Thus, the dopamine VE-822 clinical trial agonist PPI model is an example of what might be termed “receptor tautology,” insofar as the receptor mechanism of the agonist used to induce the schizophrenia-like PPI deficit predicts the antagonists that the behavioral test will identify. The serotonin agonist PPI model suffers from the same logical limitation; PPI disruptions by hallucinogenic serotonin agonists largely provide only a model to identify antagonists at the serotonin (5-hydroxytryptamine) 5-HT2A receptor because that is the receptor upon which the agonists act.21,26 Inhibitors,research,lifescience,medical While such information may well be germane to the actions

of most second-generation antipsychotics, such agonist-induced phenomena lead to circular models that are not likely to Inhibitors,research,lifescience,medical lead to

the identification of novel mechanisms or treatments. The NMDA antagonist PPI model The rodent PPI model that shows the greatest potential to provide insight into the unique effects of second- rather than first-generation antipsychotics is the NMDA antagonist model. As reviewed elsewhere,21 Inhibitors,research,lifescience,medical both competitive and noncompetitive NMDA antagonists (eg, phcncyclidinc, dizocilpine, and ketamine) produce robust deficits in PPI in rats, mice, or infra-human primates. Many studies of the effects of antipsychotics on the PPI-disruptive effects of NMDA antagonists have confirmed that first-generation antipsychotics such as haloperidol do not attenuate the PPI-disruptive effects of NMDA antagonists in rats.21,24 Similarly, the effects of NMDA antagonists on PPI are maintained in mice treated with dopamine antagonists or in Inhibitors,research,lifescience,medical mutant mice lacking specific subtypes of dopamine receptors.27,28 In contrast, clozapine

and some other secondgeneration antipsychotics have been demonstrated to reduce the disruption in PPI produced by NMDA antagonists in both rats21 and mice.27,29 This interaction between clozapine and NMDA antagonists is seen only with a limited range of doses and has been confirmed in many, but not all, studies in rats.21 Complementing the studies in rodents, clozapine has been demonstrated Inhibitors,research,lifescience,medical to attenuate the effects of phencyclidine on PPI in monkeys, while haloperidol was ineffective.30 These results in experimental animals are consistent with the observations in humans that the psychotic symptoms produced 3-mercaptopyruvate sulfurtransferase by NMDA antagonists are not reduced by typical antipsychotics but are blocked by clozapine.31,32 Such findings led to the suggestion that the phencyclidine-PPI model might enable the specific identification of atypical rather than typical antipsychotic treatments.33 The interactions between second-generation antipsychotics and NMDA antagonists with regard to their effects on PPI are not likely to be mediated by competition for a common receptor, because these antipsychotics do not have appreciable affinity for NMDA receptors.