There are two main efferent pathways from the striatum to the globus pallidus, the direct pathway, which is a monosynaptic pathway making contact with the internal globus pallidus and to a lesser extent the substantia nigra, and the indirect pathway that indirectly connects to these brain regions via the lateral globus pallidus and the subthalamic nuclei. The internal globus pallidus and, to a lesser extent, the substantia nigra modulate the activity of the circuits via the thalamocortical motor pathways; these pathways are mainly inhibitory in nature.
With regard to the neurotransmitters involved in these circuits, the striatal neurons are mainly GABAergic and they also contain met-enkephalin as a co-transmitter as part of the indirect pathway; D2 receptors are also present. In the direct pathway, in addition to GABA, dynorphin and substance P act as co-transmitters; D1 receptors are predominant in the direct pathway.
Activation of the D2 receptors inhibits the GABA/enkephalin neurons of the indirect pathway, and possibly also the direct pathway. It appears that D1 receptors could play an excitatory role in the direct pathway.
Normally, dopamine inhibits the indirect pathway to the external globus pallidus which then inhibits the subthalamic nuclei. This system can therefore no longer stimulate the substantia nigra and globus pallidus, therefore leading to a reduction in the inhibitory output from these regions. Under these conditions, it is assumed that the thalamocortical pathway can function, leading to normal movement. The role of the direct pathway is less certain. It appears that dopamine stimulates the neurons of the direct pathway so that the globus pallidus is inhibited and the thalamocortical system facilitated. This view is supported by studies of patients with Huntington's disease in which the GABA/enkephalin neurons of the indirect pathway degenerate. As a consequence the direct pathway dominates, leading to the dyskinesias which characterize patients with the disease.
In Parkinson's disease, in which the deficiency in dopamine is predominant, the inhibitory effect of the indirect pathway is reduced. This leads to a greater inhibition of the external globus pallidus that results in the subthalamic nuclei increasing the activity of the substantia nigra and internal globus pallidus to inhibit the thalamocortical circuit and thereby cause the hypokinesia which characterizes Parkinson's disease.
Because of the key role which dopamine plays in basal ganglia function, and the evidence that its deficiency results in Parkinson's disease, there are three main approaches to the effective treatment of the symptoms of the disease:
(a) By augmenting the action of dopamine.
(b) By modifying the action of other transmitters such as acetylcholine which counteract dopaminergic function.
(c) By using brain grafts, stem cells or neurotrophic factors to replace the redundant dopaminergic neurons.
The relationship between the direct and indirect pathways that affect the striatal-globus pallidus network, together with the neurotransmitters involved, is shown in Figure 13.4.
In addition to dopamine and GABA, excitatory amino acids and adenosine are now known to play an important role in the functioning of the basal ganglia. This raises the possibility that drugs modulating the activities of these transmitters may be potentially useful therapeutic agents. With regard to the excitatory amino acids, the deficiency of dopamine leads to an increased release of glutamate from the corticostriatal tract to the striatum, which may contribute to the symptoms of the disease. Thus glutamate antagonists, acting on either NMDA or AMPA receptors, could provide novel types of anti-parkinsonism drugs. There is experimental evidence from both rodent and primate models of Parkinson's disease that such drugs can alleviate the motor symptoms of the disease.
Adenosine is known to be a neurotransmitter in the striatal-substantia nigra network. It has been shown that activation of the A2 adenosine receptors increases the release of acetylcholine and reduces that of GABA from the striatum in vitro. This could lead to an increase in the activity of the striatal GABAergic neurons. Activation of the adenosine receptors has also been shown to reduce dopaminergic function in the striatum. Thus adenosine A2 antagonists would be expected to augment dopaminergic inhibition of the GABA/enkephalin neurons and thereby reduce the motor
Intrinsic striatal neurons
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