Vol. 280, Issue 1, 268-276, 1997

Persistent Spontaneous Oral Dyskinesias in Haloperidol-Withdrawn Rats Neonatally Lesioned with 6-Hydroxydopamine: Absence of an Association with the B_max for [³H]Raclopride Binding to Neostriatal Homogenates¹

Nuo-Yu Huang² , Richard M. Kostrzewa, Chuanfu Li, Kenneth W. Perry and Ray W. Fuller

Department of Pharmacology (N.-Y.H., R.M.K.) and Internal Medicine (C.L.), Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, and Lilly Research Laboratories, Eli Lilly and Company (K.W.P., R.W.F.), Lilly Corporate Center, Indianapolis, Indiana

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 the B_max for DA D₂ binding sites was elevated about 70%. With reverse transcription polymerase chain reaction, the mRNA level for DA D_2L but not D_2S receptors 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.