Effect of 5-HT₃ receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice

Abstract

Phencyclidine and ketamine (but not other NMDA channel blockers, such as memantine) produce psychotomimetic effects. Since unlike memantine, phencyclidine-like compounds show no significant affinity at 5-HT₃ receptors, we investigated if behavioral effects of ketamine could be reduced by 5HT₃ receptor blockade. Ketamine (3–40 mg/kg) produced ataxia, stereotypes and diminished exploratory activity in mice, and reduced prepulse inhibition of acoustic startle response, lowered accuracy in fixed consecutive number and in delayed non-matching-to-sample tasks in rats. The 5HT₃ receptor antagonist MDL 72222 (0.3–3 mg/kg) administration did not reverse any of these deficits and exerted no effects on discriminative stimulus properties of ketamine. In the tail suspension test, both ketamine and MDL 72222 produced anti-immobility effects when given alone (50–66 and 3 mg/kg, respectively) and together (12.5–25 and 1 mg/kg). The present data suggest that 5-HT₃ receptor blockade does not reverse the behavioral deficits of ketamine and may even enhance its certain effects, such as the antidepressant-like action.

Introduction

Phencyclidine (PCP)-like antagonists of the NMDA receptor complex are well known for their psychotomimetic effects in humans and the ability to produce a plethora of behavioral abnormalities in laboratory animals. Yet, some studies have suggested that certain NMDA receptor antagonists such as memantine are well tolerated within their therapeutic dose range compared with others such as PCP and ketamine (Parsons et al., 1999). One of the reasons of the better pharmacological profile of such drugs as memantine could be its lower affinity and strong voltage dependency at NMDA receptors (Parsons et al., 1999), although the possibility that it interacts with the targets other than NMDA receptors cannot be excluded. In a recent study, Rammes et al. (2001) reported that memantine but not ketamine demonstrated antagonistic actions at serotonin 5-HT₃ receptors. Specifically, these authors found that affinities of memantine and ketamine for NMDA receptors were 2.5 and 0.5 uM, respectively, while at 5-HT_3A receptors, these values were 2.29 and 90.4 μM, respectively. Since the potency ratio of memantine at 5-HT₃ / NMDA receptors was 0.91, while the respective value for ketamine was 180, it is possible that the better tolerability of memantine might be at least partially due to its higher affinity for 5-HT₃ receptors. Data reported by McCool and Lovinger (1995) indicate that another well tolerated and NR2B-subtype selective NMDA receptor antagonist ifenprodil, also demonstrated relatively potent antagonistic effects at the 5-HT₃ receptor.

The major concern with clinical use of the NMDA receptor antagonists are their psychotomimetic effects. For instance, studies of Krystal et al. (1994) indicate that ketamine administered at subanesthetic doses produces a broad range of symptoms, behaviors and cognitive deficits resembling symptoms of schizophrenia-like psychoses and dissociative states. Breier et al. (1997) further suggested that NMDA receptors of prefrontal cortex were involved in ketamine-induced “psychotic state”.

Deficits of sensorimotor gating, measured by prepulse inhibition (PPI), have been observed in schizophrenic patients (Braff et al., 2001). Small-scale clinical trial has demonstrated that 5-HT₃ receptor antagonists alleviated psychotic symptoms in patients affected by schizophrenia (Sirota et al., 2000) and had beneficial effect on psychosis induced by L-DOPA in Parkinson's disease patients (Zoldan et al., 1995).

In animals, disruption of PPI similar to that seen in schizophrenia can be induced by administration of noncompetitive NMDA receptor antagonists (for review see (Geyer et al., 2001)). These deficits induced by NMDA receptor antagonists can be reversed by an acute treatment with some atypical antipsychotics (e.g., clozapine), whereas typical antipsychotics (e.g., haloperidol) are ineffective in this model (for review see (Geyer et al., 2001)). Whereas typical antipsychotics block with high affinity dopamine D2 receptors, atypical antipsychotics in addition act on several 5-HT receptors (Breese et al., 2002, Rammes et al., 2004). Thus, it has been suggested that 5-HT receptor antagonism contributes to ability of atypical antipsychotics to attenuate effects of NMDA receptor antagonists (Breese et al., 2002, Varty et al., 1999). Consistent with this, it has been demonstrated that 5-HT_2A receptor antagonists reverse sensorimotor gating deficit induced by a noncompetitive NMDA receptor antagonist (Varty et al., 1999). Based on these findings, it can be hypothesized that glutamate and serotonin interact in controlling PPI and that 5-HT₃ receptor antagonistic properties of NMDA receptor antagonists such as memantine may protect against the psychotomimetic effects typically ascribed to the blockade of NMDA receptors.

The aim of the present study was to explicitly test this hypothesis by evaluating the behavioral effects of ketamine given either alone or in combination with the selective 5-HT₃ receptor antagonist, MDL 72222. Experiments were performed in rats and mice using a battery of behavioral assays sensitive to disruptive effects of PCP-like agents and ketamine in particular. In rats, ketamine was administered to induce deficits in prepulse inhibition (PPI) of the acoustic startle reflex, to reduce performance accuracy in the delayed-non-matching-to-position (DNMTP) and fixed consecutive number (FCN) tasks, and to serve as a discriminative stimulus in the food-reinforced operant task. In mice, pretreatment with ketamine was given to induce ataxia in the elevated platform test (Evoniuk et al., 1991) and PCP-like stereotypies (circling, sniffing or head waving) (Danysz et al., 1994). Finally, given that 5-HT₃ receptor antagonists (Martin et al., 1992) and ketamine (Chaturvedi et al., 1999, Yilmaz et al., 2002) exert similar antidepressant-like activity, the tail suspension test (Steru et al., 1985) was conducted in mice pretreated with the combinations of ketamine and MDL 72222. It was hypothesized that 5-HT₃ receptor inhibition might reverse behavioral abnormalities induced by ketamine and potentiate its antidepressant-like effect.