Fluoxetine improves the effect of levodopa on 6-hydroxy dopamine-induced motor impairments in rats

Long term L-DOPA therapy in Parkinson's disease is associated with troublesome motor fluctuations such as L -DOPA Induced dyskinesia and wearing off effect. Our recent study showed that activation of 5-HT1A receptors could improve the anti-cataleptic effect of L-DOPA in parkinsonian rats. In this study we investigated the effect of fluoxetine on anti-parkinsonian effect of L-DOPA in 6-hydroxydopamine (6-OHDA)-lesioned rats.

Catalepsy and motor incoordination were induced by unilateral injection of 6-OHDA (8μg/2μl/rat) into the central region of the sabstantia nigra pars compacta (SNc). After 3 weeks as a recovery period, these rats injected intraperitoneally (i.p.) L-DOPA (15 mg/kg) twice daily for 20 consecutive days, and anti-parkinsonian effect of L-DOPA was investigated by bar-test and rotarod on days 5, 10, 15 and 20.

The results showed that L-DOPA is able to improve motor coordination in rotarod only until day 15 and these effects of L-DOPA were abolished on the day 20. On day 21, rats were co-injected with fluoxetine (0.1, 0.5 and 1mg/kg, i.p.) and L-DOPA (15 mg/kg, i.p.). Fluoxetine increased anti-cataleptic effect of L-DOPA at the dose of 1 mg/kg, while fluoxetine had not any impact on the effect of L-DOPA in rotarod test. The effect of fluoxetine (1 mg/kg, i.p.) on anti-cataleptic effect of L-DOPA (15 mg/kg, i.p.) was reversed by 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl) piperazine hydrobromide (NAN-190; 0.5 mg/kg, i.p.), as a 5-HT1A receptor antagonist.

According to the results, it may be concluded that fluoxetine improves 6-OHDA-induced catalepsy and motor imbalance in L-DOPA- treated rats through activation of 5-HT1A. Further studies should be designed to clarify the precise mechanism of interaction between 5-HT1A and dopaminergic neurons.