Pharmacologic characterization of dogmatil. Pre- and postsynaptic effects on dopaminergic receptors
Ungerstedt U., Herrera-Marschitz M., Sharp T.
The pharmacology of dogmatil was studied by several models of dopamine neurotransmission in the rat brain. Using an automatic holeboard dogmatil was found to specifically counteract apomorphine-induced locomotion indicating a relative specificity on dopamine receptors in limbic areas. In the 6-hydroxy-dopamine rotational model dogmatil inhibited pergolide-induced rotation in doses 1000 times lower than those needed to inhibit apomorphine rotation. This was explained by the high specificity of dogmatil in blocking D2 receptors. Using microdialysis it was shown that such D2 effects seem to be linked to an inhibition of GABA release in the striatum. In low doses apomorphine stimulates the dopamine autoreceptors preferentially causing a decrease in spontaneous exploratory behaviour as measured in the automatic holeboard. Dogmatil was found to be unique in its ability to counteract this inhibition of exploration. The findings indicate that dogmatil inhibits dopamine autoreceptors in lower doses than those effective on postsynaptic dopamine receptors. Microdialysis experiments confirmed these findings by showing that the decrease of dopamine release was counteracted by dogmatil. The specific action of dogmatil on dopamine autoreceptor was thought to explain the dose dependent increase in dopamine release caused by dogmatil in the microdialysis experiments. This increase in dopamine release will activate the postsynaptic dopamine receptors, as dogmatil does not block these receptors in the doses used. This may form the basis for the observed antidepressive, antiautistic and activating effects of dogmatil observed after low doses in the clinic. Finally, a plea is made for clinical studies on dogmatil making possible direct comparisons between the clinical profile and the preclinical pharmacology of the drug.