The dopaminergic nigrostriatal pathway is the largest brain pathway using dopamine as neurotransmitter, and has been extensively studied not least because of its importance in degenerative brain disease. It has been found recently that there is an interaction between striatal dopaminergic inputs and those that use as neurotransmitter the nucleoside ade-nosine. In addition, hybridization studies have revealed the presence of subtypes of dopamine and adenosine receptors, situated both pre- and postsynaptically on presynaptic terminals and cell bodies respectively, in striatum, globus pallidus, and the substantia nigra. These findings underline the complexity of action of dopamine in the basal ganglia.
There is some evidence about the actions of dopamine in the striatum. Most of the cell bodies in the striatum are GABA ergic, and are projection neurons, and the next numerous are cholinergic inter-neurons. The GABAergic projection neurons to the globus pallidus also contain enkaphalins, while those projecting to the substantia nigra also contain substance P and dynorphin. In the striatum, GABAergic cell bodies that project to the substantia nigra contain on their surface mainly D, dopamine receptors, while those that project to the globus pallidus contain mainly D2 receptors. Striatal cholinergic inter-neuron cell bodies appear to contain both D1 and D2 receptors. In addition, numerous presynaptic D1 receptors have been found at striatonigral terminals. Similarly, D2 receptors have been localized to striatopal-lidal terminals.
There is evidence that adenosine modulates dopamine release from nerve terminals in the striatum through At receptors. Adenosine A1 receptor mRNA has been found in striatal GABAergic projection neurons and acetylcholine inter-neurons. Similarly, A1 receptors have been detected at nerve terminals in globus pal-lidus and substantia nigra. The evidence suggests that D1, D2, and A1 receptor subtypes are not expressed in the globus pal-lidus or the substantia nigra but by the striatofugal nerves themselves. In addition, there are high concentrations of the adenosine A2A receptor subtype in the stri-atum, and in the globus pallidus, where they are co-localized with presynaptic D2 receptors.
The functional significance of these receptors is uncertain. There is evidence, however, that adenosine acts in the stria-tum to antagonize dopamine D2 receptor-induced decreases in extracellular (i.e. released) GABA in the ipsilateral globus pal-lidus. GABA is an inhibitory neurotrans-mitter. There is perhaps a balance between dopamine and adenosine influences on pallidal GABAergic projection neurons, which ultimately affects motor activity in the thalamus and the cortex.
The basal ganglia are part of the corti-cal-subcortical circuits that control the parallel processing of motor learning and performance. The overall output of the basal ganglia appears to be a tonic inhibitory one on motor activity. The pathways involved are both direct and indirect. The pathways may balance each other, being inhibitory and excitatory, respectively. It is possible that dopamine through D2 receptors inhibits indirect pathways, and through D1 receptors stimulates direct pathways. Adenosine may act as a counterbalance to the activating and inhibiting effects of dopamine. The evidence so far suggests that the receptor interactions are (A1-D1) and (A2A-D2). Clearly, the interactions are complex, and theories of the role of basal ganglia action need to take into account the integration of several projection and interneuronal pathways.
A: adenosine D: dopamine subthalamic nucleus
thalamus glutamate acetylcholine dopamine GABA
thalamus substantia nigra R = receptor o = postsynaptic ° = presynaptic
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