Differential locomotor interactions between dopamine D1/D2 receptor agonists and the NMDA antagonist dizocilpine in monoamine-depleted mice.

Abstract

Previous work in our laboratory has shown that the non-competitive N-methyl-D-aspartate antagonist dizocilipine (MK-801) interacts synergistically with the mixed dopamine (DA) receptor agonist apomorphine and the DA D 1 agonist SKF 38393 to promote locomotion in monoamine-depleted mice. The purpose of the present study was to compare the roles of DA D 1 and DA D 2 receptors in this interaction. To that end, dizocilpine was given in combination with either the DA D 1 receptor agonist SKF 38393 or the selective DA D 2 receptor agonist quinpirole or the preferential DA D 2 agonist bromocriptine. In general, the locomotor stimulatory effects produced by SKF 38393 were potentiated by dizocilpine, whereas the locomotor stimulation produced by quinpirole and bromocriptine was counteracted. However, baseline activity, which partly depends on how much time is allowed to elapse between administration of the DA agonist and commencement of locomotor recording, and partly on the dose of the DA agonist, seems to be an important factor that determines whether dizocilpine will have a weakening or a potentiating effect. Interestingly, the competitive NMDA antagonist D-CPPene displayed a different pattern of interaction with SKF 38393 and quinpirole in that synergistic effects were observed with both DA agonists, most conspicuously so with the DA D 2 receptor agonist. The results are interpreted in the light of present knowledge of basal ganglia neuroanatomy; they are discussed in relation to the "direct" and "indirect" pathways from the striatum to the thalamus, proposed to form part of positive and negative cortico-striato-thalamo-cortical loops, respectively, as well as to the presumed presynaptic D 2 receptors on corticostriatal glutamatergic neurons.