Abstract
To investigate the influence of dopamine (DA) nerves on haloperidol (HAL)-induced oral dyskinesias, rats were first injected at 3 days after birth with 6-hydroxydopamine HBr (200 μg i.c.v., salt form; 6-OHDA) or vehicle, after desipramine HCl (20 mg/kg i.p., 1 hr) pretreatment. Two months later HAL (1.5 mg/kg/day, 2 days a week for 4 weeks, then daily for 10 months) was added to the drinking water of half the rats. Numbers of vacuous chewing movements, recorded in 1-min increments every 10 min for 1 hr, increased from <5 to about 17 oral movements per session in intact rats, 14 weeks after instituting HAL (P < .01 vs. intact rats drinking tap water). In HAL-treated 6-OHDA-lesioned rats, oral activity increased to >30 oral movements per session (P < .01 vs. HAL-treated intact rats). These levels of oral activity persisted in intact and 6-OHDA-lesioned rats as long as HAL was administered. After 11 months of HAL treatment, but 8 or 9 days after HAL withdrawal, DA was found to be reduced 97%, whereas serotonin was increased 29% in the striatum of 6-OHDA-lesioned rats. In HAL-treated intact and lesioned rats theB max for DA D2 binding sites was elevated about 70%. With reverse transcription polymerase chain reaction, the mRNA level for DA D2L but not D2Sreceptors was also found to be elevated about 70%. In a fraction of 6-OHDA-lesioned rats that were observed for 8 months after HAL withdrawal, oral activity persisted without decrement and was not accompanied by a change in the B max or mRNA level for DA D2 receptors. These findings demonstrate that in rats largely DA-denervated as neonates, long-term HAL treatment produces an unusually high number of oral movements that persists for 8 months after HAL withdrawal and is not accompanied by an increase in DA D2 receptor expression.
Footnotes
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Send reprint requests to: Dr. Richard M. Kostrzewa, Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614-0577.
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↵1 This work was supported by Grant NS 29505 from the National Institute of Neurological Disorders and Stroke.
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↵2 Current address: National Institutes of Health, Bldg. 8, Rm. 111, Bethesda, MD 20892.
- Abbreviations:
- DA
- dopamine
- 6-OHDA
- 6-hydroxydopamine
- 5-HT
- serotonin
- SKF 38393
- (±)1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol
- SCH 23390
- R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
- DOPAC
- 3,4-dihydroxyphenylacetic acid
- 5-HIAA
- 5-hydroxyindoleacetic acid
- TD
- tardive dyskinesia
- HVA
- homovanillic acid
- NE
- norepinephrine
- bp
- basepair
- RT-PCR
- reverse transcription and polymerase chain reaction
- GABA
- γ-aminobutyric acid
- i.c.v.
- intracerebroventricular
- HAL
- haloperidol
- Received December 20, 1995.
- Accepted August 2, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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