine-dependent human volunteers. Int J Neuropsychopharmacol 11:729–741Google Scholar
  12. De La Garza R, Zorick T, Heinzerling KG, Nusinowitz S, London ED, Shoptaw S, Moody DE, Newton TF (2009) The cardiovascular and subjective effects of methamphetamine combined with gamma-vinyl-gamma-aminobutyric acid (GVG) in non-treatment seeking methamphetamine-dependent volunteers. Pharmacol Biochem Behav 94:186–193CrossRefGoogle Scholar
  13. Drevets WC, Gautier C, Price JC, Kupfer DJ, Kinahan PE, Grace AA, Price JL, Mathis CA (2001) Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biol Psychiatry 49:81–96PubMedCrossRefPubMedCentralGoogle Scholar
  14. Duryee MJ, Bevins RA, Reichel CM, Murray JE, Dong Y, Thiele GM, Sanderson SD (2009) Immune responses to methamphetamine by active immunization with peptide-based, molecular adjuvant-containing vaccines. Vaccine 27:2981–2988PubMedCrossRefPubMedCentralGoogle Scholar
  15. Ellis MS, Kasper ZA, Cicero TJ (2018) Twin epidemics: the surging rise of methamphetamine use in chronic opioid users. Drug Alcohol Depend 193:14–20PubMedCrossRefPubMedCentralGoogle Scholar
  16. Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR (2007) New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol 47:681–698PubMedCrossRefPubMedCentralGoogle Scholar
  17. Fox BS, Kantak KM, Edwards MA, Black KM, Bollinger BK, Botka AJ, French TL, Thompson TL, Schad VC, Greenstein JL, Gefter ML, Exley MA, Swain PA, Briner TJ (1996) Efficacy of a therapeutic cocaine vaccine in rodent models. Nat Med 2:1129–1132PubMedCrossRefPubMedCentralGoogle Scholar
  18. Goeders NE, Clampitt DM (2002) Potential role for the hypothalamo-pituitary-adrenal axis in the conditioned reinforcer-induced reinstatement of extinguished cocaine seeking in rats. Psychopharmacology (Berl) 161:222–232CrossRefGoogle Scholar
  19. Goeders NE, Guerin GF (2000) Effects of the CRH receptor antagonist CP-154,526 on intravenous cocaine self-administration in rats. Neuropsychopharmacology 23:577–586PubMedCrossRefPubMedCentralGoogle Scholar
  20. Haile CN, Kosten TA, Shen XY, O’Malley PW, Winoske KJ, Kinsey BM, Wu Y, Huang Z, Lykissa ED, Naidu N, Cox JA, Arora R, Kosten TR, Orson FM (2015) Altered methamphetamine place conditioning in mice vaccinated with a succinyl-methamphetamine-tetanus-toxoid vaccine. Am J Addict 24:748–755PubMedCrossRefPubMedCentralGoogle Scholar
  21. Hatsukami DK, Jorenby DE, Gonzales D, Rigotti NA, Glover ED, Oncken CA, Tashkin DP, Reus VI, Akhavain RC, Fahim RE, Kessler PD, Niknian M, Kalnik MW, Rennard SI (2011) Immunogenicity and smoking-cessation outcomes for a novel nicotine immunotherapeutic. Clin Pharmacol Ther 89:392–399PubMedPubMedCentralCrossRefGoogle Scholar
  22. Holtz NA, Lozama A, Prisinzano TE, Carroll ME (2012) Reinstatement of methamphetamine seeking in male and female rats treated with modafinil and allopregnanolone. Drug Alcohol Depend 120:233–237PubMedCrossRefPubMedCentralGoogle Scholar
  23. Konuma K, Hirai S, Kasahara M (1994) Use and abuse of amphetamines in Japan. Academic Press, Amphetamine and its analogsGoogle Scholar
  24. Kosten TR, Domingo CB, Shorter D, Orson F, Green C, Somoza E, Sekerka R, Levin FR, Mariani JJ, Stitzer M, Tompkins DA, Rotrosen J, Thakkar V, Smoak B, Kampman K (2014) Vaccine for cocaine dependence: a randomized double-blind placebo-controlled efficacy trial. Drug Alcohol Depend 140:42–47PubMedPubMedCentralCrossRefGoogle Scholar
  25. Li QQ, Sun CY, Luo YX, Xue YX, Meng SQ, Xu LZ, Chen N, Deng JH, Zhai HF, Kosten TR, Shi J, Lu L, Sun HQ (2014) A conjugate vaccine attenuates morphine- and heroin-induced behavior in rats. Int J Neuropsychopharmacol:18Google Scholar
  26. Masoro EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev 126:913–922PubMedCrossRefPubMedCentralGoogle Scholar
  27. Maurer P, Jennings GT, Willers J, Rohner F, Lindman Y, Roubicek K, Renner WA, Müller P, Bachmann MF (2005) A therapeutic vaccine for nicotine dependence: preclinical efficacy, and phase I safety and immunogenicity. Eur J Immunol 35:2031–2040PubMedCrossRefPubMedCentralGoogle Scholar
  28. McMillan DE, Hardwick WC, Li M, Gunnell MG, Carroll FI, Abraham P, Owens SM (2004) Effects of murine-derived anti-methamphetamine monoclonal antibodies on (+)-methamphetamine self-administration in the rat. J Pharmacol Exp Ther 309:1248–1255PubMedCrossRefPubMedCentralGoogle Scholar
  29. Milesi-Halle A, Hendrickson HP, Laurenzana EM, Gentry WB, Owens SM (2005) Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats. Toxicol Appl Pharmacol 209:203–213PubMedCrossRefPubMedCentralGoogle Scholar
  30. Miller KD, Roque R, Clegg CH (2014) Novel anti-nicotine vaccine using a trimeric coiled-coil hapten carrier. PLoS One 9:e114366PubMedPubMedCentralCrossRefGoogle Scholar
  31. Miller ML, Aarde SM, Moreno AY, Creehan KM, Janda KD, Taffe MA (2015) Effects of active anti-methamphetamine vaccination on intravenous self-administration in rats. Drug Alcohol Depend 153:29–36PubMedPubMedCentralCrossRefGoogle Scholar
  32. Miller ML, Moreno AY, Aarde SM, Creehan KM, Vandewater SA, Vaillancourt BD, Wright MJ, Janda KD, Taffe MA (2013) A methamphetamine vaccine attenuates methamphetamine-induced disruptions in thermoregulation and activity in rats. Biol Psychiatry 73:721–728PubMedCrossRefGoogle Scholar
  33. Newton TF, De La Garza R, Kalechstein AD, Nestor L (2005) Cocaine and methamphetamine produce different patterns of subjective and cardiovascular effects. Pharmacol Biochem Behav 82:90–97PubMedCrossRefGoogle Scholar
  34. Nguyen JD, Bremer PT, Hwang CS, Vandewater SA, Collins KC, Creehan KM, Janda KD, Taffe MA (2017) Effective active vaccination against methamphetamine in female rats. Drug Alcohol Depend 175:179–186PubMedPubMedCentralCrossRefGoogle Scholar
  35. Pritchard LM, Hensleigh E, Lynch S (2012) Altered locomotor and stereotyped responses to acute methamphetamine in adolescent, maternally separated rats. Psychopharmacology (Berl) 223:27–35CrossRefGoogle Scholar
  36. Rambousek L, Kacer P, Syslova K, Bumba J, Bubenikova-Valesova V, Slamberova R (2014) Sex differences in methamphetamine pharmacokinetics in adult rats and its transfer to pups through the placental membrane and breast milk. Drug Alcohol Depend 139:138–144PubMedCrossRefGoogle Scholar
  37. Ray LA, Bujarski S, Courtney KE, Moallem NR, Lunny K, Roche D, Leventhal AM, Shoptaw S, Heinzerling K, London ED, Miotto K (2015) The effects of naltrexone on subjective response to methamphetamine in a clinical sample: a double-blind, placebo-controlled laboratory study. Neuropsychopharmacology 40:2347–2356PubMedPubMedCentralCrossRefGoogle Scholar
  38. Reichel CM, See RE (2010) Modafinil effects on reinstatement of methamphetamine seeking in a rat model of relapse. Psychopharmacology (Berl) 210:337–346CrossRefGoogle Scholar
  39. Rogers JL, De Santis S, See RE (2008) Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats. Psychopharmacology (Berl) 199:615–624CrossRefGoogle Scholar
  40. Roth ME, Carroll ME (2004) Sex differences in the acquisition of IV methamphetamine self-administration and subsequent maintenance under a progressive ratio schedule in rats. Psychopharmacology (Berl) 172:443–449CrossRefGoogle Scholar
  41. Rothman RB, Baumann MH (2003) Monoamine transporters and psychostimulant drugs. Eur J Pharmacol 479:23–40PubMedCrossRefPubMedCentralGoogle Scholar
  42. Rüedi-Bettschen D, Wood SL, Gunnell MG, West CM, Pidaparthi RR, Carroll FI, Blough BE, Owens SM (2013) Vaccination protects rats from methamphetamine-induced impairment of behavioral responding for food. Vaccine 31:4596–4602PubMedCrossRefPubMedCentralGoogle Scholar
  43. SAMHSA (2017) Key substance use and mental health indicators in the United States: Results from the 2016 National Survey on Drug Use and Health (HHS Publication No. SMA 17-5044, NSDUH Series H-52). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/
  44. Schindler CW, Bross JG, Thorndike EB (2002) Gender differences in the behavioral effects of methamphetamine. Eur J Pharmacol 442:231–235PubMedCrossRefPubMedCentralGoogle Scholar
  45. Schwendt M, Rocha A, See RE, Pacchioni AM, McGinty JF, Kalivas PW (2009) Extended methamphetamine self-administration in rats results in a selective reduction of dopamine transporter levels in the prefrontal cortex and dorsal striatum not accompanied by marked monoaminergic depletion. J Pharmacol Exp Ther 331:555–562PubMedPubMedCentralCrossRefGoogle Scholar
  46. Shen XY, Orson FM, Kosten TR (2012) Vaccines against drug abuse. Clin Pharmacol Ther 91:60–70PubMedCrossRefPubMedCentralGoogle Scholar
  47. Stevens MW, Gunnell MG, Tawney R, Owens SM (2016) Optimization of a methamphetamine conjugate vaccine for antibody production in mice. Int Immunopharmacol 35:137–141PubMedPubMedCentralCrossRefGoogle Scholar
  48. Stevens MW, Ruedi-Bettschen D, Gunnell MG, Tawney R, West CM, Owens SM (2019) Antibody production and pharmacokinetics of METH in rats following vaccination with the METH vaccine, IXT-v100, adjuvanted with GLA-SE. Drug Alcohol Depend 204:107484PubMedCrossRefPubMedCentralGoogle Scholar
  49. Sulzer D, Sonders MS, Poulsen NW, Galli A (2005) Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol 75:406–433PubMedCrossRefPubMedCentralGoogle Scholar
  50. Takashima Y, Tseng J, Fannon MJ, Purohit DC, Quach LW, Terranova MJ, Kharidia KM, Oliver RJ, Mandyam CD (2018) Sex differences in context-driven reinstatement of methamphetamine seeking is associated with distinct neuroadaptations in the dentate gyrus. Brain Sci:8Google Scholar
  51. Tonstad S, Heggen E, Giljam H, Lagerbäck P, Tønnesen P, Wikingsson LD, Lindblom N, de Villiers S, Svensson TH, Fagerström KO (2013) Niccine®, a nicotine vaccine, for relapse prevention: a phase II, randomized, placebo-controlled, multicenter clinical trial. Nicotine Tob Res 15:1492–1501PubMedCrossRefPubMedCentralGoogle Scholar
  52. Venniro M, Zhang M, Shaham Y, Caprioli D (2017) Incubation of methamphetamine but not heroin craving after voluntary abstinence in male and female rats. Neuropsychopharmacology 42:1126–1135PubMedPubMedCentralCrossRefGoogle Scholar
  53. Verrico CD, Haile CN, Newton TF, Kosten TR, De La Garza R (2013) Pharmacotherapeutics for substance-use disorders: a focus on dopaminergic medications. Expert Opin Investig Drugs 22:1549–1568PubMedPubMedCentralCrossRefGoogle Scholar
  54. Villemagne V, Yuan J, Wong DF, Dannals RF, Hatzidimitriou G, Mathews WB, Ravert HT, Musachio J, McCann UD, Ricaurte GA (1998) Brain dopamine neurotoxicity in baboons treated with doses of methamphetamine comparable to those recreationally abused by humans: evidence from [11C]WIN-35,428 positron emission tomography studies and direct in vitro determinations. J Neurosci 18:419–427PubMedPubMedCentralCrossRefGoogle Scholar
  55. Worley MJ, Swanson AN, Heinzerling KG, Roche DJ, Shoptaw S (2016) Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study. Drug Alcohol Depend 162:245–250PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Courtney M Keller
    • 1
    Email author
  • Allyson L Spence
    • 2
  • Misty W Stevens
    • 3
  • S. Michael Owens
    • 3
    • 4
  • Glenn F Guerin
    • 1
  • Nicholas E Goeders
    • 1
  1. 1.Department of Pharmacology, Toxicology & NeuroscienceLSU Health ShreveportShreveportUSA
  2. 2.Regis University School of PharmacyDenverUSA
  3. 3.InterveXion Therapeutics, LLCLittle RockUSA
  4. 4.Department of Pharmacology and ToxicologyUniversity of Arkansas for Medical SciencesLittle RockUSA

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