Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease

Abstract

In an attempt to define 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 significantly reduced by the acute administration of compounds that have antidyskinetic efficacy in parkinsonian patients and/or nonhuman primates (−91%, yohimbine 10 mg/kg; −19%, naloxone 4–8 mg/kg; −37%, 5‐methoxy 5‐N,N‐dimethyl‐tryptamine 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 deficits that share essential functional similarities with parkinsonian akinesia or dyskinesia. Such deficits can be quantified using novel and relatively simple testing procedures, whereas rotometry cannot discriminate between dyskinetic and antiakinetic effects of antiparkinsonian treatments.