The effects of haloperidol and clozapine on the disruption of sensorimotor gating induced by the noncompetitive glutamate antagonist MK-801

Abstract

The amplitude of the acoustic startle response in rats is decreased if the startle stimulus is preceded by a nonstartle-eliciting auditory stimulus. This sensory gating phenomenon, known as prepulse inhibition, is diminished in schizophrenic individuals. In rats, the noncompetitive glutamate antagonist MK-801 disrupts prepulse inhibition. The present study examined whether the disruption by MK-801 is reversible in rats pretreated with the classical antipsychotic haloperiodol or the atypical antipsychotic clozapine. Male Sprague-Dawley rats were placed into a startle chamber and presented with auditory stimuli consisting of either 95 or 105 dB tones presented alone or preceded by a 70 dB tone. Rats treated with 0.1 mg/kg MK-801 demonstrated a significant disruption of prepulse inhibition. Haloperidol (0.1 and 0.5 mg/kg) and clozapine (1.0 and 5.0 mg/kg) each consistently failed to antagonize the MK-801-induced blockade of prepulse inhibition. The effects of haloperidol and clozapine on prepulse inhibition were also examined in saline-treated rats. Clozapine and, to some extent, haloperidol produced a dose-related facilitation of prepulse inhibition. Although preliminary, this finding raises the possibility that the enhancement of prepulse inhibition by antipsychotics might provide a useful rodent model for screening potential antipsychotic drugs.

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release

“…However, the combination of the lower doses of MPEP and MK-801 that produced cognitive impairments and stereotypy in the present study did not significantly increase cortical dopamine release, suggesting a possible dissociation between their effects on dopamine release and cognitive and motoric impairments. This is in agreement with numerous other studies, suggesting that corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of NMDA antagonists (Hoffman et al, 1993;Ogren and Goldstein, 1994;Steinpreis et al, 1994;Carlezon and Wise, 1996;Moghaddam, 1998, 2001). …”

M100907, a Serotonin 5-HT2A Receptor Antagonist and Putative Antipsychotic, Blocks Dizocilpine-Induced Prepulse Inhibition Deficits in Sprague–Dawley and Wistar Rats

“…Similar effects are exhibited when D 2 antagonists, such as haloperidol and raclopride, are tested in the PPI paradigm (Swerdlow and Geyer 1993;Varty and Higgins 1995a). The high D 2 receptor affinity of risperidone does not account for its potential ability to reduce the dizocilpine effect, because neither haloperidol nor raclopride reduce the effects of dizocilpine or PCP on PPI (Geyer et al 1990;Keith et al 1991;Hoffman et al 1993;Bakshi et al 1994;Varty and Higgins 1995a).…”

“…In particular, the PPI-disruptive effects of 5-HT 2 agonists are blocked specifically by the selective 5-HT 2A antagonist M100907 (Sipes and Geyer 1995). The PPI-disruptive effects of noncompetitive NMDA antagonists, such as phencyclidine (PCP), dizocilpine , and ketamine, are not blocked by dopamine receptor antagonists (Geyer et al 1990;Keith et al 1991;Hoffman et al 1993;Bakshi et al 1994;Varty and Higgins 1995a), but are reduced by multireceptor antagonist antipsychotics, such as clozapine, risperidone, quetiapine (Seroquel), and olanzapine (Bakshi et al 1994;Bakshi and Geyer 1995;Varty and Higgins 1995a;Swerdlow et al 1996). Accordingly, several recent studies have examined the particular receptors that might contribute to the ability of these atypical antipsychotics to reduce the PPI-disruptive effects of NMDA antagonists.…”

“Early” and “Late” Effects of Sustained Haloperidol on Apomorphine- and Phencyclidine-induced Sensorimotor Gating Deficits

“…Reports from several groups have demonstrated consistently that acute treatments with high-potency D2 antagonists, such as haloperidol, do not reverse PPI deficits produced by NMDA antagonists such as PCP (Geyer et al 1990;Keith et al 1991;Hoffman et al 1993). Recent evidence, however, indicates that sustained or subchronic exposure to high-potency D2 antagonists via drinking water or repeated daily injections does attenuate or reverse PCP-or dizocilpine (MK-801)-induced PPI deficits (Pietraszek and Ossowska 1998;Feifel and Priebe 1999).…”