The effect of zotepine, risperidone, clozapine and olanzapine on MK-801-disrupted sensorimotor gating

Abstract

Dizocilpine (MK-801; 0.3 mg/kg i.p.)-induced disruption in prepulse inhibition of the acoustic startle response (PPI) can be preferentially restored by “atypical” antipsychotics. In contrast, some findings indicate that not all of the “atypical” antipsychotics, such as clozapine and risperidone, are effective in restoring the NMDA antagonist-induced deficits in PPI.

In our study, we evaluated the effect of four different “atypical” antipsychotic drugs on deficits in PPI induced by MK-801. Zotepine and risperidone have high affinities to D2-like and 5-HT_2A receptors, while clozapine and olanzapine have multipharmacological profiles with the highest affinities to serotonin 5-HT_1A,2A/2C receptors and muscarinic receptors.

Results have shown that MK-801 disrupted PPI and increased the ASR in rats. Our results showed no effect of zotepine (1 and 2 mg/kg) and risperidone (0.1 and 1 mg/kg) on disrupted PPI by MK-801. Administration of clozapine (5 and 10 mg/kg) and olanzapine (2.5 and 5 mg/kg) restored the deficits in PPI induced by MK-801. Additionally, we found a decrease of approximately 46% in PPI after administration of clozapine (5 mg/kg) and olanzapine (2.5 and 5 mg/kg) without MK-801 treatment.

In summary, the four “atypical” antipsychotics had different efficacies to restore the disrupted PPI by MK-801. Only clozapine and olanzapin restored the MK-801-induced deficits in PPI.

Introduction

The acoustic startle response (ASR) is a fast twitch of facial and body muscles evoked by a sudden and intense acoustic stimulus >80 dB (Koch, 1999). The ASR can be attenuated by a variety of experimental manipulations across species such as prior presentation of a low-intensity prepulse (prepulse inhibition of the startle response: PPI) or repeated presentation of startling stimuli (habituation). Prepulse inhibition of the startle response (PPI) measures sensorimotor gating, which is suggested to regulate environmental inputs and selectively allocate attentional resources to salient stimuli (Braff et al., 2001). Deficits in sensorimotor gating have been observed in patients with several neuropsychiatric disorders including schizophrenia (Swerdlow et al., 1998).

In animals, disruption of PPI is produced by a variety of pharmacological stimuli (Geyer et al., 2001, Swerdlow et al., 2001) such as nonselective dopaminergic agonists (amphetamine; apomorphine) or competitive and non-competitive antagonists of glutamate N-methyl-d-aspartate (NMDA) receptors (Mansbach and Geyer, 1989, Wiley and Kennedy, 2002).

Non-competitive antagonists of NMDA receptors (e.g. MK-801, ketamine, phencyclidine) induce psychotomimetic effects in humans (Luby et al., 1959, Snyder, 1980). In rats, the highly selective non-competitive NMDA antagonist, MK-801, produces changes in behaviour such as impairments related to PPI, hyperlocomotion, stereotypy and social deficits, which are so-called schizophrenia-like behaviours (Jentsch and Roth, 1999). It was previously described that the MK-801-induced disruption of PPI can be restored preferentially by “atypical” antipsychotics without affecting the startle response in rats (Corbett et al., 1995, Swerdlow et al., 1998, Geyer et al., 2001, Wiley and Kennedy, 2002). The group of antipsychotics includes drugs which ameliorate the negative and positive symptoms of schizophrenia, have a low propensity to produce extrapyramidal side effects and have a low capacity to elevate prolactine levels (Lidow, 2000). Therefore, deficits in PPI produced by MK-801 have been used in adult animals to investigate the efficacy of “typical” and “atypical” antipsychotics, and to predict the efficacy of new putative antipsychotics (Geyer et al., 2001). On the other hand, some findings indicate that not all “atypical” antipsychotics, such as clozapine and risperidone, are effective in restoring the NMDA antagonist-induced deficits in PPI (Compton et al., 2001, Wiley and Kennedy, 2002). Hence, these findings support that the effects on PPI are similar to those observed after administration of “typical” antipsychotics (Wiley and Kennedy, 2002). A majority of the studies compared the effects on sensorimotoric gating by atypical antipsychotics with the “typical” antipsychotic, haloperidol (Bakshi et al., 1998, Swerdlow et al., 1998, Martinez et al., 2002). The current manuscript reports a comparison within a single study of four atypical antipsychotics matched for D2 receptor affinity.

We evaluated the effects of four “atypical” antipsychotic drugs on the deficits in PPI induced by MK-801 and changes in the ASR. We chose commonly used antipsychotics with atypical features (risperidone, zotepine, clozapine, and olanzapine) and grouped them based on their similar pharmacodynamic profiles and dopamine D2 receptor affinity (Arnt and Skarsfeld, 1998, Richelson and Souder, 2000). Zotepine and risperidone have strong affinities to D2-like and 5-HT_2A receptors (Richelson and Souder, 2000), while clozapine and olanzapine have rather multipharmacological profiles with the highest affinity to serotonin 5-HT_1A,2A/2C (Richelson and Souder, 2000) and muscarinic receptors (Bymaster et al., 2003). In our study, we aimed to establish whether high affinity to dopamine D2 receptors determines the effect of antipsychotics with atypical features on PPI in an animal model of schizophrenia.