{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:02:40Z","timestamp":1785416560075,"version":"3.56.0"},"reference-count":57,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gonzalo R\u00edo Arronte Foundation","award":["INP-2000-2040"],"award-info":[{"award-number":["INP-2000-2040"]}]},{"name":"Gonzalo R\u00edo Arronte Foundation","award":["CI-IC092020.2"],"award-info":[{"award-number":["CI-IC092020.2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Introduction: Various models of nicotine vaccines have been evaluated. In humans, antibody levels are low and variable. In this sense, it is necessary to improve or optimize the nicotine vaccines already evaluated. We reported the efficacy of the M6-TT vaccine. Recently, we reported the efficacy of the COC-TT vaccine, which was developed from the M6-TT vaccine. Both vaccines generate high titers of antibodies and attenuate heroin- or cocaine-induced behavioral effects in rodents. Aims and Methods: The objective of this study was to determine whether the antibodies generated by a tetanus toxoid-conjugated nicotine vaccine (NIC6-TT) can produce anti-nicotine antibodies and decrease the nicotine-induced reinforcing and psychomotor effects. Male Wistar rats were immunized with the NIC6-TT. A solid-phase antibody-capture ELISA was used to monitor antibody titer responses after each booster dose in vaccinated animals. The study used nicotine self-administration and nicotine locomotor sensitization testing to evaluate the nicotine-reinforcing and psychomotor effects. Results: The NIC6-TT vaccine could generate high and sustained levels of anti-nicotine antibodies. The antibodies reduced the nicotine self-administration and expression of nicotine locomotor sensitization. Conclusions: These findings suggest that the NIC6-TT vaccine generates a robust immunogenic response capable of reducing the reinforcing and psychomotor effects of nicotine, which supports its possible future use in clinical trials for the treatment of smokers. Implications: Smoking is the second most used psychoactive substance in the world, which is associated with millions of preventable deaths. An effective treatment is required. Nicotine vaccines must generate high levels of anti-nicotine antibodies, but above all, the decay curve of the antibodies must be very slow, so that they can provide long-term protection and support long-term smoking abstinence. The NIC6-TT vaccine meets these properties.<\/jats:p>","DOI":"10.3390\/brainsci15040364","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T05:10:07Z","timestamp":1743397807000},"page":"364","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NIC6-TT Vaccine Reduces Nicotine-Seeking Behavior and Expression of Nicotine-Induced Locomotor Sensitization in Rats"],"prefix":"10.3390","volume":"15","author":[{"given":"Susana","family":"Barbosa M\u00e9ndez","sequence":"first","affiliation":[{"name":"Subdirecci\u00f3n de Investigaciones Cl\u00ednicas, Laboratorio de Neurofarmacolog\u00eda Conductual, Microcirug\u00eda y Terap\u00e9utica Experimental, Instituto Nacional de Psiquiatr\u00eda, M\u00e9xico DF 14370, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1787-1657","authenticated-orcid":false,"given":"Alberto","family":"Salazar-Ju\u00e1rez","sequence":"additional","affiliation":[{"name":"Subdirecci\u00f3n de Investigaciones Cl\u00ednicas, Laboratorio de Neurofarmacolog\u00eda Conductual, Microcirug\u00eda y Terap\u00e9utica Experimental, Instituto Nacional de Psiquiatr\u00eda, M\u00e9xico DF 14370, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1097\/ADM.0000000000001249","article-title":"Adolescent Tobacco\/Nicotine Use and the Potential Role of Contingency Management-based Interventions","volume":"18","author":"Shirazi","year":"2024","journal-title":"J. Addict. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1080\/17437199.2024.2330896","article-title":"Tobacco use; trauma exposure and PTSD: A systematic review","volume":"6","author":"Shevorykin","year":"2024","journal-title":"Health Psychol. Rev."},{"key":"ref_3","first-page":"4","article-title":"Neuronal mechanisms underlying development of nicotine dependence: Implications for novel smoking-cessation treatments","volume":"6","author":"Markou","year":"2011","journal-title":"Addict. Sci. Clin. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1080\/14622299050011361","article-title":"Altered disposition of repeated nicotine doses in rats immunized against nicotine","volume":"1","author":"Keyler","year":"1999","journal-title":"Nicotine Tob. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1016\/S0022-3565(24)37155-1","article-title":"Active immunization alters the plasma nicotine concentration in rats","volume":"283","author":"Hieda","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0091-3057(99)00206-3","article-title":"A nicotine conjugate vaccine reduces nicotine distribution to brain and attenuates its behavioral and cardiovascular effects in rats","volume":"65","author":"Pentel","year":"2000","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1037\/1064-1297.9.2.228","article-title":"Inhibition of nicotine-induced seizures in rats by combining vaccination against nicotine with chronic nicotine infusion","volume":"9","author":"Tuncok","year":"2001","journal-title":"Exp. Clin. Psychopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1159\/000063628","article-title":"Active immunization against nicotine suppresses nicotine-induced dopamine release in the rat nucleus accumbens shell","volume":"69","author":"Lindblom","year":"2002","journal-title":"Respiration"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1159\/000063629","article-title":"Active immunization against nicotine prevents reinstatement of nicotine-seeking behavior in rats","volume":"69","author":"Lindblom","year":"2002","journal-title":"Respiration"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s00213-005-0027-2","article-title":"Effects of a nicotine conjugate vaccine on the acquisition and maintenance of nicotine self-administration in rats","volume":"184","author":"LeSage","year":"2006","journal-title":"Psychopharmacology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1021\/mp900213u","article-title":"A critical evaluation of a nicotine vaccine within a self-administration behavioral model","volume":"7","author":"Moreno","year":"2010","journal-title":"Mol. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.bmc.2003.11.029","article-title":"Investigations using immunization to attenuate the psychoactive effects of nicotine","volume":"12","author":"Carrera","year":"2004","journal-title":"Bioorganic Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/j.intimp.2011.07.009","article-title":"Combined active and passive immunization against nicotine: Minimizing monoclonal antibody requirements using a target antibody concentration strategy","volume":"11","author":"Cornish","year":"2011","journal-title":"Int. Immunopharmacol."},{"key":"ref_14","first-page":"1178","article-title":"NicVAX (Nabi Biopharmaceuticals)","volume":"6","author":"Heading","year":"2003","journal-title":"IDrugs"},{"key":"ref_15","first-page":"71","article-title":"Drug evaluation: CYT-002-NicQb; a therapeutic vaccine for the treatment of nicotine addiction","volume":"8","author":"Heading","year":"2007","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"(2004). Trial watch: Xenova\u2019s TA-NIC vaccine shows promise. Expert Rev. Vaccines, 3, 386.","DOI":"10.1586\/14760584.3.4.386"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1002\/eji.200526285","article-title":"A therapeutic vaccine for nicotine dependence: Preclinical efficacy; and Phase I safety and immunogenicity","volume":"35","author":"Maurer","year":"2005","journal-title":"Eur. J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.clpt.2005.08.007","article-title":"Safety and immunogenicity of a nicotine conjugate vaccine in current smokers","volume":"78","author":"Hatsukami","year":"2005","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1080\/14622200701704921","article-title":"The immunogenicity and safety of a nicotine vaccine in smokers and nonsmokers: Results of a randomized; placebo-controlled phase 1\/2 trial","volume":"10","author":"Wagena","year":"2008","journal-title":"Nicotine Tob. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cornuz, J., Zwahlen, S., Jungi, W.F., Osterwalder, J., Klingler, K., van Melle, G., Bangala, Y., Guessous, I., M\u00fcller, P., and Willers, J. (2008). A vaccine against nicotine for smoking cessation: A randomized controlled trial. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002547"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/clpt.2010.317","article-title":"Immunogenicity and smoking-cessation outcomes for a novel nicotine immunotherapeutic","volume":"89","author":"Hatsukami","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hoogsteder, P.H., Kotz, D., van Spiegel, P.I., Viechtbauer, W., Brauer, R., Kessler, P.D., Kalnik, M.W., Fahim, R.E., and van Schayck, O.C. (2012). The efficacy and safety of a nicotine conjugate vaccine (NicVAX\u00ae) or placebo co-administered with varenicline (Champix\u00ae) for smoking cessation: Study protocol of a phase IIb; double blind; randomized; placebo-controlled trial. BMC Public Health, 12.","DOI":"10.1186\/1471-2458-12-1052"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1097\/01.JAA.0000433877.47272.13","article-title":"Vaccines in trials for nicotine cessation therapy","volume":"26","author":"Bennett","year":"2013","journal-title":"JAAPA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1111\/add.12577","article-title":"Treatment with a nicotine vaccine does not lead to changes in brain activity during smoking cue exposure or a working memory task","volume":"109","author":"Havermans","year":"2014","journal-title":"Addiction"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1111\/add.12573","article-title":"Efficacy of the nicotine vaccine 3\u2032-AmNic-rEPA (NicVAX) co-administered with varenicline and counselling for smoking cessation: A randomized placebo-controlled trial","volume":"109","author":"Hoogsteder","year":"2014","journal-title":"Addiction"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.socscimed.2013.12.011","article-title":"Constructing a trial as a personal lifestyle change project: Participants\u2019 experiences in a clinical study for nicotine vaccination","volume":"104","author":"Wolters","year":"2014","journal-title":"Soc. Sci. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1093\/ntr\/ntt003","article-title":"Niccine\u00ae; a nicotine vaccine; for relapse prevention: A phase II; randomized; placebo-controlled; multicenter clinical trial","volume":"15","author":"Tonstad","year":"2013","journal-title":"Nicotine Tob. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1176\/appi.ajp.2012.12060793","article-title":"Effect of a nicotine vaccine on nicotine binding to \u03b22*-nicotinic acetylcholine receptors in vivo in human tobacco smokers","volume":"170","author":"Esterlis","year":"2013","journal-title":"Am. J. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1089\/hum.2012.163","article-title":"Disrupted adenovirus-based vaccines against small addictive molecules circumvent anti-adenovirus immunity","volume":"24","author":"De","year":"2013","journal-title":"Hum. Gene Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"64","DOI":"10.4161\/hv.26635","article-title":"A novel and efficient nicotine vaccine using nano-lipoplex as a delivery vehicle","volume":"10","author":"Hu","year":"2014","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7164","DOI":"10.1021\/ja034805t","article-title":"A new strategy for improved nicotine vaccines using conformationally constrained haptens","volume":"125","author":"Meijler","year":"2003","journal-title":"J. Am. Chem. Soc."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zeigler, D.F., Roque, R., and Clegg, C.H. (2017). Construction of an enantiopure bivalent nicotine vaccine using synthetic peptides. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178835"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1089\/hum.2012.245","article-title":"Suppression of nicotine-induced pathophysiology by an adenovirus hexon-based antinicotine vaccine","volume":"24","author":"Rosenberg","year":"2013","journal-title":"Hum. Gene Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3232","DOI":"10.1016\/j.vaccine.2006.01.047","article-title":"A novel bivalent morphine\/heroin vaccine that prevents relapse to heroin addiction in rodents","volume":"24","author":"Anton","year":"2006","journal-title":"Vaccine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"214","DOI":"10.4161\/hv.5.4.7556","article-title":"Vaccines against morphine\/heroin and its use as effective medication for preventing relapse to opiate addictive behaviors","volume":"5","author":"Anton","year":"2009","journal-title":"Hum. Vaccine"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Barbosa-M\u00e9ndez, S., Matus-Ortega, M., Hernandez-Miramontes, R., and Salazar-Ju\u00e1rez, A. (2021). Effect of the morphine\/heroin vaccine on opioid and non-opioid drug-induced antinociception in mice. Eur. J. Pharmacol., 891.","DOI":"10.1016\/j.ejphar.2020.173718"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Barbosa-M\u00e9ndez, S., Matus-Ortega, M., Hernandez-Miramontes, R., and Salazar-Ju\u00e1rez, A. (2021). The morphine\/heroin vaccine decreased the heroin-induced antinociceptive and reinforcing effects in three inbred strains mouse. Int. Immunopharmacol., 98.","DOI":"10.1016\/j.intimp.2021.107887"},{"key":"ref_38","first-page":"783","article-title":"The M3-TT vaccine decreases the antinociceptive effects of morphine and heroin in mice","volume":"21","year":"2021","journal-title":"Int. J. Ment. Health Addict."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.1080\/21645515.2021.1935171","article-title":"Synergistic immune and antinociceptive effects induced from the combination of two different vaccines against morphine\/heroin in mouse","volume":"17","year":"2021","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Barbosa-M\u00e9ndez, S., Matus-Ortega, M., Hernandez-Miramontes, R., and Salazar-Ju\u00e1rez, A. (2023). The effect of chronic stress on the immunogenicity and immunoprotection of the M6-TT vaccine in female mice. Physiol. Behav., 271.","DOI":"10.1016\/j.physbeh.2023.114345"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Barbosa-M\u00e9ndez, S., Matus-Ortega, M., Hernandez-Miramontes, R., and Salazar-Ju\u00e1rez, A. (2024). COT-TT vaccine attenuates cocaine-seeking and cocaine-conditioned place preference in rats. Hum. Vaccines Immunother., 20.","DOI":"10.1080\/21645515.2023.2299068"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1124\/jpet.111.189506","article-title":"An oxycodone conjugate vaccine elicits drug-specific antibodies that reduce oxycodone distribution to brain and hot-plate analgesia","volume":"341","author":"Pravetoni","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1177\/0269881118764991","article-title":"Mirtazapine attenuates nicotine-seeking behavior in rats","volume":"32","year":"2018","journal-title":"J. Psychopharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.pnpbp.2016.02.010","article-title":"Mirtazapine prevents induction and expression of cocaine-induced behavioral sensitization in rats","volume":"68","author":"Jurado","year":"2016","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.ejphar.2017.06.028","article-title":"Mirtazapine attenuates the expression of nicotine-induced locomotor sensitization in rats","volume":"812","author":"Jurado","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1016\/j.vaccine.2009.12.051","article-title":"Nicotine hapten structure; antibody selectivity and effect relationships: Results from a nicotine vaccine screening procedure","volume":"28","author":"Lindblom","year":"2010","journal-title":"Vaccine"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.vaccine.2012.10.069","article-title":"High immunogenicity of nicotine vaccines obtained by intradermal delivery with safe adjuvants","volume":"31","author":"Chen","year":"2012","journal-title":"Vaccine"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Miller, K.D., Roque, R., and Clegg, C.H. (2014). Novel Anti-Nicotine Vaccine Using a Trimeric Coiled-Coil Hapten Carrier. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0114366"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3109\/10826084.2013.821658","article-title":"Exploring Smokers\u2019 Knowledge and Expectations Toward Nicotine Vaccination: A Qualitative Study","volume":"49","author":"Hoogsteder","year":"2014","journal-title":"Subst. Use Misuse"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Bayart, C., Mularoni, A., Hemmani, N., Kerachni, S., Jose, J., Gouet, P., Paladino, J., and Le Borgne, M. (2022). Tetanus toxin fragment C: Structure; drug discovery research and production. Pharmaceuticals, 15.","DOI":"10.3390\/ph15060756"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/ajad.12867","article-title":"Preclinical efficacy of an anti-methamphetamine vaccine using E6020 adjuvant","volume":"28","author":"Arora","year":"2019","journal-title":"Am. J. Addict."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1021\/acs.bioconjchem.1c00179","article-title":"Bivalent conjugate vaccine induces dual immunogenic response that attenuates heroin and fentanyl effects in mice","volume":"32","author":"Barrientos","year":"2021","journal-title":"Bioconjug. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1016\/j.nano.2018.04.016","article-title":"Hybrid nanoparticle-based nicotine nanovaccines: Boosting the immunological efficacy by conjugation of potent carrier proteins","volume":"14","author":"Zhao","year":"2018","journal-title":"Nanomedicine"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jpsychires.2017.03.021","article-title":"Mirtazapine attenuates cocaine seeking in rats","volume":"92","author":"Leff","year":"2017","journal-title":"J. Psychiatr. Res."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Barbosa-M\u00e9ndez, S., and Salazar-Ju\u00e1rez, A. (2024). Evaluation of multitarget drugs on the expression of cocaine-induced locomotor sensitization in male rats: A comparative study. Heliyon, 10.","DOI":"10.1016\/j.heliyon.2024.e29979"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Barbosa-M\u00e9ndez, S., Perez-S\u00e1nchez, G., and Salazar-Ju\u00e1rez, A. (2022). Vortioxetine treatment decreases cocaine-induced locomotor sensitization in rats. Physiol. Behav., 257.","DOI":"10.1016\/j.physbeh.2022.113989"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1080\/15622975.2022.2123954","article-title":"Agomelatine decreases cocaine-induced locomotor sensitisation and dopamine release in rats","volume":"24","year":"2023","journal-title":"World J. Biol. Psychiatry"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/4\/364\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:06:23Z","timestamp":1760029583000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/4\/364"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,31]]},"references-count":57,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["brainsci15040364"],"URL":"https:\/\/doi.org\/10.3390\/brainsci15040364","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,31]]}}}