Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

May 1995

Abstract

Due to the presumed associations of dopamine (DA) receptor supersensitivity phenomena in both long-term neuroleptic-treated tardive dyskinetic rats and neonatal 6-hydroxydopamine (n6-OHDA)-lesioned rats, we studied the influence of haloperidol on n6-OHDA-lesioned rats. At 3 days after birth rats received 6-OHDA-HBr (200 $\mu$g, bilateral intracerebroventricularly; desipramine pretreatment, 20 mg/kg, 1h) or vehicle. Two months later haloperidol (1.5/kg/day $\times$ 2 days/week for 4 weeks, then 1.5 mg/kg/day, every day for 10 months) was added to the drinking water. Spontaneous oral activity of intact and n6-OHDA-lesioned rats receiving haloperidol was reached and maintained at significantly higher levels after 15 weeks of haloperidol treatment. Haloperidol treatment produced greater oral activity in n6-OHDA-lesioned rats as compared to intact rats. At 11 months there were 35.8 $\pm$ 4.9 vs. 18.4 $\pm$ 2.1 oral movements in lesioned vs. intact rats receiving haloperidol. This high level of spontaneous oral activity was not attenuated by scopolamine and persisted in the lesioned rats for at least 8 months after haloperidol withdrawal. Reverse transcription polymerase chain reaction (RT-PCR) analysis of alternatively-spliced isoforms of DA D$\sb2$ (D$\sb{\rm 2S}$ and D$\sb{\rm 2L}$) receptors showed that D$\sb{\rm 2L}$ receptor mRNA levels of intact and n6-OHDA-lesioned rats receiving haloperidol were significantly elevated after 11 months of treatment and returned to normal level 8 months after haloperidol withdrawal. Similarly, the B$\sb{\rm max}$ for $\rm\lbrack\sp3 H\rbrack$raclopride binding to striatal homogenates was significantly increased in intact and nG-OHDA lesioned rats receiving chronic haloperidol. The B$\sb{\rm max}$ was at the control level after 8 months of haloperidol cessation. D$\sb{\rm 2L}$ and 5-HT$\sb{\rm 2C}$ receptor mRNA levels were not altered by chronic haloperidol treatment. The effects of assorted receptor-specific drugs on oral activity were tested in our rats to study possible mechanisms underlying the regulation of oral activity. The findings of this study demonstrate that alterations at mRNA and receptor levels of DA D$\sb2$ receptors are not critical for maintaining persisting enhanced oral dyskinesias after long-term haloperidol treatment. The long-lasting stable high frequency of oral dyskinesias after haloperidol withdrawal in these rats provides a means for testing agents that have the potential to attenuate dyskinetic oral activity.

Document Type

Dissertation - Open Access

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