Effects of D-2 agonists on the release of dopamine: localization of the mechanism of action.
Brain microdialysis was used to localize the mechanism of action of the effect induced by the D-2 agonists (-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin [(-)-N-0437] and (+)-4-propyl-9-hydroxynaphtoxazine [(+)-PHNO], on the release of DA in the striatum. Both agonists induced a stronger decrease in the release of DA when administered systemically in comparison to local administration. This suggests that the action of D-2 agonists is not exclusively mediated by autoreceptors regulating the release of DA at the level of the nerve terminals. By co-infusing nomifensine (10 microM) the effect of intrastriatally administered D-2 agonists on the release of DA could be completely abolished. As both agonists were effective when administered systemically in normal rats and in rats with kainic acid lesions performed in the striatum during nomifensine infusion, the effects induced by D-2 agonists seem to be partly mediated by autoreceptors situated on cell bodies, regulating the impulse flow of the neuron. In addition, D-2 receptors located on postsynaptic structures participating in the striatonigral feedback loops were suggested to be involved. (-)-N-0437 and (+)-PHNO were less effective after systemic administration when kainic acid lesioned rats were used in comparison with normal rats. Thus, D-2 agonists interact in a complex way with D-2 receptors for displaying their effect on the release of DA: autoreceptors situated on nerve terminals and on cell bodies as well as D-2 receptors located on postsynaptic structures participating in the striatonigral neuronal loops may all be involved to a certain extent in the mechanism of action of D-2 agonists.
Timmerman
W
W
Department of Medicinal Chemistry, University Centre of Pharmacy, Groningen, The Netherlands.
De Vries
J B
JB
Westerink
B H
BH
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D003956:Dialysis / Q000379:methods; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009627:Nomifensine / Q000494:pharmacology; D010078:Oxazines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*
D015259:Dopamine Agents; D010078:Oxazines; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D009627:Nomifensine; C042631:naxagolide; C047508:rotigotine; D007608:Kainic Acid; D004298:Dopamine