Prepulse inhibition

A disruption in sensory and cognitive gating is hypothesized to be at the core of many of the symptoms of schizophrenia. Prepulse inhibition (PPI) refers to the ability of a low-intensity stimulus, or prepulse, to diminish the startle response elicited by a higher-intensity stimulus. This model has gained significant favor in recent years largely due to the findings that schizophrenic patients exhibit deficits in sensory and cognitive gating. This is particularly evident in studies of event-related potentials (ERPs) in the electroencephalogram of schizophrenic patients. The most common ERP paradigm has examined the latency and amplitude of P300 in response to an unpredictable change in a stimulus series (the 'oddball' paradigm). Reduced P300 amplitude in response to novelty in schizophrenic patients has been observed in a large number of studies.43 The P50 ERP exhibits interesting behavior in response to pairs of brief auditory stimuli presented in rapid succession. In normal subjects, the P50 response to the second stimulus is attenuated relative to the first. Schizophrenic subjects, in contrast, often do not show this decreased P50 response to the second stimulus.44 These differences in ERPs suggest that schizophrenic patients have a deficit in the gating or processing of sensory information. Consistent with this, several studies have examined PPI in schizophrenic patients45'46 and found impairment relative to normal control subjects. This impaired sensorimotor gating may underlie the vulnerability in schizophrenia to sensory flooding, cognitive fragmentation, and conceptual disorganization. PPI is disrupted by a wide range of psychotomimetics and can be rescued by treatment with antipsychotic drugs.47 Based on the high degree of face validity, apparent predictive validity, and the ability to strengthen construct validity by disrupting the behavior with multiple classes of psychotomimetics, PPI stands out as the current 'gold standard' assay for evaluating animal models of schizophrenia.

Based largely on psychotomimetic properties in humans, a number of pharmacological tools have been used to induce a state in laboratory animals that is presumed to have some of the underlying pathophysiology of schizophrenia. These pharmacological models fall into three basic categories: DA releasing agents, 5HT2 agonists, and NMDA receptor antagonists.

According to the DA hyperfunction hypothesis of schizophrenia, agents that act to increase dopaminergic transmission should induce psychosis in normal individuals, and should precipitate or exacerbate psychosis in schizophrenics. Consistent with this, a large number of studies have demonstrated psychotomimetic effects of amphetamine 17, cocaine 19, and methylphenidate 20, all compounds that act to increase DA release. Interestingly, these effects do not seem to be mimicked by direct-acting DA agonists, suggesting that a degree of circuit-based spatial selectivity may be important for the psychotomimetic effects of enhanced dopaminergic transmission. The 5HT hypothesis of schizophrenia is driven largely by the hallucinogenic effects of LSD 21, and the finding that LSD interacts with 5HT receptors. Indolamines such as LSD 21 and psilocybin 22, and phenethylamines including dimethoxymethylamphetamine 23 and mescaline 24, constitute the two main classes of hallucinogens. Interestingly, these agents all have relatively high affinity for the 5HT2 subclass of 5HT receptors and in particular have been found to act as 5HT2A agonists. The glutamatergic system has also been implicated in schizophrenia based on the findings that PCP 2 induces a psychotic state in humans that is very similar to that observed in schizophrenic patients, coupled with the finding that the main mode of action of PCP is that of a noncompetitive antagonist of the NMDA subtype of ionotropic glutamate receptor. In support of this NMDA receptor hypofunction model, other noncompetitive NMDA receptor antagonists including ketamine and dizocilpine (MK-801; 25) induce a similar schizophrenia-like state.

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