CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 5, Issue 1, 2006

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.

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.

The classification of dopamine receptors proposed more than two decades ago remains valid today. Based on biochemical and pharmaceutical properties two main classes of dopamine receptors can be distuinguished: D1-like (D1, D5) and D2-like (D2, D3, and D4) dopamine receptors. Dopamine receptors belong to the class of G protein-coupled receptors and signal to a wide range of membrane bound and intracellular effectors such as ion channels, secondary messenger systems and enzymes. Although the pharmacological properties of ligands for D1-like and D2-like dopamine receptors are quite different, the number of selective ligands for each of the five receptors subtypes is rather small. Many drugs used to treat neurological and neuropsychiatric disorders like Parkinson's disease, restless leg syndrome and schizophrenia have affinities for dopamine receptors. Such medications are not without limitations so the development of novel (selective or aselective) dopamine receptor ligands is of the utmost importance for improved therapeutic approaches for these diseases. In that respect it is also important to understand how dopamine receptor ligands affect receptor signalling processes such as desensitization, receptor heterodimerization and agonist-receptor trafficking, issues which will be discussed in the present review. Furthermore, attention is paid to interactions of dopamine receptors with serotonin receptors since many drugs used to treat above mentioned disorders of the brain also posses affinities for serotonin receptors. Because of the enormity of this area we have tried to focus more specifically on interactions within the prefrontal cortex where it appears that the serotonergic modulation of dopaminergic function might be very relevant to schizophrenia.

The classification of dopamine receptors proposed more than two decades ago remains valid today. Based on biochemical and pharmaceutical properties two main classes of dopamine receptors can be distuinguished: D1-like (D1, D5) and D2-like (D2, D3, and D4) dopamine receptors. Dopamine receptors belong to the class of G protein-coupled receptors and signal to a wide range of membrane bound and intracellular effectors such as ion channels, secondary messenger systems and enzymes. Although the pharmacological properties of ligands for D1-like and D2-like dopamine receptors are quite different, the number of selective ligands for each of the five receptors subtypes is rather small. Many drugs used to treat neurological and neuropsychiatric disorders like Parkinson's disease, restless leg syndrome and schizophrenia have affinities for dopamine receptors. Such medications are not without limitations so the development of novel (selective or aselective) dopamine receptor ligands is of the utmost importance for improved therapeutic approaches for these diseases. In that respect it is also important to understand how dopamine receptor ligands affect receptor signalling processes such as desensitization, receptor heterodimerization and agonist-receptor trafficking, issues which will be discussed in the present review. Furthermore, attention is paid to interactions of dopamine receptors with serotonin receptors since many drugs used to treat above mentioned disorders of the brain also posses affinities for serotonin receptors. Because of the enormity of this area we have tried to focus more specifically on interactions within the prefrontal cortex where it appears that the serotonergic modulation of dopaminergic function might be very relevant to schizophrenia.

The role of the D3 receptor has remained largely elusive before the development of selective research tools, such as selective radioligands, antibodies, various highly specific pharmacological agents and knock-out mice. The data collected so far with these tools have removed some of the uncertainties regarding the functions mediated by the D3 receptor. The D3 receptor is an autoreceptor that controls the phasic, but not tonic activity of dopamine neurons. The D3 receptor, via regulation of its expression by the brain-derived neurotrophic factor (BDNF), mediates sensitization to dopamine indirect agonists. This process seems responsible for side-effects of levodopa (dyskinesia) in the treatment of Parkinson's disease (PD), as well as for some aspects of conditioning to drugs of abuse. The D3 receptor mediates behavioral abnormalities elicited by glutamate/NMDA receptor blockade, which suggests D3 receptor-selective antagonists as novel antipsychotic drugs. These data allow us to propose novel treatment options in PD, schizophrenia and drug addiction, which are awaiting evaluation in clinical trials.

The role of the D3 receptor has remained largely elusive before the development of selective research tools, such as selective radioligands, antibodies, various highly specific pharmacological agents and knock-out mice. The data collected so far with these tools have removed some of the uncertainties regarding the functions mediated by the D3 receptor. The D3 receptor is an autoreceptor that controls the phasic, but not tonic activity of dopamine neurons. The D3 receptor, via regulation of its expression by the brain-derived neurotrophic factor (BDNF), mediates sensitization to dopamine indirect agonists. This process seems responsible for side-effects of levodopa (dyskinesia) in the treatment of Parkinson's disease (PD), as well as for some aspects of conditioning to drugs of abuse. The D3 receptor mediates behavioral abnormalities elicited by glutamate/NMDA receptor blockade, which suggests D3 receptor-selective antagonists as novel antipsychotic drugs. These data allow us to propose novel treatment options in PD, schizophrenia and drug addiction, which are awaiting evaluation in clinical trials.

The plasma membrane dopamine transporter (DAT) tightly regulates the extracellular concentrations of dopamine (DA) by re-capturing released neurotransmitter back into the presynaptic neuronal terminals and/or neighboring DA projections thereby providing an effective way to regulate synaptic and extrasynaptic DA levels. This transporter is a primary target of many potent psychotropic drugs and neurotoxins, such as cocaine, amphetamines and 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this review we summarize recent advances in understanding the structure, regulation, and functional roles of DAT in normal DA physiology and pathological conditions, such as attention deficit hyperactivity disorder (ADHD) and neurodegenerative processes, as well as their contribution to the pharmacology of psychostimulant drugs. Significant new insights on these issues have been gained using mice with genetic deletion of DAT.

The plasma membrane dopamine transporter (DAT) tightly regulates the extracellular concentrations of dopamine (DA) by re-capturing released neurotransmitter back into the presynaptic neuronal terminals and/or neighboring DA projections thereby providing an effective way to regulate synaptic and extrasynaptic DA levels. This transporter is a primary target of many potent psychotropic drugs and neurotoxins, such as cocaine, amphetamines and 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this review we summarize recent advances in understanding the structure, regulation, and functional roles of DAT in normal DA physiology and pathological conditions, such as attention deficit hyperactivity disorder (ADHD) and neurodegenerative processes, as well as their contribution to the pharmacology of psychostimulant drugs. Significant new insights on these issues have been gained using mice with genetic deletion of DAT.

Dopaminergic neurotransmission is mediated by the vesicular release of dopamine (DA), i.e. DA exocytosis. DA exocytosis and its modulation are generally believed to affect neuronal communication, development, maintenance and survival, and contribute to extracellular DA levels in the brain. As a result, DA exocytosis likely plays an important role in several neurological and psychiatric disorders, like Parkinson's disease (PD) and schizophrenia. As exocytosis is part of a sophisticated ensemble of processes, it can be modulated at different levels, including DA synthesis, uptake and vesicular transport as well as Ca2+-homeostasis and exocytotic proteins. Nonetheless, to be effective, modulation of exocytosis should result in functional changes, which are reflected by changes in release frequency, vesicle contents, and the time course of the exocytotic event. As will be shown in this review, functional changes in DA exocytosis can be produced by e.g. pharmacological/drug treatment, feedback mechanisms and up/down-regulation of exocytosis-related proteins. Moreover, the mode of DA exocytosis, i.e. classical full fusion or kiss-and-run exocytosis, could also serve as a potential target for functional modulation of dopaminergic neurotransmission. Since the onset and progression of neurological and psychiatric disorders often show a strong correlation with changes in brain DA levels, DA synthesis, transport or uptake, the findings described in this review highlight the importance of the modulation of (the mode of) DA exocytosis for normal progression of dopaminergic neurotransmission and the potential of exocytotic processes as drug targets.

Dopaminergic neurotransmission is mediated by the vesicular release of dopamine (DA), i.e. DA exocytosis. DA exocytosis and its modulation are generally believed to affect neuronal communication, development, maintenance and survival, and contribute to extracellular DA levels in the brain. As a result, DA exocytosis likely plays an important role in several neurological and psychiatric disorders, like Parkinson's disease (PD) and schizophrenia. As exocytosis is part of a sophisticated ensemble of processes, it can be modulated at different levels, including DA synthesis, uptake and vesicular transport as well as Ca2+-homeostasis and exocytotic proteins. Nonetheless, to be effective, modulation of exocytosis should result in functional changes, which are reflected by changes in release frequency, vesicle contents, and the time course of the exocytotic event. As will be shown in this review, functional changes in DA exocytosis can be produced by e.g. pharmacological/drug treatment, feedback mechanisms and up/down-regulation of exocytosis-related proteins. Moreover, the mode of DA exocytosis, i.e. classical full fusion or kiss-and-run exocytosis, could also serve as a potential target for functional modulation of dopaminergic neurotransmission. Since the onset and progression of neurological and psychiatric disorders often show a strong correlation with changes in brain DA levels, DA synthesis, transport or uptake, the findings described in this review highlight the importance of the modulation of (the mode of) DA exocytosis for normal progression of dopaminergic neurotransmission and the potential of exocytotic processes as drug targets.

This aim of this chapter is to review literature on the excitability and function of dopamine neurons that originate in the midbrain and project to cortico-limbic and motor structures (A9 and A10 dopamine pathways). Electrophysiological studies on rodent or non-human primates have shown that these dopamine neurons are silent or spontaneously active. The spontaneously active neurons show slow regular firing, slow irregular firing or fast bursting activity. In the first section, we will review how neuronal firing is modulated by intrinsic factors, such as impulseregulating somatodendritic dopamine autoreceptors, a balance between inward voltage-gated sodium and calcium currents and outward potassium currents. We will then review the major excitatory and inhibitory pathways that play important roles in modulating dopamine cell excitability. In the second section, we will discuss how, in addition to being modulated by intrinsic and synaptic factors, excitability of dopamine neurons can also be modulated by life experiences. Dopamine neurons change their firing rate throughout the developmental period, their activity can be modified by stressful life events, and the firing mode can change as a consequence of acute or repeated exposure to psychoactive drugs. Finally, these cells change their firing pattern in response to behaviorally relevant stimuli and learning experiences. We will conclude by discussing how changes in the physiology of the dopamine neurons could participate in the development or exacerbation of psychiatric conditions such as drug addiction.

This aim of this chapter is to review literature on the excitability and function of dopamine neurons that originate in the midbrain and project to cortico-limbic and motor structures (A9 and A10 dopamine pathways). Electrophysiological studies on rodent or non-human primates have shown that these dopamine neurons are silent or spontaneously active. The spontaneously active neurons show slow regular firing, slow irregular firing or fast bursting activity. In the first section, we will review how neuronal firing is modulated by intrinsic factors, such as impulseregulating somatodendritic dopamine autoreceptors, a balance between inward voltage-gated sodium and calcium currents and outward potassium currents. We will then review the major excitatory and inhibitory pathways that play important roles in modulating dopamine cell excitability. In the second section, we will discuss how, in addition to being modulated by intrinsic and synaptic factors, excitability of dopamine neurons can also be modulated by life experiences. Dopamine neurons change their firing rate throughout the developmental period, their activity can be modified by stressful life events, and the firing mode can change as a consequence of acute or repeated exposure to psychoactive drugs. Finally, these cells change their firing pattern in response to behaviorally relevant stimuli and learning experiences. We will conclude by discussing how changes in the physiology of the dopamine neurons could participate in the development or exacerbation of psychiatric conditions such as drug addiction.

The neurotransmitter dopamine is important in reward processing, however its precise modulatory role is still being investigated. Carbon-fiber microelectrodes can be used to monitor dopamine on a subsecond time scale in the striatum and nucleus accumbens of rats during behavior, and this approach is providing new insights into the mechanisms that control its extracellular concentration as well as the conditions under which it is released. Three main processes govern the amount of dopamine measured extrasynaptically: exocytotic release, neuronal uptake, and diffusion away from the release site. By monitoring local extracellular dopamine concentrations in the striatum following electrical stimulation of dopamine-containing neurons, release, uptake and diffusion can be individually examined and quantified. Dopaminergic neurons have been shown to fire in two firing modes, tonic and bursts at higher frequency. Electrical stimulation can be designed to mimic either mode to examine their effects on dopamine release. Burst firing causes a transient increase in extracellular dopamine while tonic firing causes a new steady-state level. In behaving primates, dopaminergic neurons display short-latency, phasic firing to primary reward and conditioned cues associated with reward. These bursts code differences between actual and predicted rewards. In rats, transient dopamine release in terminal regions that mimics that seen during burst firing has been demonstrated during reward-related cues. Taken together, these studies indicate that phasic dopamine release is a critical mediator of reward-related processes.

The neurotransmitter dopamine is important in reward processing, however its precise modulatory role is still being investigated. Carbon-fiber microelectrodes can be used to monitor dopamine on a subsecond time scale in the striatum and nucleus accumbens of rats during behavior, and this approach is providing new insights into the mechanisms that control its extracellular concentration as well as the conditions under which it is released. Three main processes govern the amount of dopamine measured extrasynaptically: exocytotic release, neuronal uptake, and diffusion away from the release site. By monitoring local extracellular dopamine concentrations in the striatum following electrical stimulation of dopamine-containing neurons, release, uptake and diffusion can be individually examined and quantified. Dopaminergic neurons have been shown to fire in two firing modes, tonic and bursts at higher frequency. Electrical stimulation can be designed to mimic either mode to examine their effects on dopamine release. Burst firing causes a transient increase in extracellular dopamine while tonic firing causes a new steady-state level. In behaving primates, dopaminergic neurons display short-latency, phasic firing to primary reward and conditioned cues associated with reward. These bursts code differences between actual and predicted rewards. In rats, transient dopamine release in terminal regions that mimics that seen during burst firing has been demonstrated during reward-related cues. Taken together, these studies indicate that phasic dopamine release is a critical mediator of reward-related processes.

Dysfunction of central dopaminergic neurotransmission has been implicated in a series of neuropsychiatric disorders, including Tourette's syndrome, schizophrenia, and drug and alcohol dependence. The behavioral and psychopathological manifestations of central dopaminergic dysfunction differ depending on the site of their neurobiological correlate. These sites may be found in the dorsal or ventral striatum, but also in cortical regions such as the limbic and prefrontal cortex, among other locations. A low basic dopamine turnover and an increase in the availability of dopamine D2 receptors in the caudate body have been associated with the severity of motor tics in Tourette's syndrome. In the ventral striatum and particularly in the nucleus accumbens, different drugs of abuse stimulate dopamine release and thus reinforce drug consumption. The downregulation of dopamine D2 receptors in this area of the brain has been associated with alcohol craving and an increase in the processing of alcohol-related stimuli in the medial prefrontal cortex. Brain imaging studies in which intrasynaptic dopamine release is manipulated in vivo have shown that increased subcortical dopamine release is associated with the pathogenesis of positive symptoms in schizophrenia. This review discusses a broad range of brain imaging and neuroendocrinological studies on dopaminergic dysfunction in neuropsychiatric disorders, including relevant findings on the basis of primate studies. In addition, the hypothesis is examined that phasic dopamine release is associated with salience attribution to external stimuli, insofar as it mediates reward anticipation in the ventral striatum and limbic cortex, habit formation in the dorsal striatum, and working memory function in the prefrontal cortex.

Dysfunction of central dopaminergic neurotransmission has been implicated in a series of neuropsychiatric disorders, including Tourette's syndrome, schizophrenia, and drug and alcohol dependence. The behavioral and psychopathological manifestations of central dopaminergic dysfunction differ depending on the site of their neurobiological correlate. These sites may be found in the dorsal or ventral striatum, but also in cortical regions such as the limbic and prefrontal cortex, among other locations. A low basic dopamine turnover and an increase in the availability of dopamine D2 receptors in the caudate body have been associated with the severity of motor tics in Tourette's syndrome. In the ventral striatum and particularly in the nucleus accumbens, different drugs of abuse stimulate dopamine release and thus reinforce drug consumption. The downregulation of dopamine D2 receptors in this area of the brain has been associated with alcohol craving and an increase in the processing of alcohol-related stimuli in the medial prefrontal cortex. Brain imaging studies in which intrasynaptic dopamine release is manipulated in vivo have shown that increased subcortical dopamine release is associated with the pathogenesis of positive symptoms in schizophrenia. This review discusses a broad range of brain imaging and neuroendocrinological studies on dopaminergic dysfunction in neuropsychiatric disorders, including relevant findings on the basis of primate studies. In addition, the hypothesis is examined that phasic dopamine release is associated with salience attribution to external stimuli, insofar as it mediates reward anticipation in the ventral striatum and limbic cortex, habit formation in the dorsal striatum, and working memory function in the prefrontal cortex.