Clozapine reduces nicotine self-administration, blunts reinstatement of nicotine-seeking but increases responding for food.

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People with schizophrenia display significantly higher rates of smoking than the general population, which may be due to an interaction between nicotine and antipsychotic medication. While the conventional antipsychotic drug haloperidol sometimes increases cigarette smoking in patients with schizophrenia, there is some evidence suggesting that clozapine, an atypical antipsychotic drug, may reduce nicotine use in these patients. However, the effects of antipsychotic drugs like clozapine on aspects of nicotine self-administration and reinstatement have not been systematically examined. In the current study, we assessed the effect of clozapine on nicotine self-administration under fixed ratio and progressive ratio schedules of reinforcement, as well as reinstatement of nicotine-seeking following a period of abstinence. To determine the specificity of its effect on nicotine reward, we also tested the effect of clozapine on responding for food reinforcement under fixed ratio and progressive ratio schedules. For comparison, we also examined the effects of haloperidol, a first-generation antipsychotic drug, under some of the same behavioral conditions as clozapine. We show that clozapine inhibits nicotine self-administration and reinstatement of nicotine-seeking but also increases the amount of effort that rats will exert for food reward. In contrast, haloperidol at a wide range of doses attenuated responding for nicotine and food reward, suggestive of a non-specific reduction in reinforcer efficacy. These results show the potential utility of clozapine as a smoking cessation treatment for patients with schizophrenia, in addition to its antipsychotic properties.