Effects of the Nanoparticle-Based Vaccine, SEL-068, on Nicotine Discrimination in Squirrel Monkeys.
A key feature of addiction to nicotine likely resides in its ability to produce subjective effects that, in turn, may be reflected in its discriminative-stimulus properties. Vaccination against such effects of nicotine offers an intriguing therapeutic approach for smoking cessation, but a reliably effective and immunologically safe vaccine remains to be identified. Here we report on the ability of SEL-068, a nanoparticle-based vaccine that targets nicotine, to modify the discriminative-stimulus effects of nicotine in a primate species. Results indicate that squirrel monkeys vaccinated with SEL-068 failed to acquire 0.1 mg/kg nicotine discrimination but readily learned to discriminate 0.001 mg/kg of the nicotinic full agonist (+)-epibatidine ((+)-EPI). After (+)-EPI training, doses of nicotine ⩾ 0.32 mg/kg, which produced behaviorally adverse actions, still failed to substitute for the (+)-EPI training stimulus in immunized monkeys, whereas (+)-EPI and the partial agonist varenicline engendered, respectively, complete and partial substitution in all monkeys with potency comparable to their potency in non-immunized subjects. In other subjects, nicotine was trained as a discriminative-stimulus and then replaced by (+)-EPI. Subsequent vaccination with SEL-068 led to a threefold and long-lasting (>30 weeks) decrease in the potency of nicotine but not (+)-EPI or varenicline. Collectively, our results show that SEL-068 can block the development of nicotine discrimination and attenuate nicotine's effects in nicotine-experienced monkeys without altering the discriminative-stimulus properties of other nicotinic drugs. The difference in the vaccine's effects in naive and nicotine-experienced subjects provides important insight into the conditions under which immunotherapy may be effective in combating nicotine addiction.
Preclinical Pharmacology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, USA.
Rajeev I
RI
Desai
Preclinical Pharmacology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, USA.
Jack
J
Bergman
D000704:Analysis of Variance; D000818:Animals; D001599:Berberine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007114:Immunization; D007155:Immunologic Factors / Q000494:pharmacology*; D008297:Male; D053758:Nanoparticles; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D012453:Saimiri; D013997:Time Factors; D014612:Vaccines / Q000494:pharmacology*; D000068580:Varenicline / Q000008:administration & dosage
D007155:Immunologic Factors; D018722:Nicotinic Agonists; D014612:Vaccines; D001599:Berberine; C061432:epiberberine; D009538:Nicotine; D000068580:Varenicline