Editorial [Hot Topic: Dopaminergic Neurotransmission (Guest Editor: Remco H.S. Westerink)]

Decades ago, in 1959, dopamine was found to be an essential neurotransmitter. In the years that followed, dopaminergic neurotransmission turned out to be critical for normal motor-, motivational- and reward-related functions. Nowadays it is known that dopaminergic signaling is not restricted to point-to-point synaptic contacts, but also involves volume transmission, which requires synaptic spillover of released dopamine to reach distant target cells through extracellular diffusion. Consequently, dopaminergic neurotransmission critically depends on exocytotic release and neuronal uptake of dopamine, as well as on diffusion away from the release site. Once target cells are reached, dopamine can bind to and activate dopamine receptors. The subsequent cellular response depends on the type of dopamine receptor that is activated and the signal transduction mechanisms that are coupled to these receptors. Disturbances in one or more of the above-mentioned aspects of dopaminergic transmission could lead to severe neurological and neuropsychiatric disorders such as Parkinson's disease, depression, addiction, schizophrenia, attention deficit hyperactivity disorder, restless legs syndrome and Tourette syndrome. Not surprisingly, the role of dopamine receptors and transporters, the excitability of dopaminergic neurons and the regulation of extracellular dopamine levels in the brain, especially in relation to the diseased state, has received ample attention and has proven to be imperative for a further understanding of dopaminergic neurotransmission as a whole. This theme issue on Dopaminergic Neurotransmission, consisting of seven reviews written by eminent experts in the field, aims to cover the major aspects of dopaminergic neurotransmission. The structure, function and pharmacology of the dopamine receptors are dealt with in the first two chapters. Werkman et al. review the D1-like and D2-like receptors and provide an indepth discussion on their coupling to second messenger systems and ion channels and the pharmacological properties of these dopamine receptors as well as their interaction with serotonin receptor systems, providing insight in recent drug developments and clinical applications. Sokoloff et al. focus specifically on the dopamine D3 receptor, which acts as an autoreceptor that controls the phasic activity of dopaminergic neurons, in relation to brain-derived neurotrophic factor, the treatment of Parkinson's disease and conditioning to drugs of abuse. Importantly, the reviewed data point to D3-receptor-selective antagonists as novel antipsychotic drugs for the treatment of neurological and psychiatric disorders. In the third chapter, the structure, regulation, and functional roles of the membrane dopamine transporter are discussed by Sotnikova et al. Though the main function of this transporter is the regulation of the extracellular concentrations of dopamine, recent experiments using knockout mice identified this transporter as a primary target of many potent psychotropic drugs and neurotoxins, and demonstrated its role in several pathological conditions. Dopaminergic neurotransmission is generally initiated by the vesicular release of dopamine, which can be modulated at different levels including dopamine synthesis, uptake and vesicular transport as well as Ca2+-homeostasis and exocytotic proteins. In chapter four, Westerink reviews the modulation of dopamine exocytosis with respect to the onset and progression of neurological and psychiatric disorders. The excitability of dopaminergic neurons plays an important role in neurotransmission, e.g., by modulating dopamine exocytosis. Marinelli et al. describe the regulation of the firing frequency of dopaminergic neurons by intrinsic factors, life experiences and excitatory and inhibitory inputs as well as the physiological, behavioral and pathological consequences thereof in chapter five. In chapter six, by Heien and Wightman, the local extracellular dopamine concentration in the striatum is related to dopamine release, uptake and diffusion. Emphasis is on the relation between the firing frequency of dopaminergic neurons and phasic dopamine release in rewardrelated processes. In order to put all of the above in a macroscopic view of dopaminergic neurotransmission, a broad range of brain imaging and neuroendocrine studies on dopaminergic dysfunction in neuropsychiatric disorders are discussed by Kienast and Heinz in the final chapter. These seven reviews not only provide extensive insight into our current knowledge on dopaminergic neurotransmission, but also indicate the gaps in our understanding. Until these gaps are filled, the dopaminergic system will continue to attract the attention of hundreds of scientist around the world. Hopefully, this special issue acts as a guide for their future research and I would like to acknowledge the authors as well as all the reviewers that contributed to this guide.