Ketanserin and mianserin treatment reverses hyperactivity in neonatally dopamine-lesioned rats

Selective brain dopamine (DA) depletions in rats, induced by neonatal intracisternal administration of 6-hydroxydopamine (6-OHDA; 75 μg), caused spontaneous hyperactivity at the adult stage as measured using determinations of locomotion, rearing and total activity. Treatment with ketanserin (0.5 or 1.0 mg/kg, s.c.) reversed the hyperactivity in 6-OHDA-treated animals during a 90-min period following injection, although only the low dose of ketanserin reduced rearings. In control animals ketanserin treatment did not affect the locomotion or total activity counts, while the high dose of ketanserin increased rearings. Following treatment with mianserin (0.5 or 1.0 mg/kg, s.c.), a similar effect was seen; however, it was longer-lasting and mianserin treatment increased activity in controls. Regional analysis of monoamine levels demonstrated a marked reduction of basal forebrain DA levels, while in striatum an increase in serotonin (5-HT) concentration was seen following the 6-OHDA treatment. The results indicate that drugs with a high affinity to 5-HT(2) binding sites can influence the hyperactivity seen in neonatally DA-lesioned rats. This effect might be related to inhibition of 5-HT pathways directly involved in regulation of motor activity or due to alterations in the interaction between the DA and 5-HT systems as a consequence of the early DA lesion.