The effects of ritanserin, RU 24969 and 8-OH-DPAT on latent inhibition in the rat

Abstract

When animals are exposed to a stimulus that has no consequences they are subsequently impaired in learning that this stimulus predicts an important event, such as footshock. This retarding effect of stimulus pre-exposure is called latent inhibition (LI) and is reliably disrupted by amphetamine, antipsychotics having an opposite effect. The present experiments investigated whether agents which affect serotonergic transmission also attenuate LI, using a conditioned suppression of drinking procedure. The results showed that the 5-HT(2) antagonist ritanserin (2.0 mg/kg), and the 5-HT(1b) agonist RU 24969 (0.5 and 10.0 mg/kg) attenuated LI by increasing learning in pre-exposed animals, whilst the effects of the 5-HT(1a) agonist 8-OH-DPAT (0.38 mg/kg), though in a similar direction, were not significant. These experiments provide partial support for the involvement of serotonin in LI. Since amphetamine-induced attenuation of LI has been proposed as a model for the attentional deficits found in acute schizophrenia, these results are discussed in terms of the possible involvement of reduced serotonergic function in schizophrenic attentional disorder.

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

“…Haloperidol left LI intact in all administration conditions, clozapine disrupted LI when administered in preexposure, and ritanserin disrupted LI when administered in preexposure and in both stages. The latter result replicates that of Cassaday et al (1993a) but we now show that ritanserin-induced LI disruption at this dose is due to its action in the preexposure stage.…”

“…The serotonergic component of atypicality is particularly relevant to LI, because LI is disrupted by brain serotonin depletion (Asin et al 1980;Cassaday et al 1993b;Lorden et al 1983;Solomon et al 1978Solomon et al , 1980, as well as by systemic administration of the 5-HT2 antagonist ritanserin (Cassaday et al 1993a). In spite of this, there is no evidence that atypical APD's disrupt LI, although it has been suggested that a competition between a 5HT2-mediated disruptive effect and a DA2-mediated potentiating effect may explain why clozapine fails to potentiate LI or does so within a certain dose range only (Dunn et al 1993;Moran et al 1996;Trimble et al 1998).…”

“…Since serotonergic antagonists disrupt LI when given in both the preexposure and conditioning stages (Cassaday et al 1993a), and atypical APD's potentiate LI when given in conditioning but not when given in preexposure Shadach et al 1999), it follows that if atypical APD's disrupt LI via serotonergic antagonism, the site of such an effect must be the preexposure stage. 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.…”

“…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. In all of the present experiments, the drugs were administered in either the preexposure stage, the conditioning stage, or in both.…”

5-Hydroxytryptamine 2A serotonin receptors in the primate cerebral cortex: Possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites

“…However, excessive 5-HT 2A receptor activation may be disruptive. For example, 5-HT 2A agonists impair latent inhibition in rats (51). We suggest that the gating mechanisms of apical dendritic ion channels may be dysfunctional in psychotic behavioral states occurring in the acute ''positive'' phase of schizophrenia or induced by 5-HT 2A agonist drugs (e.g.…”