Circling behaviour induced by dopamine releasers and/or uptake inhibitors during degeneration of the nigrostriatal pathway

Abstract

A number of compounds which induced ipsilateral circling behaviour in rats with chronic unilateral 6-hydroxy-dopamine (6-OHDA) destruction of the nigrostriatal dopamine (DA0 pathway through their postulated DA-releasing and/or uptake-inhibiting properties, have been tested 24 h after a 6-OHDA lesion. Under these conditions, in contrast to chronically lesioned animals, d- or l-amphetamine, mazindol, HR 370, nomifensine and benztropine still induced ipsilateral turns. The monoamine oxidase inhibitor pargyline was inactive and the DA receptor agonist apomorphine induced a mild contralateral circling response at high doses only. The contralateral circling response to d-amphetamine was hardly antagonized by a high dose of α-methyl-p-tyrosine (AMT), and was increased by reserpine. Striatal DA levels were increased in the lesioned side and restored to normal values after d-amphetamine, in contrast to methylphenidate. Ipsilateral turns recorded with chronically lesioned rats were strongly decrease by AMT except in the case of p-chloroamphetamine, methylphenidate and pipradrol. The response of reserpinized rats was decreased except with d-amphetamine and its N-methyl derivative. It was concluded that drugs inducing contralateral turns during degeneration of the nigrostriatal DA pathway predominantly release newly-synthetized DA independently of nerve impulse flow whilst ipsilateral turns are either triggered by inhibiting of DA uptake or by the release of the reserpine-sensitive pool of DA, both on the intact side. This last effect may require a normal nerve impulse flow. This method thus provides the first direct behavioural evidence of differences in the mode of action of drugs interfering presynaptically with DA.