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           Dr. Feifel's Animal Laboratory


       
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                           Table: Animal Models of Schizophrenia

                  Modeling Psychosis in Animals



For obvious reasons, it is not straightforward to model psychiatric symptoms in animals. Consider the problem of modeling psychosis in a laboratory rat or mouse. It is rare to find a rodent who feels that his colony mates are talking in hushed tones about him or that they are conspiring to do him harm.  There is not a single report in the literature of a rat hearing voices (or even squeaks).  As a result, those interested in modeling psychosis have needed to look for other relevant ”cross-species” markers of the disease.  For schizophrenia, one such cross-species measure is prepulse inhibition (PPI).


What is PPI? 

PPI is a normal modulation of the startle reflex exhibited by all mammals.  Specifically, PPI refers to the normal decrease in a startle response to a sudden stimuli (be it tactile audio or visual) when that startling stimuli is preceded 50 to 500 msec by a much weaker stimuli (“prepulse”).  For example, a loud sudden noise will produce a startle reflex. When that loud sudden noise is preceded a few hundred milliseconds by a barely audible click, the startle reflex is greatly diminished (see figure below).  Prepulse inhibition is thought to be much more than simply a trivial finding since PPI is thought to be an operational measure of something called “sensorimotor gating.”  Sensorimotor gating refers to the central nervous system’s function of regulating the flow of environmental stimuli to the brain by filtering it. Normal PPI is thought to represent normal sensorimotor gating function.






Prepulse inhibition (PPI) of the startle reflex is a normal physiological process by which the reflexive startle response to a sudden intense stimulus ("pulse") is suppressed when the "pulse" is preceded close in time (30-500 msecs) by a much weaker stimulus ("prepulse"). The reduction in startle reflex produced by the prepulse (represented by lighter outline) is measured as PPI. Therefore greater PPI is associated with a smaller startle response and vice versa.


PPI and Schizophrenia

It has been well established by several laboratories that PPI is decreased in symptomatic schizophrenia patients.  That is to say, prepulses do not diminish the startle reflex in schizophrenia patients to the extent that they do in people that don’t have schizophrenia (Braff et al., 1978). This is thought to reflect an abnormality in sensorimotor gating of schizophrenia patients, an abnormality that is believed to account, at least in part, for their symptoms. Further evidence suggesting PPI abnormalities and schizophrenia symptoms are linked is that brain circuitry underlying both phenomena overlap considerably (Swerdlow et al., 2001) and evidence that drugs that improve psychotic symptoms in schizophrenia patients also improve their PPI abnormalities (Kumari and Sharma, 2002).


PPI in Animals

The finding that PPI could be disrupted in rats by administering them drugs, which are known to be psychosis-inducing in humans, for example, amphetamines, PCP, led to interest in PPI as a model for the sensorimotor gating deficits of schizophrenia. Generally, PPI deficits can be induced by administering drugs with increased dopamine activity (amphetamine, apomorphine) or by drugs that are noncompetitive antagonists at the NMDA (glutamate) receptors such as PCP or MK801, or by hallucinogens that are agonists at the serotonin-2A receptors such as DOI.  What makes this model even more interesting is that established antipsychotic drugs have an ability to reverse drug-induced PPI disruptions.  All established antipsychotics tested to date are able to reverse PPI disruption induced by dopamine agonists. 


How Do We Test PPI?

In humans, PPI is tested in a number of ways. The most common way is by measuring the contraction of the obicularis occuli muscle (the muscle that produces eye blinks) after human subjects are presented with pulses and prepulses through a headphone.





Measuring prepulse inhibition in a healthy volunteer.  Contraction of muscles involved in the eye blink reflex in response to sound pulses presented via headphones are recorded to measure PPI in humans.



Prepulse inhibition is exhibited by mammals under very similar stimulus conditions as it is in humans. In rats, PPI is measured by recording the whole body movement in specialized chambers after presentation of stimuli. 

There may be significant variation in the baseline startle reaction to startling stimuli among individual people and animals.  To control for this possibility, PPI is usually measured as a proportional decrease in an individual’s (human or animal) startle response by comparing the startle in an individual when the startling stimuli is not preceded by a prepulse to when it is.





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