| 1. |
- Bergquist, Filip, 1970, et al.
(författare)
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Evidence for different exocytosis pathways in dendritic and terminal dopamine release in vivo.
- 2002
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Ingår i: Brain research. - 0006-8993. ; 950:1-2, s. 245-53
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Tidskriftsartikel (refereegranskat)abstract
- Although dendritic release was first proposed in the 1970s, the mechanism of release is still subject to debate. We have used in vivo microdialysis to study the acute effects of botulinum toxin A, B and tetanus toxin injected in the substantia nigra or striatum of freely moving rats. Spontaneous and evoked dopamine release decreased in both regions after treatment with the SNAP-25 (synaptosome-associated protein of 25 kDa) cleaving protease botulinum toxin A (1000 mouse lethal doses, MLD). Tetanus toxin (4000 MLD) did not significantly change spontaneous or evoked dopamine release in striatum or in the substantia nigra. Another synaptobrevin cleaving protease, botulinum toxin B, inhibited release in the striatum by 55% but did not affect dopamine release when injected in the substantia nigra. The results indicate that both terminal and somatodendritic dopamine release need intact SNAP-25 to occur, but somatodendritic dopamine release in contrast to terminal release depends on a botulinum toxin B resistant pathway.
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| 2. |
- Bergquist, Filip, 1970, et al.
(författare)
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Influence of R-type (Cav2.3) and t-type (Cav3.1-3.3) antagonists on nigral somatodendritic dopamine release measured by microdialysis.
- 2003
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Ingår i: Neuroscience. - 0306-4522. ; 120:3, s. 757-64
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Tidskriftsartikel (refereegranskat)abstract
- The release of dopamine from soma and dendrites of dopaminergic neurons in substantia nigra has been reported to be calcium-dependent, but it remains to be determined which calcium channels mediate this effect. We have used in vivo microdialysis in rat substantia nigra and striatum to investigate the effect of Ca(v)3.1-3.3 (T-type) and Ca(v)2.3 (R-type) calcium channel antagonists on somatodendritic and terminal dopamine release. Local reverse dialysis administration of 0.1-10 microM of the Ca(v)2.3 inhibitor SNX-482, or 100 microM of mibefradil, decreased the concentrations of dopamine and its metabolites in dialysate from substantia nigra, whereas 1 microM mibefradil or 40-80 microM nickel(II) induced an increase in nigral dialysate dopamine concentrations. Dopamine concentrations in striatal dialysates were decreased only by 10 microM of SNX-482 or 100 microM of mibefradil. Nickel(II) induced an increase in striatal dialysate dopamine concentration similar to that in substantia nigra. The results indicate a role for Ca(v)2.3 (R-type) voltage sensitive calcium channels in the calcium dependency of somatodendritic dopamine release, but argue against a calcium dependency mediated substantially by Ca(v)3.1-3.3 (T-type) channels.
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| 3. |
- Bergquist, Filip, 1970
(författare)
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On the mechanisms and physiological function of somatodendritic dopamine release in substantia nigra
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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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| 4. |
- Bergquist, Filip, 1970, et al.
(författare)
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Somatodendritic dopamine release in rat substantia nigra influences motor performance on the accelerating rod.
- 2003
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Ingår i: Brain research. - 0006-8993. ; 973:1, s. 81-91
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Tidskriftsartikel (refereegranskat)abstract
- The physiological role of somatodendritic dopamine release in the rat substantia nigra was evaluated with a combination of dual probe microdialysis and simultaneous motor performance tests on an accelerating rod. Three main findings support a modulating influence of somatodendritic dopamine release on motor coordination. (1) The rod performance tests were associated with an increase in extracellular dopamine but not 5-hydroxytryptamine concentrations in substantia nigra and with increases in both dopamine and 5-hydroxytryptamine concentrations in the striatum. (2) Nigral application of dopamine antagonists without intrinsic activity resulted in changed performances on the accelerating rod. The response to nigral perfusion with low concentrations (0.1, 1.0 microM) of the D(2)/D(3)-antagonist raclopride consisted of an impairment in rod performance to 63% of the pre-perfusion performance. Higher concentrations (10, 100 microM), however, were not associated with impaired rod performance, but with increased striatal dopamine concentrations. Perfusion of the substantia nigra with 1, 10 and 100 microM of the D(1)/D(5)-antagonist SCH 23390 dose-dependently impaired rod performance. SCH 23390 consistently increased dopamine and 5-hydroxytryptamine concentrations in substantia nigra but did not change the dialysate in the striatum. (3) In unilaterally 6-hydroxydopamine-lesioned rats, a dose-dependent improvement in rod performance was observed during perfusion of the substantia nigra with the non-selective dopamine agonist apomorphine.
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| 5. |
- Niazi Shahabi, Haydeh, 1966, et al.
(författare)
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An investigation of dopaminergic metabolites in the striatum and in the substantia nigra in vivo utilising radiolabelled L-DOPA and high performance liquid chromatography: a new approach in the search for transmitter metabolites.
- 2003
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Ingår i: Neuroscience. - 0306-4522. ; 120:2, s. 425-33
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Tidskriftsartikel (refereegranskat)abstract
- Although the major routes of dopamine metabolism seem to be established, at least in terminal regions such as the striatum, it is important to search for previously unknown metabolites and to investigate the relevance of previously suggested minor alternative pathways. An urgent issue is to verify and quantify the transformation of dopamine to putative toxic species, another is to further explore metabolism of dopamine located in cell bodies/dendrites, e.g. in the substantia nigra. We have developed a new method in order to widen the search for alternative metabolites of dopamine. The method is based on systemic injection of tritiated L-DOPA to rats in vivo. Brain tissue was homogenised and centrifuged and the resulting supernatant fractioned following passage through a liquid chromatography system. The radioactivity of each fraction was measured using a scintillation system. By identifying fractions containing major catecholamines and metabolites, according to a standard solution, novel metabolites can be searched for in the remaining fractions. It was possible to obtain sufficient radioactivity in separate fractions of supernatant of homogenised tissue, even from such a small brain nucleus as substantia nigra. Radioactivity was obtained in those fractions that contained the major catecholamines and their metabolites, as well as in other fractions where it may represent previously unknown metabolites of L-DOPA/dopamine. The method was used to evaluate the possibility that cytochrome P450 2E1 is involved in the metabolism of dopamine in the substantia nigra. Significant changes in the radioactivity pattern were induced by inhibition of the enzyme but conclusions about whether cytochrome P450 2E1 is involved in the metabolism of dopamine or not requires further studies. The method can be used to study the metabolism of dopamine and can be extended, by using other radiolabelled precursors, also to evaluate metabolism of other transmitters, e.g. serotonin.
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