BEHAVIORAL-STUDIES OF HALLUCINOGENIC DRUGS IN ANIMALS - IMPLICATIONS FOR SCHIZOPHRENIA RESEARCH

Schizophrenic and schizotypal patients exhibit deficits in the habitua tion and prepulse inhibition (PPI) of startle responses, providing ope rational measures of the sensorimotor gating or filtering deficits sug gested to contribute to cognitive disorganization in these patients. I n rats, hallucinogens, entactogens, and NMDA antagonists share the abi lity to both retard startle habituation and disrupt PPI. Extensive pha rmacological studies in rats have indicated that the effects of halluc inogens on habituation are mediated by direct agonist actions at 5-HT2 receptors. The effects of the entactogens on both habituation and PPI reflect indirect agonist actions due to the stimulation of presynapti c serotonin release. These observations in rats have supported the dev elopment of 5-HT2A antagonists for the treatment of schizophrenia. Ani mal studies have shown that PPI is modulated by multiple interacting n eurotransmitters, including dopaminergic, serotonergic, cholinergic, G ABAergic, and glutamatergic systems within cortical, limbic, striatal, and brainstem structures. The effects of PCP and other NMDA antagonis ts on PPI are insensitive to either dopaminergic or serotonergic antag onists, but are reduced by atypical antipsychotics such as clozapine, olanzapine, and Seroquel. Thus, the PCP model of schizophrenia-like de ficits in sensorimotor gating offers promise for the identification an d neurobiological investigation of atypical antipsychotics. The cross- species study of homologous gating functions, such as habituation and PPI, in animal models and psychiatric patients provides novel opportun ities for the exploration of neurobiological substrates relevant to th e group of schizophrenias.