MDL 73,147EF, a 5-HT3 antagonist, facilitates latent inhibition in the rat

doi:10.1016/0091-3057(92)90148-9

Pharmacology Biochemistry and Behavior

Volume 42, Issue 3, July 1992, Pages 519-522

https://doi.org/10.1016/0091-3057(92)90148-9 Get rights and content

Abstract

Latent inhibition (LI) is a behavioral model of selective attention that has been used to study the attentional seen in schizophrenia. In the present study, we examined the effect of 5-hydroxytryptamine₃ (5-HT₃) receptor blockade on LI using the conditioned emotional response (CER) procedure. Prior exposure to 20, 30,or 40 stimulus presentations significantly, and almost completely, inhibited the CER to that stimulus. This LI effect was much weaker when only 10 preexposures were given. 1H-indole-3-carboxylic acid, trans-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester methanesulfonate (MDL 73,147EF), a selective 5-HT₃ receptor antagonist, significantly facilitated the LI effect observed after 10 preexposures at 0.1 mg/kg but nnot at 0.01 mg/kg. The magnitude of this effect was comparable to that observed with the classical haloperidol (0.1 mg/kg). Neither MDL 73,147EF nor haloperidol affected the CER in animals not preexposed to the stimulus. These results strongly corroborate suggestions that 5-HT₃ receptor antagonists will be of use in the treatment of schizophrenia.

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Cited by (30)

Effect of dopamine and serotonin receptor antagonists on fencamfamine-induced abolition of latent inhibition
2013, European Journal of Pharmacology
Citation Excerpt :
Two selective dopamine D2 receptor antagonists were used because of relevant differences in their mechanism of action. METH has both 5-HT3 receptor antagonist action and 5-HT4 receptor agonist action, which could affect latent inhibition, learning, and memory (Fontana et al., 1998; Meneses and Hong, 1997; Moran and Moser, 1992; Terry et al., 1996). PIM also blocks both dopamine D3 and serotonin 5-HT2A receptors (Bezchlinyk-Butler and Jeffries, 1997; Freedman et al., 1994; Griffon et al., 1996; Sokoloff et al., 1992), which have been implicated in schizophrenia and latent inhibition (Alves and Silva, 2001; Seeman and Van Tol, 1994).
The purpose of this investigation was to verify the role of dopamine and serotonin receptors in the effect of fencamfamine (FCF) on latent inhibition. FCF is a psychomotor stimulant with an indirect dopaminergic action. Latent inhibition is a model of attention. Latent inhibition is blocked by dopaminergic agents and facilitated by dopamine receptor agonists. FCF has been shown to abolish latent inhibition. The serotonergic system may also participate in the neurochemical mediation of latent inhibition. The selective dopamine D₁ receptor antagonist SCH 23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), D₂ receptor antagonists pimozide (PIM) and methoclopramide (METH), and serotonin 5-HT_2A/C receptor antagonist ritanserin (RIT) were used in the present study. Latent inhibition was evaluated using a conditioned emotional response procedure. Male Wistar rats that were water-restricted were subjected to a three-phase procedure: preexposure to a tone, tone-shock conditioning, and a test of the effect of the tone on licking frequency. All of the drugs were administered before the preexposure and conditioning phases. The results showed that FCF abolished latent inhibition, and this effect was clearly antagonized by PIM and METH and moderately attenuated by SCH 23390. At the doses used in the present study, RIT pretreatment did not affect latent inhibition and did not eliminate the effect of FCF, suggesting that the FCF-induced abolition of latent inhibition is not mediated by serotonin 5-HT_2A/C receptors. These results suggest that the effect of FCF on latent inhibition is predominantly related to dopamine D₂ receptors and that dopamine D₂ receptors participate in attention processes.
Serotonergic mechanisms of memory trace retrieval
2008, Behavioural Brain Research
This review summarizes our research examining the role of serotonergic mechanisms in memory processes. Analysis of serotonin (5-HT) metabolism and specific binding of radioligand [³H]5-HT in various brain structures at different stages of a conditioned passive avoidance response in rats has demonstrated that 5-HT is involved in the processes of memory retrieval rather than in acquisition. The process of retrieving a conditioned response formed to a new conditioned stimulus is accompanied by a reduction in postsynaptic 5-HT receptor binding in the amygdala, periacqueductal gray matter, and striatum, while no changes have been seen in the hippocampus or prefrontal cortex. The changes in 5-HT activity found in the amygdala and periacqueductal gray matter indicate that 5-HT is involved in the emotional mechanisms activating a memory trace. The animals that due to developed amnesia had impaired memory trace retrieval showed no decreases in 5-HT receptor binding in either the emotional areas of the brain or the striatum. Furthermore, a memory retrieval deficit evoked by presentation of a habituated conditioned stimulus (latent inhibition) resulted in an enhanced 5-HT activity in these structures. From these data it appears that a reduction in postsynaptic 5-HT receptor binding in such brain structures as the amygdala and periacqueductal gray matter is necessary for memory trace retrieval relating to an aversive event. Without this, the emotional mechanisms of reinforcement of conditioned stimulus are not triggered and extraction of a corresponding engram does not occur.
7-OH-DPAT effects on latent inhibition: low dose facilitation but high dose blockade: Implications for dopamine receptor involvement in attentional processes
2007, Pharmacology Biochemistry and Behavior
7-OH-DPAT is a dopamine D2/D3 agonist, which at low doses acts preferentially on D3 receptors but at high doses it acts on D2 and D3 receptors. The present study investigated the contribution of D3 and D2 receptors on latent inhibition (LI) by using two dose levels of 7-OH-DPAT: a low dose, 0.1 mg/kg (D3 receptor activation) and a high dose, 1.0 mg/kg, (D2/D3 receptor activation) in a conditioned emotional response (CER) paradigm. The LI Protocols included CS pre-exposure (10 or 40 CS alone trials), CER induction and a non-drug CER test phase. Additionally, the drug effects upon CER acquisition without LI were assessed using the same treatments and test environment pre-exposure protocols but without the tone CS. The effects of 7-OH-DPAT on crossing, rearing and grooming were also measured in an open field 1 day after the CER test phase. The results showed that the low dose 7-OH-DPAT treatment potentiated LI at 10 but not at 40 CS pre-exposures. The high dose 7-OH-DPAT treatment blocked LI at both the 10 and 40 stimulus pre-exposures; and it also induced hyperactivity. Thus, D3 stimulation induced by a low dose of 7-OH-DPAT can facilitate LI but these effects are contingent upon and are specific to the number of stimulus presentations. Altogether, these findings indicate that D3 stimulation can enhance attentional processes, but D2 stimulation can impair attentional processes.
Effects of the selective dopamine D<inf>1</inf> antagonists NNC 01-0112 and SCH 39166 on latent inhibition in the rat
2002, Physiology and Behavior
Citation Excerpt :
Ten preexposures were used since it has been established that using a low number of preexposures produces a small LI effect and hence a more accurate evaluation of drug influences [14,21,41,59].
Dopamine D₁ receptor blockade does not appear to be a prerequisite for antipsychotic activity since many clinically effective antipsychotics have little or no affinity for this receptor subtype. Clozapine, however, which has minimal liability for extrapyramidal symptoms, possesses affinities of similar order for D₁ and D₂ receptors. In earlier animal models used to predict antipsychotic effect, selective D₁ antagonists have shown effects similar to standard antipsychotics with preferential D₂ or mixed D₁/D₂ antagonism. We investigated the effects of haloperidol (0.1 mg/kg) and two selective D₁ antagonists, NNC 01-0112 (0.05, 0.1 and 0.2 mg/kg) and SCH 39166 (0.02, 0.2 and 2.0 mg/kg), on latent inhibition (LI) in rats. LI is a behavioural paradigm in which repeated nonreinforced preexposure to a stimulus retards subsequent associations to that stimulus. Disrupted LI has been suggested as a model for the attentional deficits in schizophrenia. Using preexposure to a flashing light stimulus, which subsequently served as a conditioned stimulus for suppression of water licking, we demonstrated a clear LI effect with haloperidol but with neither of the two D₁ antagonists. Since selective D₁ antagonists are not clinically effective, these results add further credibility for the relevance of LI as an animal model of psychosis.
The pharmacology of latent inhibition as an animal model of schizophrenia
2000, Brain Research Reviews
Citation Excerpt :
The effects of serotonergic compounds on facilitation of LI are shown in Table 2. Those compounds that facilitated LI include the 5-HT1A receptor antagonist WAY 100,635 [150] and the 5-HT3 receptor antagonists dolasetron [192] and ondansetron [276]. In addition to these antagonists, the 5-HT uptake inhibitors fluoxetine and sertraline have also been reported to facilitate LI [128,163].
The nature of the primary symptoms of schizophrenia and our lack of knowledge of its underlying cause both contribute to the difficulty of generating convincing animal models of schizophrenia. A more recent approach to investigating the biological basis of schizophrenia has been to use information processing models of the disease to link psychotic phenomena to their neural basis. Schizophrenics are impaired in a number of experimental cognitive tasks that support this approach, including sensory gating tasks and models of selective attention such as latent inhibition (LI). LI refers to a process in which noncontingent presentation of a stimulus attenuates its ability to enter into subsequent associations, and it has received much attention because it is widely considered to relate to the cognitive abnormalities that characterise acute schizophrenia. Several claims have been made for LI having face and construct validity for schizophrenia. In this review of the pharmacological studies carried out with LI we examine its claim to predictive validity and the role of methodological considerations in drug effects. The data reviewed demonstrate that facilitation of low levels of LI is strongly related to demonstrated antipsychotic activity in man and all major antipsychotic drugs, both typical and atypical, have been shown to potentiate LI using a variety of protocols. Very few compounds without antipsychotic activity are active in this model. In contrast, disruption of LI occurs with a wide range of drugs and the relationship with psychotomimetic potential is less clear. Although reversal of disrupted LI has also been used as a model for antipsychotic acticity, mostly using amphetamine-induced disruption, insufficient studies have been carried out to evaluate its claim to predictive validity. However, like facilitation, it is sensitive to both typical and atypical antipsychotic agents. The data we have reviewed here demonstrate that facilitation of LI and, perhaps to a lesser extent, reversal of disrupted LI fulfil the criteria for predictive validity.
Enhancement of latent inhibition in the rat by the CCK antagonist proglumide
1998, Pharmacology Biochemistry and Behavior
The behavioral paradigm of latent inhibition (LI) involves the retardation of conditioning to a stimulus when paired with reinforcement, if preexposure to that stimulus with no significant consequence has occurred. This phenomenon is believed to reflect a process of learning to ignore stimuli as irrelevant. Disruption in LI can be considered to be an attentional deficit observed in schizophrenia. The neuropeptide cholecystokinin (CCK), which coexists with dopamine (DA) in some brain regions, has been implicated in the pathophysiology of schizophrenia. The present study examined the effects of the nonselective CCK antagonist proglumide on LI (0.25, 0.5, and 1.0 mg/kg) using a conditioned suppression of drinking procedure in rats. For purposes of comparison the effects of haloperidol (0.1 mg/kg) were also investigated. Administration of 1.0 and 0.5 mg/kg, but not 0.25 mg/kg, proglumide was found to reduce suppression of drinking behavior in animals preexposed (PE) to a flashing light stimulus. These animals developed LI under conditions where preexposed control animals exhibited suppression of drinking behavior similar to that of nonpreexposed (NPE) control animals. These findings for proglumide were comparable to the effects on drinking behavior of 0.1 mg/kg haloperidol. The enhancement of LI by proglumide may be interpreted in terms of CCK–dopamine interactions. Because CCK may modulate dopamine, the results reported here for proglumide strengthen the argument for the investigation of CCK-based drugs as potential antipsychotic agents.

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Rapid communicationMDL 73,147EF, a 5-HT3 antagonist, facilitates latent inhibition in the rat

Abstract

Pharmacol. Biochem. Behav.

Biol. Psychiatry

Pharmacol. Ther.

Biol. Psychiatry

Physiol. Behav.

Eur. J. Pharmacol.

Neurosci. Biobehav. Rev.

Pharmacol. Biochem. Behav.

Differential performance of acute and chronic schizophrenics in a latent inhibition task

J. Nerv. Ment. Dis.

Animal models with construct validity for schizophrenia

Behav. Pharmacol.

Rapid communication
MDL 73,147EF, a 5-HT₃ antagonist, facilitates latent inhibition in the rat