Elsevier

Brain Research

Volume 973, Issue 1, 23 May 2003, Pages 81-91
Brain Research

Research report
Somatodendritic dopamine release in rat substantia nigra influences motor performance on the accelerating rod

https://doi.org/10.1016/S0006-8993(03)02555-1Get rights and content

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 μM) of the D2/D3-antagonist raclopride consisted of an impairment in rod performance to 63% of the pre-perfusion performance. Higher concentrations (10, 100 μM), however, were not associated with impaired rod performance, but with increased striatal dopamine concentrations. Perfusion of the substantia nigra with 1, 10 and 100 μM of the D1/D5-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.

Introduction

The motor symptoms of Parkinson’s disease are caused by the degeneration of the nigrostriatal dopaminergic pathway. It is generally accepted that the rigidity, tremor and bradykinesia are caused by the loss of dopaminergic neurotransmission in the striatum. In the past 25 years there has been growing evidence for dopamine release also from the dendrites of nigrostriatal dopamine neurons. According to current models of basal ganglia circuitry, the substantia nigra reticulata (SNr) is a fundamental component of the cortical–basal ganglia–thalamic–cortical loop and mediates the output from the basal ganglia to thalamus [4], [15], [35]. Consequently, somatodendritic dopamine release in SNr could have an important modulating influence on motor functions. This concept is indirectly supported by findings of dopaminergic influences on electrophysiology and on neurochemical transmission in SNr [2], [17], [31], [37], [50]. A possible nigral dopaminergic influence on abnormal behavior has also been suggested in dopamine-lesioned rats [36], [52] as well as in dopamine-lesioned rats or primates receiving dopaminergic transplants in SNr [12], [34], [51]. The latter findings have recently inspired a clinical study with dopaminergic transplants both in the striatum and the substantia nigra (SN) of Parkinson patients [32].

The question of how somatodendritic dopamine release in the intact SNr influences motor activity is less studied, and mostly by observing agonist-induced abnormal behavior [5], [22], [23], [24], [44], [46], [47], [53]. Because the methodology of such studies involves supra-physiological stimulation of dopamine systems they do not provide information on whether physiologically released dopamine in SNr has a role in overall motor functions. The findings that nigral application of dopamine-receptor antagonists lead to increased muscle tone [14] and decreased lever-pressing in rats [48] provide more support for a physiological role of nigral dopamine transmission in SNr, but integrated measures of a motor control function of somatodendritic dopamine release in SNr are still lacking, and a causal relationship largely remains to be shown.

To clarify this potentially important function of somatodendritic dopamine release in SNr, we have employed a novel combination of dual-probe microdialysis and simultaneous rotarod testing. A similar rotarod test has previously been thoroughly evaluated with unilateral and bilateral rodent models of Parkinson’s disease [38], [39] and shown to correlate well with the more commonly used drug-induced Ungerstedt rotation test as well as with histological evaluations of lesion extent. The rotarod test provides sustained drug-independent motor activity and is performed in a limited space, which facilitates simultaneous microdialysis measurements.

Section snippets

Animals

Female rats of Sprague–Dawley strain (B&K Universal AB, Sollentuna, Sweden) were used to minimize loss of rotarod performance due to weight gain [8], [38]. At the outset of the experiments the mean weight of the animals was 221±3 g and the weight gain was 16 g both in intact and lesioned animals over the experimental period. The animals were housed four in each cage under controlled environmental conditions (21 °C, 50–60% humidity, light 6 a.m.–6 p.m., dark 6 p.m.–6 a.m.). Training and

The influence of microdialysis on motor performance and the effect of Acc10 tests on dialysate outlet concentrations ([DA]d.o., [DOPAC]d.o., [HVA]d.o., [3-MT]d.o., [5-HT]d.o. and [5-HIAA]d.o.)

Implantation of microdialysis probes did not by itself affect rod performance since the result of the Acc10 test was 289±23 s before implantation and 310±22 s in the pre-perfusion test 2 days after implantation (P=0.3187, paired t-test, n=31). The control group was Acc10-tested before and during perfusion of the SN and striatum probes with modified Ringer solution on days 3, 4 and 5 (see Fig. 1). Time on rod in this group was 294±21 s in the pre-perfusion tests and 260±20 s during perfusion (P

Discussion

A role for somatodendritic dopamine release in motor coordination is supported by three findings in this study: the rod activity induced increase in dopamine concentration in SN; the impairment in rod performance seen during nigral treatment with the D2/D3 antagonist raclopride or the D1/D5 antagonist SCH 23390; and the rod performance improvement in hemiparkinsonian rats induced by acute nigral treatment with the D1/D2-receptor agonist apomorphine.

The rotating rod test integrates several

Acknowledgments

This study was supported by grants from the Swedish Medical Research Council (grant No. 12208) and the Göteborg Medical Society.

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