The latent inhibition model of schizophrenia: Further validation using the atypical neuroleptic, clozapine

The Latent Inhibition Model Dissociates between Clozapine, Haloperidol, and Ritanserin

“…Lack of LI potentiation with clozapine and haloperidol administered in both stages is consistent with previous results showing that APD's do not facilitate LI under conditions which lead to LI in control rats (Dunn et al 1993;Killcross et al 1994b;Ruob et al 1998;Weiner et al 1996). The results with clozapine provide a first demonstration that under such conditions, this drug can disrupt LI when given in preexposure, although clearly, this is limited to the dose tested here.…”

“…The reason that such an effect has gone undetected may stem from the fact that most experiments testing the effects of atypical APD's on LI used parameters of preexposure and conditioning which did not yield LI in controls, thus not allowing the demonstration of LI disruption. Clearly, the latter requires conditions which yield LI in controls; however, experiments which tested clozapine under conditions which led to LI in controls (Dunn et al 1993;Trimble et al 1998;Weiner et al 1996), found neither potentiation nor disruption of LI. Since in these experiments clozapine was administered in both the preexposure and conditioning stages, it is possible that its administration in conditioning masked the expression of its LI disruptive effect in preexposure.…”

“…Both typical and atypical APD's were shown to produce two effects in the LI model: to block amphetamine-induced disruption of LI, and to potentiate LI under conditions that are insufficient to produce robust LI in control animals, namely, low number of preexposures or high number of conditioning trials (Christison et al 1988;Dunn et al 1993;Feldon and Weiner 1991;Gosselin et al 1996;Killcross et al 1994b;Moran et al 1996;Peters and Joseph 1993;Solomon et al 1981;Trimble et al 1997Trimble et al , 1998Warburton et al 1994;Weiner et al 1996. The site at which APD's act to potentiate LI is the conditioning stage, and it has been attributed to DA blockade (Peters and Joseph 1993;Shadach et al 1999;Weiner 1990;).…”

“…Experiments 1-3 used 40 preexposures and five conditioning trials, which do not lead to LI in control rats (e.g., , and Experiments 4-6 used 40 preexposures and two conditioning trials, which produce LI in normal rats (e.g., Weiner et al 1996). The doses of haloperidol and clozapine were chosen because they had previously been shown by us to potentiate LI when administered in conditioning or in both preexposure and conditioning (Feldon and Weiner 1991;Shadach et al 1999;Weiner et al 1996; the 50:1 ratio between these two drugs was based on data from ex vivo and in vivo studies of D2 receptor occupancy in the rat brain (Baldessarini and Frankenburg 1991;Schotte et al 1996). The dose of ritanserin was shown by Cassaday et al (1993a) to disrupt LI when given in both stages.…”

Sensorimotor Gating Deficits in Transgenic Mice Expressing a Constitutively Active Form of Gsα

“…The endophenotypes of schizophrenia that have been studied in animals include alterations in sensorimotor gating, latent inhibition, attention, social behavior, and cognition (Baruch et al, 1988;Dulawa et al, 1997;Feldon and Weiner, 1991;Hoffman and Donovan, 1994;Kline et al, 1998;Martinez and Geyer, 1997;Mohn et al, 1999;Solomon et al, 1981;Swerdlow and Geyer, 1998;Weiner et al, 1996). Prepulse inhibition of the startle response is a form of sensorimotor gating that has been studied intensely, because it can easily be measured in both humans and laboratory animals, and because patients with schizophrenia, Huntington's disease, obsessive compulsive disorder, Tourette's syndrome, or attention deficit disorder show reliable deficits in PPI (Geyer and Braff, 1987;Koch, 1999;Swerdlow and Geyer, 1998).…”