Chapter 28 - D1 Dopamine Receptor Supersensitivity in the Dopamine-Depleted Striatum: Aberrant ERK1/2 Signaling

Abstract

Publisher Summary This chapter discusses that a key to understanding the function of dopamine in the basal ganglia is the demonstration that D1 and D2 dopamine receptors are segregated in the direct and indirect striatal projection neurons. Striatal medium spiny neuronsare composed of two major subtypes based on their axonal projections. One subtype projects axons through the globus pallidus, making some contacts there, but extends axons to terminate in the internal segment of the globus pallidus and substantia nigra. These nuclei constitute the major output system of the basal ganglia; striatal neurons that project to them directly make up the so-called direct striatal projection pathway. The other subtype of striatal projection neurons extends its axon only to the globus pallidus. Neurons in this nucleus provide inputs to the internal segment of the globus pallidus and substantia nigra and to the subthalamic nucleus, which in turn projects to these basal ganglia output nuclei. Thus, striatal neurons that project only to the globus pallidus are connected through multiple synaptic connections to the output of the basal ganglia, and are considered to give rise to the indirect striatal projection pathway. The chapter reviews that the demonstration of a segregation of D1 and D2 receptors in direct and indirect pathway neurons, provides the basis for under­standing of functional changes in movement disorders such as Parkinson's disease. The central tenet of the theory of movement disorders is that they result from imbalanced activity in the direct and indirect striatal pathways. In Parkinson's disease, which is marked by akinesia, the theory suggested that there is increased activity in the indirect pathway. Neurons of this pathway express the D2 receptor, which is coupled to the inhibitory G protein, Gi.