Attentional and information processing dysfunctions have long been considered important in understanding schizophrenia and other psychiatric disorders. Prepulse inhibition is disrupted in certain neuropsychiatric disorders that are characterized by an inability to filter or "gate" sensory (and, theoretically, cognitive) information. Theoretically, impairments in basic information processing functions such as sensorimotor gating contribute to disordered thought and cognitive fragmentation observed in psychotic disorders such as ► schizophrenia (Braff and Geyer 1990). Prepulse inhibition is used commonly as an operational measure of sensorimotor gating in studies in rodents, infrahuman primates, and humans. Patients with schizophrenia exhibit reduced sensorimotor gating as indexed by prepulse inhibition when compared to healthy control subjects and several categories of nonpsychotic
Prepulse Inhibition. Fig. 1. Diagrammatic representation of prepulse inhibition of startle. The top panel illustrates a pulse-alone trial in which startle is elicited by a 120 dB(A) noise burst above a 70 dB(A) background. The startling stimulus is presented for 20 msec in this example. The startle response is typically measured for 100 (rodents) or 250 (humans) msec after the on set of the pulse. The lower panel illustrates the prepulse-plus-pulse trail, in which startle inhibited by a weak (e.g. 80 dB(A) prepulse given 30-1000 msec (in this example 100 msec onset-to-onset) before the same startle-eliciting noise used in the pulse-alone trial. In experiments examining tactile rather than acoustic startle, the pulse is an air-puff or mild electric shock to the neck (humans) or back (rodents). The right side of each panel illustrates the measured response, typically assessed using the electromyographic signal from orbicularis occuli muscle as a measure of the eyeblink response in humans or using an accelerometer-based signal as a measure of the whole-body flinch response in rodents. A typical test session includes presentations of serveral pulse-alone trials and several occasions of prepulse trials that may vary in the intensity of the prepulse stimulus or the interval between the prepulse and pulse onsets.
psychiatric disorders (Braff et al. 2001). Strikingly, similar prepulse inhibition abnormalities have also been observed in unmedicated and non-psychotic schizotypal patients and asymptomatic first-degree relatives of schizophrenia patients, supporting a strong role for genetic influences on sensorimotor gating. The reproducibility of the finding in schizophrenia, the fact that abnormal prepulse inhibition parallels a putative central abnormality in the disease, and the fact that prepulse inhibition is a conserved phenomenon among vertebrates make prepulse inhibition a promising candidate ► endophenotype to use in genetic association studies and animal models of schizophrenia (Swerdlow et al. 2009). The identification of genetic contributions to startle and prepulse inhibition in humans can be readily confirmed and extended in parallel studies using genetically engineered mice or other relevant strains of rats or mice (Geyer et al. 2002).
Using startle plasticity measures such as prepulse inhibition is advantageous in neuroscientific research for a number of reasons. First, startle plasticity in rodents has proven face, predictive, and construct validity for startle plasticity in humans. Second, startle behavior remains relatively stable across repeated testing sessions in mice, rats, healthy humans, and clinically stable psychiatric patients. This stability enables one to use longitudinal designs to explore developmental and environmental perturbations on prepulse inhibition over time and across experience. Third, startle and prepulse inhibition involve fairly rapid tests that do not involve complex stimuli, increasing their ease of use and their reliability. Since startle relies on a simple reflex measure, its reliability and reproducibility is greater than more complex behavioral measures that are modulated by competing behaviors or motivations (e.g., approach/avoidance behavior), and increases the chances of translation of these effects to humans. Fourth, the neuroanatomical and neurochemical substrates mediating and modulating startle plasticity are well defined, allowing greater hypothesis generation and interpretability before and after obtaining results.
The neuroanatomical substrates that contribute to the modulation of prepulse inhibition in rats have been studied extensively, providing an excellent example of the regulation of behavior by integrated neuronal circuits (Swerdlow et al. 2001). The deficits in prepulse inhibition observed in psychiatric patient populations appear to reflect abnormal information processing and may result from pathology within forebrain cortico-striato-pallido-pontine circuitry that modulates this form of startle plasticity (Koch 1999; Swerdlow et al. 2001). Furthermore, a wide range of developmental and pharmacological manipulations have been found to alter prepulse inhibition in rats, leading to multiple rat models having utility in the identification of antipsychotic medications (Geyer et al. 2001). Prepulse inhibition has shown good predictive validity as a screen for ► antipsychotic drugs. In keeping with the ► dopamine hypotheses of psychotic disorders such as schizophrenia and mania, dopamine agonists such as ► apomorphine and ► amphetamine disrupt prepulse inhibition in rodents. These effects can be reversed by antipsychotics having selective antagonist effects at dopamine D2, but not dopamine D1 receptors. One important aspect of animal models of schizophrenia is their ability to distinguish between typical and atypical antipsychotic drugs. Prepulse inhibition deficits induced by apomorphine are reversed by both typical and ► atypical antipsychotics. Thus, although the ability of antipsy-chotics to restore prepulse inhibition in apomorphine-treated rats strongly correlates with their clinical potency, when used with the dopamine agonist apomorphine, this paradigm fails to make the important distinction between these two classes of antipsychotic drugs. In contrast, the prepulse inhibition disruptions produced by glutamate antagonists (e.g., ► phencyclidine, dizocilpine, and ► ke-tamine) differentiate between typical and atypical anti-psychotics to some degree (Geyer et al. 2001). Specifically, typical antipsychotics such as ► haloperidol do not attenuate the prepulse inhibition-disruptive effects of glutamate antagonists in rats, while ► clozapine and some other atypical antipsychotics reduce the disruption in prepulse inhibition produced by these psychotomimetics in both rats and mice. Thus, prepulse inhibition already serves an important role in the identification of novel treatments for schizophrenia (Braff and Light 2004) and may ultimately contribute to our understanding of other psychiatric disorders such a ► bipolar disorder, ► panic disorder, and ► post-traumatic stress disorder.
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