Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat

In an attempt to de®ne clinically relevant models of akinesia and dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, we have examined the effects of drugs with high (L-DOPA) vs. low (bromocriptine) dyskinesiogenic potential in Parkinson's disease on three types of motor performance, namely: (i) abnormal involuntary movements (AIMs) (ii) rotational behaviour, and (iii) spontaneous forelimb use (cylinder test). Rats with unilateral 6-OHDA lesions received single daily i.p. injections of L-DOPA or bromocriptine at therapeutic doses. During 3 weeks of treatment, L-DOPA but not bromocriptine induced increasingly severe AIMs affecting the limb, trunk and orofacial region. Rotational behaviour was induced to a much higher extent by bromocriptine than L-DOPA. In the cylinder test, the two drugs initially improved the performance of the parkinsonian limb to a similar extent. However, L-DOPA-treated animals showed declining levels of performance in this test because the drug-induced AIMs interfered with physiological limb use, and gradually replaced all normal motor activities. L-DOPA-induced axial, limb and orolingual AIM scores were signi®cantly reduced by the acute administration of compounds that have antidyskinetic ef®cacy in parkinsonian patients and/or nonhuman primates (±91%, yohimbine 10 mg/kg; ±19%, naloxone 4±8 mg/kg; ±37%, 5-methoxy 5-N,N-dimethyltryptamine 2 mg/kg; ±30%, clozapine 8 mg/kg; ±50%, amantadine 40 mg/kg). L-DOPA-induced rotation was, however, not affected. The present results demonstrate that 6-OHDA-lesioned rats do exhibit motor de®cits that share essential functional similarities with parkinsonian akinesia or dyskinesia. Such de®cits can be quanti®ed using novel and relatively simple testing procedures, whereas rotometry cannot discriminate between dyskinetic and antiakinetic effects of antiparkinsonian treatments.