The Delayed Effects of DTG and MK-801 on Latent Inhibition in a Conditioned Taste-Aversion Paradigm

Abstract

. The delayed effects of DTG and MK-801 on latent inhibition in a conditioned taste-aversion paradigm. PHARMACOL BIOCHEM BEHAV 66 (3) 533-539, 2000.-The delayed effects of phencyclidine (PCP) have been shown to disrupt latent inhibition (LI) in a conditioned taste-aversion paradigm. In an attempt to understand the mechanism of this disruption, the delayed effects of the selective sigma receptor agonist 1,3-Di(2-tolyl)guanidine (DTG) and the selective NMDA receptor antagonist MK-801 on latent inhibition were assessed in the same paradigm. Water-deprived male rats were allowed access to either water (nonpreexposed; NPE) or 5% sucrose (preexposed; PE) for 30 min on 2 consecutive days. On the third day, animals were allowed access to sucrose and subsequently injected with lithium chloride. On the forth day, animals were allowed access to both sucrose and water. LI was assessed by comparing the percent sucrose consumed in PE and NPE groups on the fourth day. DTG (1.0, 5.0, or 10.0 mg/kg), MK-801 (0.5, 1.0, or 2.0 mg/kg), or vehicle was administered IP 20 h before preexposure (days 1 and 2) and conditioning (day 3). In vehicle-treated groups, PE animals consumed a significantly higher percent sucrose on the test day than NPE animals, indicating the presence of LI. DTG (10.0 mg/kg) and MK-801 (2.0 mg/kg) decreased the percent sucrose consumed by animals in the PE group to the level observed in the NPE group, indicating disrupted LI. However, this dose of MK-801 was found to produce a decrease in percent sucrose consumed in PE animals not treated with lithium chloride, indicating that the decrease observed in the LI paradigm could be due to MK-801-induced decrease in taste preference for sucrose rather than a disruption of LI. Lower doses of MK-801 that did not produce a decrease in taste preference for sucrose did not significantly disrupt LI. None of the doses of DTG tested altered taste preference for sucrose. These data suggest a role for sigma receptors in the previously observed PCP-induced disruption of LI. LATENT inhibition (LI) is the impaired acquisition of a conditioned response to a stimulus that has been previously presented without reinforcement (35). LI is thought to be a measure of an organism's capacity to ignore irrelevant stimuli, and has been demonstrated in a variety of species including humans (4,35,36). Disruption of LI has been observed in nonmedicated acute schizophrenics (4) as well as animals and humans treated with the psychotomimetic drug amphetamine (14,22,49,(64)(65)(66)(67). Medicated schizophrenic patients do not demonstrate disrupted LI (4,37). In addition, antipsychotic medications reverse amphetamine-induced disruption of LI in animals (49,68), and can enhance LI on their own (11,15). These observations suggest that the disruption of LI is a useful animal model for this specific attentional deficit seen in schizophrenia (12,15). Phencyclidine (PCP) is a drug that can produce a psychotomimetic effect in humans (3,28,38) as well as a number of behavioral and cognitive changes in animals...

Ketamine, at a Dose that Disrupts Motor Behavior and Latent Inhibition, Enhances Prefrontal Cortex Synaptic Efficacy and Glutamate Release in the Nucleus Accumbens

“…This result is consistent with two previous studies showing that ketamine or MK-801, injected before or just after preexposure, disrupted latent inhibition in a conditioned tasteaversion paradigm whereas no effect was obtained when these compounds were injected only at the conditioning stage (Aguado et al, 1994;Traverso et al, 2003). Several studies have failed however to find any disruption of latent inhibition after acute injection of noncompetitive NMDA antagonists (Moser et al, 2000) or reported abolition of latent inhibition with concomitant decrease in the conditioned response in control groups (Turgeon et al, 2000). Moreover, a recent study has shown that MK-801 induced, on the contrary, a persistent latent inhibition in a conditioned emotional response procedure when it was administered at the conditioning stage but not at the pre-exposure stage (Gaisler-Salomon and Weiner, 2003).…”

Systemic administration of MK-801 produces an abnormally persistent latent inhibition which is reversed by clozapine but not haloperidol

“…Experiment 1 showed that under conditions which led to LI in controls (40 pre-exposures and two conditioning trials), MK-801-treated rats showed intact LI, in line with previous studies in which NMDA antagonists administered at a low dose range spared LI (Weiner and Feldon 1992;Robinson et al 1993;Aguado et al 1994;Turgeon et al 1998Turgeon et al , 2000. Furthermore, experiment 2 showed that at this same dose, MK-801 led to the emergence of LI under conditions that disrupted LI in controls (40 preexposures and five conditioning trials), and this was replicated in the next three experiments.…”

“…Studies testing the effects of acute systemic administration of non-competitive NMDA receptor antagonists on LI reported that PCP, ketamine, and the more potent and selective NMDA antagonist MK-801 spared LI (Weiner and Feldon 1992;Robinson et al 1993;Aguado et al 1994;Turgeon et al 1998Turgeon et al , 2000; although at high doses, PCP and MK-801 given 20 h before the LI procedure disrupted LI in conditioned taste aversion; Turgeon et al 1998Turgeon et al , 2000. Likewise, MK-801 infusion into the dorsal hippocampus left LI intact (Zhang et al 2000).…”

Procognitive and antipsychotic efficacy of glycine transport 1 inhibitors (GlyT1) in acute and neurodevelopmental models of schizophrenia: latent inhibition studies in the rat

“…Unlike amphetamine, acute administration of low-dose NMDA antagonists spares LI under conditions yielding LI in nontreated controls (Weiner and Feldon 1992;Aguado et al 1994;Klamer et al 2004;Palsson et al 2005;Robinson et al 1993;Turgeon et al 1998Turgeon et al , 2000 and in fact, produce an opposite behavioral effect on LI from that of amphetamine, namely, an abnormally persistent LI, that becomes manifested under conditions that prevent the expression of LI in no-drug controls (Gaisler-Salomon and Weiner 2003;Gaisler-Salomon et al 2008;Lipina et al 2005). This MK-801-induced attentional perseveration is reversed by atypical (clozapine and risperidone) but not typical (haloperidol) antipsychotic drugs (Gaisler-Salomon and Weiner 2003;Gaisler-Salomon et al 2008).…”