Elsevier

Progress in Neurobiology

Volume 56, Issue 5, December 1998, Pages 507-540
Progress in Neurobiology

Involvement of basal ganglia transmitter systems in movement initiation

https://doi.org/10.1016/S0301-0082(98)00041-0Get rights and content

Abstract

The basal ganglia have been implicated in a number of important motor functions, in particular in the initiation of motor responses. According to the current model of basal ganglia functions, motor initiation is supposed to be associated with an inhibition of basal ganglia output structures (substantia nigra pars reticulata/entopeduncular nucleus) which, in turn, might be brought about by corresponding striatal activity changes conveyed via direct and indirect intrinsic pathways to the substantia nigra pars reticulata and the entopeduncular nucleus. Rodent studies using neuropharmacological manipulations of basal ganglia transmitter systems by neurotoxins or drugs provide converging evidence that dopamine within the caudate-putamen, but also within extrastriatal basal ganglia nuclei, is involved in motor initiation by modulating the activity of direct and indirect intrinsic pathways. However, the striatal segregation of dopamine D1 and D2 receptors in control of the direct and indirect projection neurons seems not to be maintained throughout the basal ganglia. In dopamine intact animals, striatal glutamate plays a major role in response initiation probably through actions on striatopallidal neurons involving N-methyl-d-aspartate, but not α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. Striatal adenosine might also contribute to movement initiation by acting on adenosine A2A receptors located on striatopallidal neurons. Analysis of two integral parts of the indirect pathway revealed that inactivation of the subthalamic nucleus was found to facilitate response initiation, while inactivation of the globus pallidus resulted in facilitation as well as inhibition of response initiation indicating a complex contribution of this latter nucleus. Glutamate and γ-amino-butyric acid (GABA) controlling the activity of the substantia nigra pars reticulata could be involved in control of response initiation in a way predicted by the simplified model of basal ganglia functions. In contrast, the role of the entopeduncular nucleus in response initiation and its control through GABA and glutamate is at variance with this hypothesis, suggesting functional differences of the output structures. Taken together, neurochemical systems of the basal ganglia significantly contribute to intact response initiation by mechanisms which are only partly consistent with predictions of the current functional scheme of the basal ganglia. This suggests that a more complex model is required to account for these disparate findings.

Introduction

The basal ganglia comprise several interconnected nuclei located in the telencephalon, diencephalon and midbrain which have been implicated in a wide range of behavioural functions including motor, cognitive, emotional and mnemonic functions. The prominent involvement of the basal ganglia in motor control has been recognized early in clinical and experimental investigations. From this large body of data it was inferred that the basal ganglia could contribute to the initiation and execution of movements (Denny-Brown and Yanagisawa, 1976; Evarts et al., 1981; Flowers, 1976; Hallett and Khoshbin, 1980; Wilson, 1925), sequencing of movements (Schwab et al., 1954), automatic execution of routine movements (Marsden and Obeso, 1994), inhibition of competing motor programs (Mink, 1996), motor learning (Kimura, 1995) and reward mechanisms (Schultz, 1994). Despite considerable progress, the role of the basal ganglia in motor control is still poorly defined in detail. Furthermore, the involvement of major neurochemical systems of the basal ganglia in motor control is hardly understood. The basal ganglia have the richest array of neurotransmitters and receptors of any region of the brain (McGeer and McGeer, 1993). Most of these transmitters are associated either with afferent connections or intrinsic basal ganglia pathways and interact in distinct basal ganglia nuclei in complex ways. The functional role and significance of these transmitter interactions with regard to different aspects of motor control is far from being understood.

The present review focuses on the contribution of major basal ganglia transmitter systems and their receptors to motor initiation which is presumed to be an important motor function of the basal ganglia (Denny-Brown and Yanagisawa, 1976; Graybiel, 1990; Kimura, 1995). It is not primarily intended to identify several processes that contribute to response initiation, for example, attention or motor readiness, but to characterize major transmitter systems in their contribution to response initiation in behavioural terms. This issue will be addressed mainly from the perspective of behavioural pharmacology on rodents. This field of research provides a relatively detailed analysis of transmitter interactions related to motor control thus allowing some new conclusions on and a reconsideration of current models of basal ganglia circuitry and their possible significance to motor initiation.

There are several processes which precede movement onset including perception of internal or external stimuli to move and selection, assembly and subsequent initiation of a motor plan (Fig. 1). A delayed initiation of movements represents a major impairment associated with basal ganglia dysfunctions and is termed as akinesia. It may be caused theoretically by a defective stimulus perception, movement selection or movement initiation, that is, initiation of a preprogrammed movement, or a combination of these impairments. Although it is sometimes difficult to separate these deficits clearly from another, respective impairments are termed here collectively as impairments of movement initiation, in order to separate processes and impairments related to motor initiation, that is, akinesia, from those related to motor execution. These latter impairments are termed as bradykinesia which refers to slowness of ongoing movement and represent another important motor deficit resulting from basal ganglia dysfunctions [see Hallett (1990)for a review].

A useful experimental approach to investigate neural processes related to motor initiation are operant sensorimotor tasks with reaction time constraint. In these paradigms, reaction times are used as an index for the time required for motor initiation. By means of various reaction time paradigms demanding different modes of response programming (i.e. simple or choice reaction time tasks; Fig. 1), several aspects of motor initiation can be investigated. In combination with measurement of movement times, the use of reaction time tasks further allows to separate processes related to motor initiation and execution and to distinguish akinesia from bradykinesia. Consequently, a closer description of the nature of impaired motor initiation is possible, in particular whether akinesia is caused primarily by defective processes related to motor initiation or reflects secondarily impaired postural control or altered muscular tone which could delay the build-up of motor activity. Besides reaction time paradigms and other sensorimotor tasks employing conditioned motor behaviour, impairments of motor initiation can be investigated using unconditioned motor behaviour as for instance catalepsy, that is, the persistent assumption of an abnormal posture due to experimental manipulations of the basal ganglia. Catalepsy can be regarded as active inhibition of neural circuits that mediate motor initiation, thus enabling akinesia with awkward postures (Klemm, 1989). Taken together, there exist a number of rodent models which allow to examine processes related to the initiation of movements and, by means of experimental manipulations of basal ganglia transmitter systems, some of the underlying neurochemical mechanisms.

This review is subdivided into three sections. It starts with a brief overview on major basal ganglia pathways, their neurotransmitters and receptors including some recent findings on the functional anatomy of the basal ganglia circuits. Then, effects on motor initiation induced by neuropharmacological manipulations of these transmitter systems by lesions and other techniques such as intracerebral drug infusions will be described. In the last section, major conclusions to be drawn from these findings will be discussed with regard to current models of basal ganglia functions.

Section snippets

Overview

The basal ganglia consist of several subcortical nuclei (Fig. 2) including the striatum, the globus pallidus, the subthalamic nucleus, the entopeduncular nucleus and the substantia nigra (with reference to rodent terminology). In functional terms, the striatum is the main input structure of the basal ganglia receiving afferents from the entire cerebral cortex. The incoming signals to the striatum are relayed via a direct and an indirect pathway to the entopeduncular nucleus and the substantia

Dopamine

Studies with systemic drug administration in rats have consistently shown a dopaminergic involvement in motor initiation and execution (Table 1). This might reflect predominantly, but not exclusively, a dopaminergic dysfunction in the basal ganglia, because, for instance, depletion of prefrontal dopamine also resulted in akinesia (Hauber et al., 1994). Impairments of motor initiation and execution induced by dopamine antagonists have been assessed in various operant sensorimotor tasks with time

Functional considerations: involvement of basal ganglia transmitter systems in movement initiation and models of basal ganglia functions

The review presented here provided, in behavioural terms, evidence for a role of major basal ganglia transmitter systems to contribute to motor initiation, which has been suggested to be an important motor function of the basal ganglia (Denny-Brown and Yanagisawa, 1976; Graybiel, 1990; Kimura, 1995).

According to the current functional model of basal ganglia functions (Albin et al., 1989), motor initiation is supposed to be associated with an inhibition of basal ganglia output structures brought

Conclusions

The basal ganglia have been implicated in a number of important motor functions, in particular in the initiation of motor responses. According to the current model of basal ganglia functions, increased or decreased activity of the substantia nigra pars reticulata and the entopeduncular nucleus is associated with facilitation or inhibition of response initiation. The activity of these basal ganglia output nuclei is controlled through direct striatal GABAergic projections as well as indirect

Acknowledgements

The author is grateful to S. Schmidt for her excellent help in organizing the references, S. Nitschke for his assistance in the preparation of the figures and R. Crolla-Rusch for her critical reading of the manuscript. The author is also indebted to Dr. W. J. Schmidt for his valuable comments, suggestions and criticisms on the manuscript. Permission by Freund Publishing House Ltd to include Fig. 7 is kindly acknowledged.

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