The rotational model and microdialysis: Significance for dopamine signalling, clinical studies, and beyond.
The detailed anatomy of the monoamine pathways of the rat by the students of Nils-Ake Hillarp provided the basis for a neurocircuitry targeting pharmacology. Further progress was achieved by the introduction of 6-hydroxydopamine as a tool for performing specific lesions, leading to the first stereotaxic mapping of the monoamine pathways in the rat brain by Urban Ungerstedt at the Karolinska Institutet, Stockholm, Sweden. Unilateral intracerebral injections with 6-hydroxydopamine led to the proposal of 'Rotational Behaviour', as a classical model for screening drugs useful for alleviating Parkinson's disease and other neuropathologies. The direction of the rotational behaviour induced by drugs administrated to lesioned rats reveals their mechanisms of action on dopamine synapses, as demonstrated when rotational behaviour was combined with microdialysis. The model was useful for proposing a role of dopamine receptors in the gating of the flow of information through different efferent pathways of the basal ganglia. It is established now that the coupling of dopamine receptors is regulated by a number of proteins acting as GTPases, the regulators of G-protein signalling (RGS) family. More than 20 RGS proteins have been identified, organised into subfamilies based on structural features and specificity for different G-protein subunits. These protein subfamilies represent alternative pathways gating the flow of information generated in the basal ganglia. Microdialysis has been developed as a general tool for studying tissue and organ chemistry, leading to a truly translational venture as microdialysis is brought into clinical use, monitoring energy metabolism following global or focal ischemia in the neurosurgery and general medicine scenario.
Herrera-Marschitz
Mario
M
Programme of Molecular & Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, Santiago 7, Casilla 70.000, Chile. mh-marschitz@med.uchile.cl
Arbuthnott
Gordon
G
Ungerstedt
Urban
U
D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049673:History, 20th Century; D006801:Humans; D007150:Immunohistochemistry / Q000266:history / Q000379:methods; D017551:Microdialysis / Q000379:methods*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009448:Neurochemistry / Q000379:methods; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism; D045442:Rotarod Performance Test; D015398:Signal Transduction / Q000502:physiology*
D015259:Dopamine Agents; D011954:Receptors, Dopamine; D016627:Oxidopamine; D004298:Dopamine