Differentiation of dopamine agonists using drug-induced rotation in rats with unilateral or bilateral 6-hydroxydopamine destruction of ascending dopamine pathways

Abstract

Eighteen compounds with dopamine agonist properties were examined in two rat rotational models. In the classical Ungerstedt model, a unilateral 6-hydroxydopamine (60HDA) lesion destroyed nigrostriatal and mesolimbic dopamine pathways on one side. Indirectly acting compounds, amphetamine, amantadine, methylphenidate and S1694, produced ipsiversive rotation, which was inhibited by pretreatment with alpha-methyl-p-tyrosine (AMPT). All other compounds produced contraversive rotation, but the rotation caused by CM 29-712, bromocriptine and ET 495 was reduced by AMPT. In animals with a bilateral 60HDA lesion removing both dopaminergic inputs to nucleus accumbens and the dopaminergic input into one striatum, indirectly acting drugs caused ipsiversive posturing prevented by AMPT, but little rotation. All other compounds produced contraversive rotation, but the effects of CM 29-712, bromocriptine and ET 495 were reduced by AMPT pretreatment. Inhibition of monooxygenase drug metabolising activity utilising SKF-525A inhibited contraversive turning induced by bromocriptine and ET 495 in the unilateral lesion model, but had no effect on rotation caused by apomorphine or CM 29-712. We conclude that, in addition to indirect pre-synaptically acting agonists and direct post-synaptic receptor agonists, there are a small group of compounds which produce rotation associated with direct receptor activation, which is inhibited by disruption of pre-synaptic dopamine function. The mechanism of action of this latter group is not understood, but cannot be attributed solely to active metabolite formation.