Persistent Spontaneous Oral Dyskinesias in Haloperidol- Withdrawn Rats Neonatally Lesioned with 6-Hydroxydopamine:

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 mg 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 Bmax for DA D2 binding sites was elevated about 70%. With reverse transcription polymerase chain reaction, the mRNA level for DA D2L but not D2S 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 Bmax 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. Tardive dyskinesia, an extrapyramidal syndrome caused by neuroleptics in the treatment of psychiatric disorders, is a disorder for which there is no satisfactory treatment. The prevalence of TD has increased steadily by about 1% per year during the past two decades (Casey, 1987; Jeste and Caligiuri, 1993). Spontaneous oral dyskinesias constitute the most common symptom of TD. In numerous studies delving into the mechanisms underlying the neural regulation of oral activity, it has been determined that abnormal oral movements in rodents are induced by agonist (SKF 38393 or A 77636) stimulation of DA D1 receptors or by antagonist inhibition of DA D2 receptors (Rosengarten et al., 1983; Huang and Kostrzewa, 1994a). An imbalance in the functional ratio of DA D1/D2 receptors is considered to be an important element related to oral activity behavior (Rosengarten et al.,