Neurochemical changes in the entopeduncular nucleus and increased oral behavior in rats treated subchronically with clozapine or haloperidol

Abstract

The purpose of the present experiment was to test the possibility that atypical antipsychotics and classical antipsychotics differentially regulate specific neurochemical processes within the entopeduncular nucleus. For these experiments, rats were administered clozapine (25 mg/kg), haloperidol (1 mg/kg), or Tween-80 (control) daily for 21 days. Dopamine D(1)-receptor binding was assessed with in vitro receptor autoradiographic methods and the mRNAs corresponding to the two forms of glutamate decarboxylase (glutamate decarboxylase-65 and glutamate decarboxylase-67) were analyzed using in situ hybridization histochemical methods. In addition, vacuous chewing movements (VCM) were measured throughout the drug administration period as a functional indicator of drug action and changes in striatal dopamine D(2)-receptor binding were measured as a positive control for D(2)-receptor antagonist properties of haloperidol and clozapine. In agreement with previous reports, haloperidol increased D(2)-receptor binding throughout the striatum while clozapine had a more limited impact on D(2)-receptors. Behavioral analysis revealed that both haloperidol and clozapine enhanced the display of vacuous chewing movements to a similar extent but with a different postinjection latency. In the entopeduncular nucleus, clozapine increased D(1)-receptor binding compared to controls while haloperidol was without effect. With respect to the regulation of GAD mRNAs, haloperidol increased glutamate decarboxylase-65 and glutamate decarboxylase-67 mRNA levels throughout the entopeduncular nucleus. The effects of clozapine were restricted to increases in glutamate decarboxylase-65 mRNA. These studies show that clozapine and haloperidol, both of which increase the occurrence of VCM, differentially modulate the neurochemistry of the entopeduncular nucleus.

Prepulse Inhibition Deficits in GAD65 Knockout Mice and the Effect of Antipsychotic Treatment

“…The latter finding may suggest that untreated schizophrenic patients might inherently have reduced GAD65 expression in the hippocampus, which can be upregulated with exposure to antipsychotic drugs. Consistent with this idea, chronic administration of antispychotics in rodents has been associated with an upregulation of GAD mRNAs (Lipska et al, 2003;Yu et al, 1999).…”

Prepulse Inhibition Deficits in GAD65 Knockout Mice and the Effect of Antipsychotic Treatment

“…The latter finding may suggest that untreated schizophrenic patients might inherently have reduced GAD65 expression in the hippocampus, which can be upregulated with exposure to antipsychotic drugs. Consistent with this idea, chronic administration of antispychotics in rodents has been associated with an upregulation of GAD mRNAs (Lipska et al, 2003;Yu et al, 1999).…”

Metabolic changes in the basal ganglia of patients with Huntington's disease: an in situ hybridization study of cytochrome oxidase subunit I mRNA

“…Indeed, COI mRNA expression in the GPi was slightly albeit nonsigni®cantly increased in non-HD patients who had received neuroleptic treatment. In agreement with this hypothesis, several experimental studies have provided evidence of metabolic changes in the GP with neuroleptic systemic administration (Mercugliano et al 1992;Delfs et al 1995a;Delfs et al 1995b;Yu et al 1999). On the other hand, some factors tend to decrease GPi activity, such as an involvement of the subthalamic nucleus or the GPi itself by the neurodegenerative process.…”

Selective Brain Distribution and Distinctive Synaptic Architecture of Dual Glutamatergic-GABAergic Neurons

“…The posterior EPN appears to be involved in classic basal ganglia disorders, such as schizophrenia and movement disorders. For example, the antipsychotic clozapine increases GAD mRNA mostly in the posterior EPN compared with the anterior EPN (Yu et al, 1999). Furthermore, torsinA, the causative protein of a severe form of dystonia, is selectively reduced in the posterior EPN from rats with levodopa-induced dyskinesia (Yamada et al, 2006).…”

Prepulse Inhibition Deficits in GAD65 Knockout Mice and the Effect of Antipsychotic Treatment

“…The latter finding may suggest that untreated schizophrenic patients might inherently have reduced GAD65 expression in the hippocampus, which can be upregulated with exposure to antipsychotic drugs. Consistent with this idea, chronic administration of antispychotics in rodents has been associated with an upregulation of GAD mRNAs (Lipska et al, 2003;Yu et al, 1999).…”

Metabolic changes in the basal ganglia of patients with Huntington's disease: an in situ hybridization study of cytochrome oxidase subunit I mRNA

“…Indeed, COI mRNA expression in the GPi was slightly albeit nonsigni®cantly increased in non-HD patients who had received neuroleptic treatment. In agreement with this hypothesis, several experimental studies have provided evidence of metabolic changes in the GP with neuroleptic systemic administration (Mercugliano et al 1992;Delfs et al 1995a;Delfs et al 1995b;Yu et al 1999). On the other hand, some factors tend to decrease GPi activity, such as an involvement of the subthalamic nucleus or the GPi itself by the neurodegenerative process.…”

Selective Brain Distribution and Distinctive Synaptic Architecture of Dual Glutamatergic-GABAergic Neurons

“…The posterior EPN appears to be involved in classic basal ganglia disorders, such as schizophrenia and movement disorders. For example, the antipsychotic clozapine increases GAD mRNA mostly in the posterior EPN compared with the anterior EPN (Yu et al, 1999). Furthermore, torsinA, the causative protein of a severe form of dystonia, is selectively reduced in the posterior EPN from rats with levodopa-induced dyskinesia (Yamada et al, 2006).…”

Prepulse Inhibition Deficits in GAD65 Knockout Mice and the Effect of Antipsychotic Treatment

“…The latter finding may suggest that untreated schizophrenic patients might inherently have reduced GAD65 expression in the hippocampus, which can be upregulated with exposure to antipsychotic drugs. Consistent with this idea, chronic administration of antispychotics in rodents has been associated with an upregulation of GAD mRNAs (Lipska et al, 2003;Yu et al, 1999).…”

Metabolic changes in the basal ganglia of patients with Huntington's disease: an in situ hybridization study of cytochrome oxidase subunit I mRNA

“…Indeed, COI mRNA expression in the GPi was slightly albeit nonsigni®cantly increased in non-HD patients who had received neuroleptic treatment. In agreement with this hypothesis, several experimental studies have provided evidence of metabolic changes in the GP with neuroleptic systemic administration (Mercugliano et al 1992;Delfs et al 1995a;Delfs et al 1995b;Yu et al 1999). On the other hand, some factors tend to decrease GPi activity, such as an involvement of the subthalamic nucleus or the GPi itself by the neurodegenerative process.…”

Selective Brain Distribution and Distinctive Synaptic Architecture of Dual Glutamatergic-GABAergic Neurons

“…The posterior EPN appears to be involved in classic basal ganglia disorders, such as schizophrenia and movement disorders. For example, the antipsychotic clozapine increases GAD mRNA mostly in the posterior EPN compared with the anterior EPN (Yu et al, 1999). Furthermore, torsinA, the causative protein of a severe form of dystonia, is selectively reduced in the posterior EPN from rats with levodopa-induced dyskinesia (Yamada et al, 2006).…”