Antipsychotic Effects on Prepulse Inhibition in Normal ‘Low Gating’ Humans and Rats

Abstract

Development of new antipsychotics and their novel applications may be facilitated through the use of physiological markers in clinically normal individuals. Both genetic and neurochemical evidence suggests that reduced prepulse inhibition of startle (PPI) may be a physiological marker for individuals at-risk for schizophrenia, and the ability of antipsychotics to normalize PPI may reflect properties linked to their clinical efficacy. We assessed the effects of the atypical antipsychotic quetiapine (12.5 mg po) on PPI in 20 normal men with a 'low PPI' trait, based on PPI levels in the lowest 25% of a normal PPI distribution. The effects of quetiapine (7.5 mg/kg s.c.) on PPI were then assessed in rats with phenotypes of high PPI (Sprague Dawley (SD)) and low PPI (Brown Norway (BN)); effects of clozapine (7.5 mg/kg i.p.) and haloperidol (0.1 mg/kg s.c.) on PPI were also tested in SD rats. At a time of maximal psychoactivity, quetiapine significantly enhanced PPI to short prepulse intervals (20-30 ms) in 'low gating' human subjects. Quetiapine increased PPI in low gating BN rats for prepulse intervals o120 ms; this effect of quetiapine was limited to 20 ms prepulse intervals in SD rats, who also exhibited this pattern in response to clozapine but not haloperidol. In both humans and rats, normal 'low gating' appears to be an atypical antipsychotic-sensitive phenotype. PPI at short intervals may be most sensitive to pro-gating effects of these drugs.

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

“…This set of findings provided us with a cross-species model in which PPI is enhanced by a drug within neurologically intact rodents and HS. Similar findings had been reported using the SGAPs, quetiapine (Swerdlow et al 2006), and clozapine (Vollenweider et al 2006).…”

“…Compared with matched controls, PPI is deficient in patients with schizophrenia (e.g., Braff et al 1978;Swerdlow et al 2006), Huntington's disease Valls-Sole et al 2004), obsessive-compulsive disorder (OCD) Hoenig et al 2005;Ahmari et al 2012), nocturnal enuresis (Ornitz et al 1992), Asperger's syndrome (McAlonan et al 2002), 22q11 syndrome (Sobin et al 2005), Kleinfelter syndrome (Van Rijn et al 2011), fragile X syndrome (Frankland et al 2004), blepharospasm (Gomez-Wong et al 1998, and Tourette syndrome (Castellanos et al 1996;Swerdlow et al 2001b).…”

“…This may reflect the fact that, at baseline, mechanisms for sensorimotor gating function at their optimal levels; additionally, experimental stimulus parameters (in particular, prepulse intervals) are typically selected to maximize inhibitory effects of prepulses and thereby are most sensitive for detecting drug-induced reductions in inhibition. However, strains of both mice and rats have been identified with relatively low basal PPI levels, and investigators have also taken the strategy of identifying "low gating" rats within a particular strain, and in both cases, these strains and substrains have been shown to be more sensitive to PPI-enhancing effects of drugs or brain stimulation (Acheson et al 2012;Angelov et al 2014;Swerdlow et al 2006). Roussos et al (2008) reported parallel findings in humans, in which healthy subjects homozygous for the Val allele of the rs4680 COMT polymorphism exhibited low basal PPI levels and PPI-enhancing effects of the COMT inhibitor, tolcapone, while individuals homozygous for the MET allele of rs4680 exhibited high basal PPI and PPI-reducing effects of tolcapone.…”

Haloperidol Differentially Modulates Prepulse Inhibition and P50 Suppression in Healthy Humans Stratified for Low and High Gating Levels

“…So far none of the studies investigating whether atypical antipsychotics increase PPI in normal subjects exhibiting a wide range of PPI yielded positive results (Graham et al, 2001(Graham et al, , 2004Barrett et al, 2004). However, two recent studies demonstrated that atypical antipsychotics such as clozapine or quetiapine increase PPI in clinically unaffected healthy subjects with low baseline PPI (Vollenweider et al, 2006;Swerdlow et al, 2006). Specifically, we have found that the mixed 5-HT 2 /D 2 receptor antagonist clozapine increased PPI in those normal subjects with a characteristically low PPI level at stimulus onset asynchrony (SOA) of 60 and 120 ms (Vollenweider et al, 2006), whereas Swerdlow et al (2006) reported that quetiapine increased PPI at relatively brief SOAs of 20 and 30 ms in a similar group of healthy subjects with low PPI.…”

“…However, two recent studies demonstrated that atypical antipsychotics such as clozapine or quetiapine increase PPI in clinically unaffected healthy subjects with low baseline PPI (Vollenweider et al, 2006;Swerdlow et al, 2006). Specifically, we have found that the mixed 5-HT 2 /D 2 receptor antagonist clozapine increased PPI in those normal subjects with a characteristically low PPI level at stimulus onset asynchrony (SOA) of 60 and 120 ms (Vollenweider et al, 2006), whereas Swerdlow et al (2006) reported that quetiapine increased PPI at relatively brief SOAs of 20 and 30 ms in a similar group of healthy subjects with low PPI. On the other hand, two studies investigating the effects of the typical antipsychotic haloperidol found a disruption of PPI (Abduljawad et al, 1998;Oranje et al, 2004b) in healthy subjects, although the former study could not be replicated by that group (Abduljawad et al, 1999).…”