Abstract
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, GA-BAergic, 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.
