Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We reported strain differences in the sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in adult rats, with greater sensitivity in Harlan Sprague Dawley (SDH) versus Wistar (WH) rats. However, Kinney et al. (1999) recently reported opposite findings, using Bantin-Kingman Sprague Dawley (SDBK) and Wistar (WBK) rats; in fact, SDBK rats did not exhibit clear apomorphine-induced reductions in sensorimotor gating. These new findings of Kinney et al. (1999) directly conflict with over 15 years of results from our laboratories and challenge interpretations from a large body of literature. The present studies carefully assessed drug effects on sensorimotor gating in SD versus W strains, across rat suppliers (H vs BK). Significantly greater SDH than WH apomorphine sensitivity in PPI measures was observed in both adult and 18 d pups, confirming that these strain differences are both robust and innate. These strain differences in apomorphine sensitivity were not found in adult BK rats. Supplier differences in sensitivity (SDH > SDBK) were also evident in the PPI-disruptive effects of D1 but not D2-family agonists; PPI was clearly disrupted by quinpirole in both SDH and SDBK rats. These findings demonstrate robust, innate, neurochemically specific, and apparently heritable phenotypic differences in an animal model of sensorimotor gating deficits in human neuropsychiatric disorders.

Phencyclidine (PCP), a non-competitive

Both dopamine (DA) agonists and NMDA antagonists produce prepulse inhibition (PPI) deficits in rats that

No abstract

gating of the startle reflex can be assessed via measures of prepulse inhibition (PPI), which is the reduction in startle magnitude when the startling stimulus is preceded immediately by a weak prepulse. PPI is reduced in humans with specific neuropsychiatric disorders and in rats after treatment with certain classes of drugs, including serotonin (5-HT) agonists. Because of the relative loss of PPI in inherited, neurodevelopmental disorders such as schizophrenia, there is great interest in understanding the inherited and developmental features of the neurochemical regulation of PPI in animals.In the present study, PPI was disrupted significantly by the 5-HT2A agonist 2, Prepulse inhibition (PPI) is the reduction in startle reflex magnitude when a startling stimulus is preceded by a weak prestimulus. PPI is diminished in patients with schizophrenia (Braff et al. 1978;Grillon et al. 1992;Bolino et al. 1994), obsessive compulsive disorder ), Huntington's disease (Swerdlow et al. 1995), nocturnal enuresis and attention deficit disorder (Ornitz et al. 1992), and Tourette Syndrome (Castellanos et al. 1996). These disorders are all marked by an inability to inhibit, or "gate" irrelevant information in sensory, motor, or cognitive domains. In schizophrenia, this loss of gating is conceptually linked to processes responsible for sensory flooding and cognitive fragmentation (McGhie and Chapman 1961).In the rat, disruption of PPI occurs after acute administration of dopamine (DA) agonists (Swerdlow et al. 1986;Mansbach et al. 1988), NMDA antagonists Geyer 1989a, 1991), or serotonin (5-HT) agonists (Mansbach et al. 1989b;Rigdon and Weatherspoon 1992;Kehne et al. 1992;Sipes and Geyer 1994). Studies in rats of the neural basis for drug effects on PPI may provide a means to further understand the pathophysiology of neuropsychiatric disorders characterized by deficits in 23 , NO . 6 sensorimotor gating (Swerdlow et al. 1994;. The present studies were designed to assess two aspects of the regulation of PPI by 5-HT2A receptors in rats: 1) the sensitivity to the PPI-disruptive effects of the 5-HT2A receptor agonist, 2,5-dimethoxy-4 iodopheny-lisopropylamine (DOI), in Wistar/Harlan ("WH") vs. Sprague Dawley/Harlan ("SDH") rats; and 2) the developmental time-course of the PPI-disruptive effects of DOI in male and female SDH pups.The regulation of PPI by brain 5-HT receptors is a topic of particular interest based on the 5-HT receptorblocking properties of novel atypical antipsychotics, such as clozapine, olanzapine, and quetiapine. In rats, PPI is disrupted by 5-HT agonists, and these effects are opposed by 5-HT antagonists. For example, the PPI disruptive effects of the direct 5-HT2A receptor agonist DOI are prevented by the putative novel antipsychotic and 5-HT2A antagonist M100907 (Sipes and Geyer 1995b). Other 5-HT receptor agonists have also been shown to disrupt PPI, including 5-HT releasers (Mansbach et al. 1989b;Kehne et al. 1996; Martinez and Geyer 1997), direct 5-HT1A agonists such as 8-OH-DPAT (Rigdon and Weathersp...