Basal Ganglia GABAA and Dopamine D1 Binding Site Correlates of Haloperidol-Induced Oral Dyskinesias in Rat

Osamu Shirakawa, Carol A. Tamminga

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Chronic haloperidol treatment in the laboratory rat induces spontaneous orofacial movements in some but not all of the animals, a behavior which has been described in the literature as vacuous chewing movements (VCMs). In an attempt to understand the neurochemical mechanism of these rat dyskinesias, we measured regional dopamine D1, D2, and GABAA binding density in rats with and without VCMs after chronic haloperidol treatment and in untreated controls using in vitro receptor autoradiography and correlated the binding changes with the dyskinetic behavior. Chronic haloperidol treatment produced an overall increase in dopamine D2 family receptor binding in the caudate putamen and in nucleus accumbens in both groups of treated rats, those with and without VCMs. In the haloperidol-treated rats with VCMs, a significant increase in GABAA receptor density occurred in the substantia nigra pars reticulata (SNR), with a trend in those rats without VCMs. However, only in those haloperidol-treated animals with VCMs did a significant decrease in dopamine D1 receptor density occur in SNR. These receptor alterations are consistent with a process of haloperidol-induced neuronal death of striatonigral fibers. However, we have failed to identify cellular evidence of such toxicity. Alternatively, the receptor changes may reflect increased dendritic dopamine release in SNR, or, more speculatively a functional response to chronically diminished striatonigral pathway activity. Perhaps the release of dopamine from dendrites of the local DA-containing neurons might be variably enhanced with ongoing haloperidol treatment. Increased nigral dopamine would itself cause the release of GABA, presynaptically, onto nigral efferent neurons. This would overinhibit nigral GABA-containing efferent neuronal pathways, disinhibiting motor areas in the thalamus, and result in dyskinesias. In support of the latter interpretation is the finding of a correlation in the mediodorsal thalamus between VCMs and GABAA binding. These findings may have implications for the pathophysiology of neuroleptic-induced dyskinesias in humans.

Original languageEnglish (US)
Pages (from-to)62-69
Number of pages8
JournalExperimental Neurology
Volume127
Issue number1
DOIs
StatePublished - May 1994

Fingerprint

Mastication
Movement Disorders
Haloperidol
Basal Ganglia
Dopamine
Binding Sites
Dyskinesias
Substantia Nigra
Thalamus
gamma-Aminobutyric Acid
Efferent Neurons
Efferent Pathways
Dopamine D1 Receptors
Animal Behavior
Dopamine D2 Receptors
Putamen
Nucleus Accumbens
Motor Cortex
GABA-A Receptors
Dendrites

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

Cite this

Basal Ganglia GABAA and Dopamine D1 Binding Site Correlates of Haloperidol-Induced Oral Dyskinesias in Rat. / Shirakawa, Osamu; Tamminga, Carol A.

In: Experimental Neurology, Vol. 127, No. 1, 05.1994, p. 62-69.

Research output: Contribution to journalArticle

@article{753a1e46619446529dbfd925845cc28b,
title = "Basal Ganglia GABAA and Dopamine D1 Binding Site Correlates of Haloperidol-Induced Oral Dyskinesias in Rat",
abstract = "Chronic haloperidol treatment in the laboratory rat induces spontaneous orofacial movements in some but not all of the animals, a behavior which has been described in the literature as vacuous chewing movements (VCMs). In an attempt to understand the neurochemical mechanism of these rat dyskinesias, we measured regional dopamine D1, D2, and GABAA binding density in rats with and without VCMs after chronic haloperidol treatment and in untreated controls using in vitro receptor autoradiography and correlated the binding changes with the dyskinetic behavior. Chronic haloperidol treatment produced an overall increase in dopamine D2 family receptor binding in the caudate putamen and in nucleus accumbens in both groups of treated rats, those with and without VCMs. In the haloperidol-treated rats with VCMs, a significant increase in GABAA receptor density occurred in the substantia nigra pars reticulata (SNR), with a trend in those rats without VCMs. However, only in those haloperidol-treated animals with VCMs did a significant decrease in dopamine D1 receptor density occur in SNR. These receptor alterations are consistent with a process of haloperidol-induced neuronal death of striatonigral fibers. However, we have failed to identify cellular evidence of such toxicity. Alternatively, the receptor changes may reflect increased dendritic dopamine release in SNR, or, more speculatively a functional response to chronically diminished striatonigral pathway activity. Perhaps the release of dopamine from dendrites of the local DA-containing neurons might be variably enhanced with ongoing haloperidol treatment. Increased nigral dopamine would itself cause the release of GABA, presynaptically, onto nigral efferent neurons. This would overinhibit nigral GABA-containing efferent neuronal pathways, disinhibiting motor areas in the thalamus, and result in dyskinesias. In support of the latter interpretation is the finding of a correlation in the mediodorsal thalamus between VCMs and GABAA binding. These findings may have implications for the pathophysiology of neuroleptic-induced dyskinesias in humans.",
author = "Osamu Shirakawa and Tamminga, {Carol A.}",
year = "1994",
month = "5",
doi = "10.1006/exnr.1994.1080",
language = "English (US)",
volume = "127",
pages = "62--69",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Basal Ganglia GABAA and Dopamine D1 Binding Site Correlates of Haloperidol-Induced Oral Dyskinesias in Rat

AU - Shirakawa, Osamu

AU - Tamminga, Carol A.

PY - 1994/5

Y1 - 1994/5

N2 - Chronic haloperidol treatment in the laboratory rat induces spontaneous orofacial movements in some but not all of the animals, a behavior which has been described in the literature as vacuous chewing movements (VCMs). In an attempt to understand the neurochemical mechanism of these rat dyskinesias, we measured regional dopamine D1, D2, and GABAA binding density in rats with and without VCMs after chronic haloperidol treatment and in untreated controls using in vitro receptor autoradiography and correlated the binding changes with the dyskinetic behavior. Chronic haloperidol treatment produced an overall increase in dopamine D2 family receptor binding in the caudate putamen and in nucleus accumbens in both groups of treated rats, those with and without VCMs. In the haloperidol-treated rats with VCMs, a significant increase in GABAA receptor density occurred in the substantia nigra pars reticulata (SNR), with a trend in those rats without VCMs. However, only in those haloperidol-treated animals with VCMs did a significant decrease in dopamine D1 receptor density occur in SNR. These receptor alterations are consistent with a process of haloperidol-induced neuronal death of striatonigral fibers. However, we have failed to identify cellular evidence of such toxicity. Alternatively, the receptor changes may reflect increased dendritic dopamine release in SNR, or, more speculatively a functional response to chronically diminished striatonigral pathway activity. Perhaps the release of dopamine from dendrites of the local DA-containing neurons might be variably enhanced with ongoing haloperidol treatment. Increased nigral dopamine would itself cause the release of GABA, presynaptically, onto nigral efferent neurons. This would overinhibit nigral GABA-containing efferent neuronal pathways, disinhibiting motor areas in the thalamus, and result in dyskinesias. In support of the latter interpretation is the finding of a correlation in the mediodorsal thalamus between VCMs and GABAA binding. These findings may have implications for the pathophysiology of neuroleptic-induced dyskinesias in humans.

AB - Chronic haloperidol treatment in the laboratory rat induces spontaneous orofacial movements in some but not all of the animals, a behavior which has been described in the literature as vacuous chewing movements (VCMs). In an attempt to understand the neurochemical mechanism of these rat dyskinesias, we measured regional dopamine D1, D2, and GABAA binding density in rats with and without VCMs after chronic haloperidol treatment and in untreated controls using in vitro receptor autoradiography and correlated the binding changes with the dyskinetic behavior. Chronic haloperidol treatment produced an overall increase in dopamine D2 family receptor binding in the caudate putamen and in nucleus accumbens in both groups of treated rats, those with and without VCMs. In the haloperidol-treated rats with VCMs, a significant increase in GABAA receptor density occurred in the substantia nigra pars reticulata (SNR), with a trend in those rats without VCMs. However, only in those haloperidol-treated animals with VCMs did a significant decrease in dopamine D1 receptor density occur in SNR. These receptor alterations are consistent with a process of haloperidol-induced neuronal death of striatonigral fibers. However, we have failed to identify cellular evidence of such toxicity. Alternatively, the receptor changes may reflect increased dendritic dopamine release in SNR, or, more speculatively a functional response to chronically diminished striatonigral pathway activity. Perhaps the release of dopamine from dendrites of the local DA-containing neurons might be variably enhanced with ongoing haloperidol treatment. Increased nigral dopamine would itself cause the release of GABA, presynaptically, onto nigral efferent neurons. This would overinhibit nigral GABA-containing efferent neuronal pathways, disinhibiting motor areas in the thalamus, and result in dyskinesias. In support of the latter interpretation is the finding of a correlation in the mediodorsal thalamus between VCMs and GABAA binding. These findings may have implications for the pathophysiology of neuroleptic-induced dyskinesias in humans.

UR - http://www.scopus.com/inward/record.url?scp=0028176517&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028176517&partnerID=8YFLogxK

U2 - 10.1006/exnr.1994.1080

DO - 10.1006/exnr.1994.1080

M3 - Article

C2 - 8200438

AN - SCOPUS:0028176517

VL - 127

SP - 62

EP - 69

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

IS - 1

ER -