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Blockade of ionotropic glutamate receptors can induce changes in central dopamine and glutamate circuits, which model the symptoms of schizophrenia. Nicotine evokes dopamine release through activation of nicotinic acetylcholine receptors, and human research indicates that nicotine improves negative and cognitive symptoms of schizophrenia. The objective was to determine the effect of the glutamate receptor antagonist ketamine on the function of nicotinic receptors that mediate dopamine release. Ketamine (0.1-100 µM) did not evoke [³H]overflow from rat striatal and prefrontal cortical slices preloaded with [³H]dopamine. Subanesthetic ketamine concentrations (1-10 µM) increased nicotine-evoked [³H]overflow. To model the progression of schizophrenia, rats received ketamine (30 mg/kg) or vehicle for 30 days and then nicotine-evoked [³H]overflow was measured. The effect of nicotine was greater in ketamine-treated rats, suggesting that subchronic exposure changes nicotinic receptor activity. Overall, these data indicate that nicotinic receptor function is altered in this model of schizophrenia, and support a role for nicotinic receptors in schizophrenia treatment. [ABSTRACT FROM AUTHOR]

Modafinil is a wake-promoting psychostimulant that is used for the treatment of sleep and mood disorders; however, its mechanism of action is unclear. Presently, modafinil neuropsychopharmacology was investigated using drug discrimination and slice superfusion techniques. Rats were trained to discriminate cocaine (1.6 or 5 mg/kg) or amphetamine (0.3 mg/kg) from saline injection for food reinforcement. Modafinil (64-128 mg/kg) substituted partially for both cocaine doses and amphetamine. Pretreatment with a lower modafinil dose (32 mg/kg) shifted the dose-response curves for cocaine and amphetamine to the left. Modafinil (100-300 µM) evoked [³H]overflow from rat striatal slices preloaded with [³H]dopamine in a concentration-dependent manner; however, modafinil was less potent and efficacious than amphetamine and nicotine. Nomifensine (10 µM) attenuated (∼50%) modafinil-evoked [³H]overflow, and concentrations of modafinil (< 100 µM) that did not have intrinsic activity attenuated amphetamine (1-3 µM)-evoked [³H]overflow. Modafinil-evoked [³H]overflow was not altered by mecamylamine, and modafinil did not alter nicotine-evoked [³H]overflow, indicating that nicotinic acetyleholine receptors likely are not important for modafinil's mechanism of action. These results indicate that modafinil is a psychostimulant that is similar to, but less potent than, amphetamine and cocaine. Modafinil's behavioral effects likely are mediated through the dopamine transporter, but this mechanism is not solely responsible for modafinil's efficacy. [ABSTRACT FROM AUTHOR]