N-methyl-D-aspartate (NMDA) and dopamine (DA) receptors and their interactions control an incredible variety of functions in the intact brain and, when abnormal, these interactions underlie and contribute to numerous disease states. These receptor interactions are relevant in such diverse functions as motor control, cognition and memory, neurodegenerative disorders, schizophrenia, and addiction. It is thus not surprising that a wealth of information has been generated by the neuroscience community interested in the coordinated functions of NMDA and DA receptors. This chapter will describe the numerous mechanisms underlying DA–NMDA receptor interactions, particularly in the striatum, the main focus of our investigations.
DA modulation of spontaneous or glutamate-induced action potentials in the caudate nucleus has been known for some time [1–3]. Since the discoveries of different subtypes of glutamate and DA receptors, the number of potential interactions and their mechanisms has multiplied because the functions of glutamate and DA receptor subtypes are governed by multiple factors that tap into different types of signaling systems. Thus, the outcomes of interactions of these receptor families can be very diverse.
It has been 10 years since we published our first review summarizing known DA–NMDA receptor interactions and their mechanisms [4]. Since then, exciting findings have added new levels of complexity. For example, in addition to intracellular interactions via second messenger pathways, recent studies revealed the presence of physical interactions between NMDA and DA receptors at the membrane and cytoplasm levels. Furthermore, the generation of mice deficient of specific DA receptors or NMDAR subunits and mice expressing enhanced green fluorescent protein (EGFP) under the control of specific DA receptor subtype promoters has provided new tools for studying relationships of DA and NMDA receptors.
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