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Background: Tobacco smoking is the largest preventable cause of morbidity and premature mortality in the world. Although its medical consequences are well documented, 20–50% of the population even in developed countries remain tobacco smokers. The drugs presently used in smoking cessation have limited efficiency and, therefore, there is a need for alternative and improved treatments. One novel approach in this regard may be provided by immunization against nicotine. Objective: The present study in male Wistar rats investigated if active immunization with a novel nicotine immunogen, IP18-KLH, may generate nicotine-selective antibodies and, furthermore, whether this treatment might prevent nicotine from exerting its stimulating effect on the mesolimbic, dopaminergic reward system in the brain. Methods: Enzyme-linked immunosorbent assay (ELISA) was used to determine the titer of nicotine antibodies in plasma after immunization with IP18-KLH in Freund’s adjuvant. Competitive ELISA was used to assess the selectivity of the antibodies. Finally, we used in vivo voltammetry to investigate whether active immunization with IP18-KLH could prevent nicotine-induced dopamine release in the shell of nucleus accumbens (NAC_shell). Results: The present study shows that active immunization with IP18-KLH generates antibodies that are highly selective for nicotine. Furthermore, immunization with IP18-KLH prevented the nicotine-induced increase in dopamine release in the NAC_shell, a biochemical correlate to the rewarding properties of nicotine. Conclusions: Active immunization with IP18-KLH prevents a central effect of nicotine that is considered critical for the induction of nicotine dependence. Consequently, active immunization may provide long-term protection against initiation of tobacco dependence, an effect that may prove particularly advantageous in relapse prevention.

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Antidepressant drugs are frequently used to treat affective symptoms in schizophrenia. We have recently shown that escitalopram, but not citalopram or R-citalopram, increases firing rate and burst firing of midbrain dopamine neurons, potentiates cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission and enhances cognition, effects that might influence the outcome of concomitant antipsychotic medication. Here, we studied, in rats, the behavioral and neurobiological effects of adding escitalopram, citalopram, or R-citalopram to the second-generation antipsychotic drug risperidone. We examined antipsychotic efficacy using the conditioned avoidance response (CAR) test, extrapyramidal side effect (EPS) liability using a catalepsy test, dopamine outflow in the medial prefrontal cortex (mPFC) and nucleus accumbens using in vivo microdialysis in freely moving animals, and NMDA receptor-mediated transmission in the mPFC using intracellular electrophysiological recording in vitro. Only escitalopram (5 mg/kg), but not citalopram (10 mg/kg), or R-citalopram (10 mg/kg), dramatically enhanced the antipsychotic-like effect of a low dose of risperidone (0.25 mg/kg), without increasing catalepsy. Given alone, escitalopram, but not citalopram or R-citalopram, markedly enhanced both cortical dopamine output and NMDA receptor-mediated transmission. Addition of escitalopram and to some extent R-citalopram, but not citalopram, significantly enhanced both cortical dopamine output and cortical NMDA receptor-mediated transmission induced by a suboptimal dose/concentration of risperidone. These results suggest that adjunct treatment with escitalopram, but not citalopram, may enhance the effect of a subtherapeutic dose of risperidone on positive, negative, cognitive, and depressive symptoms in schizophrenia, yet without increased EPS liability.

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