The effects of cyclo(leucyl-glycyl) on nigrostriatal dopaminergic supersensitivity--inhibition of apomorphine-induced climbing.

In a previous study we showed that cyclo(leu-gly) (CLG) prevents the behavioural supersensitivity induced in the mesolimbic dopamine (DA) tract (in mice) by chronic haloperidol (HAL). In the current study, we evaluated the effects of CLG on supersensitivity to DA agonists in the nigrostriatal DA tract induced by chronic HAL (1.0 mg/kg, i.p. x 21 days--Experiment 1) or by acute injection of a high dose of apomorphine (APO) (Experiment 2). In Experiment 1 CLG was given at doses of either (a) 0 mg/kg/day (b) 1 mg/kg every third day (30 minutes prior to HAL), (c) 1 mg/kg every day, or (d) 8 mg/kg every third day. In Experiment 2 the dose of CLG was 8 mg/kg, s.c., given 24h after APO. Co-administration of CLG with HAL attenuated the development of HAL-induced supersensitivity in both paradigms (b) and (c) above, although the attenuation was significantly greater in (c) compared to (b). This biphasic dose response (D-R) curve for CLG in Experiment 1 indicates that a therapeutic window exists for CLG (bell-shaped D-R curve) and is similar to previous curves for CLG effects on the mesolimbic DA tract. In Experiment 2, CLG attenuated the DA receptor supersensitivity caused by acute high dose APO. The capacity of CLG to down-regulate DA receptors and attenuate dopaminergic supersensitivity in these experiments suggests a potential therapeutic use in the prevention of tardive and/or L-dopa-induced dyskinesias.