Screening of antipsychotic drugs in animal models

Abstract

Behavioral models of antipsychotic drug (APD) action in the rat are widely used for the screening and developing APDs. Valid models are not only required to be selective and specific for APDs, but also to be able to dissociate between typical and atypical APDs. In recent years, newer models have been developed that are claimed to processes impaired in schizophrenic patients. However, these models depend on previous administration of propsychotic drugs for revealing the effects of APDs, rais- ing the possibility that the model of APD action is not the specific behavior assessed but the administra- tion of the propsychotic drug. A valid behavioral of APD action should posses the following characteristics: 1) The behavior assessed in the has relevance to the clinical condition; 2) The behavioral paradigm used to index the action of APDs can be used in rats and humans. 3) The is selective and specific to APDs differing in their in vitro and in vivo pharmacology. 4) The can dissociate between typical and atypical APDs. and 5) The does not require previous pharmacologi- cal manipulations to manifest the behavioral index of antipsychotic activity. In this overview, data are summarized showing that the latent inhibition (LI) of APD action, which measures a cognitive process known to be impaired in schizophrenia, namely, the ability to ignore stimuli that had been incon- sequential in the past, fulfills all of the above criteria. The utility of the LI can be further extended when it is combined with the forced swim test (FST) model, which is sensitive to the antidepressant-like activity of the atypical APDs, such that the combined LI-FST can dissociate between typical APDs, atypical APDs, and antidepressants. Finally, the use of the LI alone or in combination with FST in rats that sustain lesions or other physiological manipulations (e.g., stimulation) to specific brain regions may provide clues as to the relationship between the effects of these drugs and the site of brain damage, and possibly reveal differential effects of typical and atypical APDs, depending on the site of the damage. Drug Dev. Res. 50:235-249, 2000. © 2000 Wiley-Liss, Inc.