The effect of zotepine, risperidone, clozapine and olanzapine on MK-801-disrupted sensorimotor gating
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-HT2A receptors (Richelson and Souder, 2000), while clozapine and olanzapine have rather multipharmacological profiles with the highest affinity to serotonin 5-HT1A,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.
Section snippets
Animals
A total of 339 male Wistar rats (200–250 g, specific pathogen-free animals; Hannover breed Konárovice, Czech Republic) were used in this study. Cages with two male rats were housed in a temperature-controlled room (21–22 °C), having a 12:12 h light/dark regime (lights on at 6:00 a.m.) with free access to food (ST-1 diet) and water. Each rat was experimentally naive and was tested only once. All manipulations with the animals respected the Guidelines of the European Union Council (86/609/EU) and
Statistics
Data from both parts of the experiment (ASR and PPI) were collected and statistically evaluated by a two-way analysis of variance (ANOVA) with antipsychotic treatment as one factor and MK-801 treatment as the second factor. When appropriate, comparisons between treatment groups were conducted using a Tukey post hoc test. P<0.05 was considered significant.
The effect of antipsychotics on the startle response
Table 1 shows the average values of the startle response [mV] after administration of MK-801 and/or after pre-treatment with antipsychotics. Administration of MK-801 increased the average startle amplitude (P<0.01) compared to the controls by about 49%.
Discussion
In our experimental schedule, administration of MK-801 (0.3 mg/kg) in male Wistar rats decreased PPI by about 85% and increased the ASR by about 49% compared to the control animals. These results are in accordance with previous studies (Bakshi et al., 1994, Bast et al., 2000; see review Geyer et al., 2001, Schulz et al., 2001). It was established that doses of MK-801 higher than 0.05 mg/kg s.c. can disrupt PPI of the acoustic startle response (Bast et al., 2000). Thus, we chose the dose of 0.3
Conclusions
Systemic administration of MK-801 produced marked deficits in sensorimotor gating and increased the response to acoustic stimuli. Administration of antipsychotics with multipharmacological profiles and low affinity to dopamine D2 receptors (clozapine, olanzapine) restored the deficits in PPI induced by MK-801. Antipsychotics with high affinities at dopamine D2 receptors had no effect on the disrupted PPI induced by MK-801. We observed a decrease of spontaneous PPI after administration of
Acknowledgements
This research was supported by the Grant No. NL 7684-3 from the Grant Agency of the Ministry of Health, the Czech Republic.
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