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On the mechanisms and physiological function of somatodendritic dopamine release in substantia nigra

Doctoral thesis
Authors Filip Bergquist
Date of public defense 2002-11-29
ISBN 91-628-5454-2
Place of publication Göteborg
Publication year 2002
Published at Institute of Physiology and Pharmacology, Dept of Pharmacology
Language en
Keywords Calcium channels, dopamine release, microdialysis, rotarod, SNARE, striatum, substantia nigra
Subject categories Pharmacology and Toxicology

Abstract

Somatodendritic release of neurotransmitters is a neuronal function that is poorly understood in comparison with the more abundant terminal release. This study aimed at characterising somatodendritic dopamine release in substantia nigra in terms of release mechanisms and possible physiological function in motor control.In vivo microdialysis in conscious rats was used to identify the calcium channels involved in somatodendritic and terminal dopamine release in substantia nigra and striatum, respectively. Microdialysis probes were modified to allow local application of high molecular weight compounds like clostridial toxins, which were used to characterise the SNAP-receptor dependency of somatodendritic and terminal dopamine release. Finally, a novel method with combined dual probe microdialysis and simultaneous motor performance testing on an accelerating rod was developed to investigate the physiological role of somatodendritic dopamine release in motor control.The results indicate that a major portion of somatodendritic dopamine release is calcium dependent. Local treatment with selective and non-selective calcium channel blockers confirmed that N-, and P/Q-type voltage sensitive calcium channels (VSCC) mediate most of the calcium dependency of terminal dopamine release, but revealed that somatodendritic dopamine release is only inhibited by unselective VSCC blockers, or the Cav2.3 (R-type VSCC) blocker SNX-482. Local treatments with clostridial toxins showed that striatal and nigral dopamine release were equally sensitive to SNAP-25 destruction. The VAMP-cleaving botulinum toxin B inhibited striatal, but not nigral, dopamine release. A role for somatodendritic dopamine release in the physiological regulation of motor control was supported by: 1) increases in nigral dopamine release related to physical activity; 2) a modulation of motor performance induced by nigral application of D1-like, or D2-like receptor antagonists; and 3) a partial restoration of motor performance in 6-hydroxydopamine lesioned rats during nigral treatment with the dopamine agonist apomorphine.It is suggested that somatodendritic and terminal dopamine release are mediated by different release mechanisms, in particular different VSCC-types and different vesicle associated membrane protein (VAMP) isoforms. The study also presents evidence for a physiological role of somatodendritic dopamine release in substantia nigra in normal motor control. Nigral dopamine release should therefore be considered in future treatment strategies for Parkinson's disease.

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