Kindling with clozapine: Behavorial and molecular consequences

J. R. Stevens, Donald (Duane) Denney, P. Szot

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Clozapine is an 'atypical' neuroleptic that improves symptoms of many patients with schizophrenia whose illness is resistant to treatment with other neuroleptics. Unlike the 'typical' neuroleptics (chlorpromazine, haloperidol), clozapine does not induce extrapyramidal symptoms such as Parkinsonism and tardive dyskinesia in humans or catalepsy in the rat. However, clozapine frequently causes epileptiform EEG changes and causes seizures in 3-5% of patients treated with this drug in therapeutic doses. Clozapine also induces dose dependent myoclonus in the partially restrained rat. In the experiments reported here, partially restrained rats were administered repeated alternate day or weekly low, fixed doses of clozapine (1 mg/kg). This dose initially caused no behavioral Following the third and subsequent administrations, the same dose elicited an increasing number of myoclonic seizure-like jerks reaching 140/h following the 15th injection in rats receiving the same low dose of clozapine on alternate days and 160/h following the 9th injection in animals that received the same dose once weekly. These effects are consistent with kindling, i.e. a progressive increase of brain excitability following repeated administration of a fixed subconvulsive dose of an excitatory agent. Clozapine kindled animals exhibited a significantly different pattern of early gene expression in ventral tegmental area, origin of the mesolimbic-mesocortical dopamine system and in the anterior thalamic nuclei, compared with saline treated controls subjected to exactly the same recording conditions. The evidence of central nervous system excitation with clozapine may be important to the unique therapeutic effect of this atypical antipsychotic in the treatment of symptoms, especially the deficit symptoms, of schizophrenia.

Original languageEnglish (US)
Pages (from-to)295-304
Number of pages10
JournalEpilepsy Research
Volume26
Issue number1
DOIs
StatePublished - Dec 1 1996

Fingerprint

Clozapine
Antipsychotic Agents
Schizophrenia
Seizures
Anterior Thalamic Nuclei
Catalepsy
Ventral Tegmental Area
Myoclonus
Injections
Chlorpromazine
Parkinsonian Disorders
Therapeutic Uses
Haloperidol
Electroencephalography
Dopamine
Therapeutics
Central Nervous System
Gene Expression
Brain
Pharmaceutical Preparations

Keywords

  • clozapine
  • kindling
  • myoclonus
  • schizophrenia

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Kindling with clozapine : Behavorial and molecular consequences. / Stevens, J. R.; Denney, Donald (Duane); Szot, P.

In: Epilepsy Research, Vol. 26, No. 1, 01.12.1996, p. 295-304.

Research output: Contribution to journalArticle

Stevens, J. R. ; Denney, Donald (Duane) ; Szot, P. / Kindling with clozapine : Behavorial and molecular consequences. In: Epilepsy Research. 1996 ; Vol. 26, No. 1. pp. 295-304.
@article{0288deef33ad4ce48fd472969ac5e8d3,
title = "Kindling with clozapine: Behavorial and molecular consequences",
abstract = "Clozapine is an 'atypical' neuroleptic that improves symptoms of many patients with schizophrenia whose illness is resistant to treatment with other neuroleptics. Unlike the 'typical' neuroleptics (chlorpromazine, haloperidol), clozapine does not induce extrapyramidal symptoms such as Parkinsonism and tardive dyskinesia in humans or catalepsy in the rat. However, clozapine frequently causes epileptiform EEG changes and causes seizures in 3-5{\%} of patients treated with this drug in therapeutic doses. Clozapine also induces dose dependent myoclonus in the partially restrained rat. In the experiments reported here, partially restrained rats were administered repeated alternate day or weekly low, fixed doses of clozapine (1 mg/kg). This dose initially caused no behavioral Following the third and subsequent administrations, the same dose elicited an increasing number of myoclonic seizure-like jerks reaching 140/h following the 15th injection in rats receiving the same low dose of clozapine on alternate days and 160/h following the 9th injection in animals that received the same dose once weekly. These effects are consistent with kindling, i.e. a progressive increase of brain excitability following repeated administration of a fixed subconvulsive dose of an excitatory agent. Clozapine kindled animals exhibited a significantly different pattern of early gene expression in ventral tegmental area, origin of the mesolimbic-mesocortical dopamine system and in the anterior thalamic nuclei, compared with saline treated controls subjected to exactly the same recording conditions. The evidence of central nervous system excitation with clozapine may be important to the unique therapeutic effect of this atypical antipsychotic in the treatment of symptoms, especially the deficit symptoms, of schizophrenia.",
keywords = "clozapine, kindling, myoclonus, schizophrenia",
author = "Stevens, {J. R.} and Denney, {Donald (Duane)} and P. Szot",
year = "1996",
month = "12",
day = "1",
doi = "10.1016/S0920-1211(96)00061-7",
language = "English (US)",
volume = "26",
pages = "295--304",
journal = "Epilepsy Research",
issn = "0920-1211",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Kindling with clozapine

T2 - Behavorial and molecular consequences

AU - Stevens, J. R.

AU - Denney, Donald (Duane)

AU - Szot, P.

PY - 1996/12/1

Y1 - 1996/12/1

N2 - Clozapine is an 'atypical' neuroleptic that improves symptoms of many patients with schizophrenia whose illness is resistant to treatment with other neuroleptics. Unlike the 'typical' neuroleptics (chlorpromazine, haloperidol), clozapine does not induce extrapyramidal symptoms such as Parkinsonism and tardive dyskinesia in humans or catalepsy in the rat. However, clozapine frequently causes epileptiform EEG changes and causes seizures in 3-5% of patients treated with this drug in therapeutic doses. Clozapine also induces dose dependent myoclonus in the partially restrained rat. In the experiments reported here, partially restrained rats were administered repeated alternate day or weekly low, fixed doses of clozapine (1 mg/kg). This dose initially caused no behavioral Following the third and subsequent administrations, the same dose elicited an increasing number of myoclonic seizure-like jerks reaching 140/h following the 15th injection in rats receiving the same low dose of clozapine on alternate days and 160/h following the 9th injection in animals that received the same dose once weekly. These effects are consistent with kindling, i.e. a progressive increase of brain excitability following repeated administration of a fixed subconvulsive dose of an excitatory agent. Clozapine kindled animals exhibited a significantly different pattern of early gene expression in ventral tegmental area, origin of the mesolimbic-mesocortical dopamine system and in the anterior thalamic nuclei, compared with saline treated controls subjected to exactly the same recording conditions. The evidence of central nervous system excitation with clozapine may be important to the unique therapeutic effect of this atypical antipsychotic in the treatment of symptoms, especially the deficit symptoms, of schizophrenia.

AB - Clozapine is an 'atypical' neuroleptic that improves symptoms of many patients with schizophrenia whose illness is resistant to treatment with other neuroleptics. Unlike the 'typical' neuroleptics (chlorpromazine, haloperidol), clozapine does not induce extrapyramidal symptoms such as Parkinsonism and tardive dyskinesia in humans or catalepsy in the rat. However, clozapine frequently causes epileptiform EEG changes and causes seizures in 3-5% of patients treated with this drug in therapeutic doses. Clozapine also induces dose dependent myoclonus in the partially restrained rat. In the experiments reported here, partially restrained rats were administered repeated alternate day or weekly low, fixed doses of clozapine (1 mg/kg). This dose initially caused no behavioral Following the third and subsequent administrations, the same dose elicited an increasing number of myoclonic seizure-like jerks reaching 140/h following the 15th injection in rats receiving the same low dose of clozapine on alternate days and 160/h following the 9th injection in animals that received the same dose once weekly. These effects are consistent with kindling, i.e. a progressive increase of brain excitability following repeated administration of a fixed subconvulsive dose of an excitatory agent. Clozapine kindled animals exhibited a significantly different pattern of early gene expression in ventral tegmental area, origin of the mesolimbic-mesocortical dopamine system and in the anterior thalamic nuclei, compared with saline treated controls subjected to exactly the same recording conditions. The evidence of central nervous system excitation with clozapine may be important to the unique therapeutic effect of this atypical antipsychotic in the treatment of symptoms, especially the deficit symptoms, of schizophrenia.

KW - clozapine

KW - kindling

KW - myoclonus

KW - schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=0030300074&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030300074&partnerID=8YFLogxK

U2 - 10.1016/S0920-1211(96)00061-7

DO - 10.1016/S0920-1211(96)00061-7

M3 - Article

C2 - 8985708

AN - SCOPUS:0030300074

VL - 26

SP - 295

EP - 304

JO - Epilepsy Research

JF - Epilepsy Research

SN - 0920-1211

IS - 1

ER -