Screening of antipsychotic drugs in animal models

Behavioral models of antipsychotic drug (APD) action in the rat are widely used for the screening and developing APDs. Valid models are not only requi red to be selective and specific for APDs, but also to be able to dissociat e between typical and atypical APDs. In recent years, newer models have bee n developed that are claimed to model processes impaired in schizophrenic p atients. However, these models depend on previous administration of propsyc hotic drugs for revealing the effects of APDs, raising the possibility that the "model" of APD action is not the specific behavior assessed but the ad ministration of the propsychotic drug. A valid behavioral model of APD acti on should posses the following characteristics: 1) The behavior assessed in the model has relevance to the clinical condition; 2) The behavioral parad igm used to index the action of APDs can be used in rats and humans. 3) The model is selective and specific to APDs differing in their in vitro and in vivo pharmacology. 4) The model can dissociate between typical and atypica l APDs. and 5) The model does not require previous pharmacological manipula tions to manifest the behavioral index of antipsychotic activity. In this o verview, data are summarized showing that the latent inhibition (LI) model of APD action, which measures a cognitive process known to be impaired in s chizophrenia, namely, the ability to ignore stimuli that had been inconsequ ential in the past, fulfills all of the above criteria. The utility of the LI model can be further extended when it is combined with the forced swim t est (FST) model, which is sensitive to the antidepressant-like activity of the atypical APDs, such that the combined LI-FST model can dissociate betwe en typical APDs, atypical APDs, and antidepressants. Finally, the use of th e LI model alone or in combination with FST in rats that sustain lesions or other physiological manipulations (e.g., stimulation) to specific brain re gions may provide clues as to the relationship between the effects of these drugs and the site of brain damage, and possibly reveal differential effec ts of typical and atypical APDs, depending on the site of the damage. Drug Dev. Res. 50:235-249, 2000. (C) 2000 Wiley-Liss, Inc.