Schizophrenic and schizotypal patients exhibit deficits in the habituation and prepulse inhibition (PPI) of startle responses, providing operational measures of the sensorimotor gating or filtering deficits suggested to contribute to cognitive disorganization in these patients. In rats,
hallucinogens, entactogens, and
NMDA antagonists share the ability to both retard startle habituation and disrupt PPI. Extensive pharmacological studies in rats have indicated that the effects of
hallucinogens 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 presynaptic
serotonin release. These observations in rats have supported the development of 5-HT2A antagonists for the treatment of
schizophrenia. Animal studies have shown that PPI is modulated by multiple interacting
neurotransmitters, including dopaminergic, serotonergic,
cholinergic, GABAergic, and glutamatergic systems within cortical, limbic, striatal, and brainstem structures. The effects of PCP and other
NMDA antagonists on PPI are insensitive to either dopaminergic or serotonergic antagonists, but are reduced by atypical
antipsychotics such as
clozapine,
olanzapine, and
Seroquel. Thus, the PCP model of
schizophrenia-like deficits in sensorimotor gating offers promise for the identification and 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 opportunities for the exploration of neurobiological substrates relevant to the group of
schizophrenias.