Animal models of negative symptoms: M100907 antagonizes PCP-induced immobility in a forced swim test in mice

Schizophrenia is characterized by three types of symptoms: positive, disorg anized, and negative. The pathophysiology of negative symptoms is less well understood than that of positive symptoms. Consequently, there ave move mo dels of positive symptoms than negative symptoms, and the characterization of novel compounds with respect to their potential effects on negative symp toms has been limited to the use of behavioral models with face validity. B ehavioral models of negative symptoms that are currently being used in the development of novel antipsychotic agents include: the social withdrawal mo del in rodents and nonhuman primates; and the forced swim test. In addition , our data suggest that the chronic mild stress model of anhedonia may also be predictive for compounds with efficacy for negative symptoms. In rodent s, chronic administration of PCP increases the duration of immobility in th e forced swim test and has been used as a model of the negative symptoms of schizophrenia, such as flattening of affect and avolition. An experiment i s presented that evaluated the effects of clozapine, haloperidol, and M1009 07 against PCP-induced immobility in the forced swim test. M100907 is a sel ective serotonin 5-HT2A receptor antagonist that is currently being evaluat ed in clinical trials as a treatment for schizophrenia. Clozapine, which ha s been found to be clinically active against negative symptoms, significant ly attenuated PCP-induced immobility, whereas haloperidol, which is clinica lly inactive against negative symptoms, had no effect. M100907 (0.3 and 1 m g/kg) significantly attenuated PCP-induced immobility, showing a similar pr ofile to clozapine in the forced swim test. Therefore, M100907 may have a u nique ability to alleviate the negative symptoms of schizophrenia without t he side effects of current antipsychotic medication. [Neuropsychopharmacolo gy 21:S211-S218, 1999] (C) 1999 American College of Neuropsychopharmacology . Published by Elsevier Science inc.