In this chapter, I will attempt to briefly describe what dopamine consists of, where it is located in the brain, and what basic actions it has. Much of this information will be applied in Chapters 3 and 4 with reference to the roles of dopamine in normal and abnormal behavior.

The neurochemistry of dopamine

Like all brain neurotransmitters, dopamine is a chemical that contains most of the important building blocks of life – carbon, hydrogen, oxygen, and nitrogen. It is a phylogenetically old transmitter, found in primitive lizards and reptiles existing tens of millions of years ago. The chemical structure of dopamine is shown in Figure 2.1. Dopamine is known as a catecholamine, which derives from its having a catechol group and an amine group that are joined by an additional carbon pair. The catechol group consists of a hexagonal benzene (carbon-bonded) ring with two hydroxyl (oxygen and hydrogen, or OH) groups. The amine group is a molecule comprised of an atom of nitrogen and two atoms of hydrogen (NH2). The chemical structure of dopamine is not all that special, in that its atoms and molecules derive from some of the most common elements on Earth and especially those found in organic compounds. Carbon, in particular, is essential to life on Earth, partly because it so readily makes bonds with other biological molecules.

The “hyperdopaminergic” syndrome

Despite the many positive dopaminergic traits described in Chapter 3, the dopaminergic story has another, darker side. Whereas too little dopaminergic transmission in disorders such as Parkinson's disease and phenylketonuria is debilitating to motor and intellectual functioning, excessive dopamine activity in one or more brain systems has been implicated in an even larger number of prominent neuropsychological disorders – including attention-deficit disorder (also known as attention-deficit/hyperactivity disorder when accompanied by hyperactivity), autism, Huntington's disease, mania (also known as hypomania and bipolar disorder when it alternates with depression), obsessive-compulsive disorder, schizophrenia, and Tourette's syndrome. Other hyperdopaminergic disorders include substance abuse (highly associated with attention-deficit/hyperactivity disorder and bipolar disorder) and stuttering (linked to Tourette's syndrome). All of the hyperdopaminergic disorders are closely related to one another in terms of their co-morbidities and symptoms, and more than one set of hyperdopaminergic symptoms are surprisingly often found in the same individual (e.g. autism with obsessive-compulsive and Tourette's features; mania with schizophrenic-like psychosis and obsessive-compulsive behavior) or within families. The various hyperdopaminergic disorders also are highly amenable to the same pharmacological interventions (principally D2 receptor-blocking drugs). In fact, drugs that decrease dopamine levels in either the brain generally or in a specific system (e.g. the ventromedial one) are the main or secondary pharmacological treatment of choice in every hyperdopaminergic disorder except for Huntington's desease.

Dopamine excess contributes to the motor symptoms (e.g. hyperactivity, tics, motor stereotypies), delusions and hallucinations, and social withdrawal found to varying degrees in the above disorders.

General aspects of D1 receptors

In the presence of a D2 antagonist, the binding of [3H]dopamine to rat brain sections is very selective for dopamine D1 sites, and is entirely displaced by low concentrations of the prototypic D1 antagonist Sch 23390 (Herve et al. 1992). However, the D1 receptors linked to adenylate cyclase may constitute a subset of the binding sites for [3H]Sch 23390 (Andersen & Braestrup 1986). In the absence of sodium ion, two affinity states of dopamine D1 receptors for dopamine can be distinguished. The high-affinity state of the receptor, which is sensitive to the presence of GTP, seems to constitute about one half of the total binding in membranes prepared from bovine caudate (Seeman et al. 1985). Likewise, increasing concentrations of a D1 agonist displace [3H]Sch 23390 from D1 receptors in human caudate in a biphasic manner, revealing approximately equal proportions of D1Low and D1High states of the receptor. In contrast, others report the fraction of dopamine D1 receptors in rat cryostat sections in a high-affinity state for dopamine to be only 20%, versus 77% for D2 receptors (Richfield, Penney, & Young 1989).

The regulation of dopamine D1 receptor expression in living brain is poorly understood. Steroid hormones play a role, since the striatal binding of [3H]Sch 23390 in female rat decreased following ovariectomy, and varied across the estrus cycle (Levesque, Gagnon, & Di Paolo 1989).

Methods for measuring dopamine release

HPLC with electrochemical detection

Biological samples are mixtures of many compounds. The assay of biological samples usually begins with separation of the mixture into its components. Classically, dopamine and its metabolites have been separated from tissue samples by extraction into organic solvents or by ion exchange. During the past 25 years, the preferred method of separation of dopamine and its metabolites has been HPLC. Using this technique, dopamine, its acidic metabolites, and its amino acid precursors can be separated from extracts of brain tissue, or in samples of extracellular fluid acquired by cerebral microdialysis. Once this separation has been obtained, the separate analytes must be detected by some means, either due to the presence of a radioactive label, or on the basis of some other inherent property.

The chemical structure of dopamine is based upon catechol, an aromatic ring in which two adjacent ring protons are replaced with hydroxyl groups. The catechol structure imparts critical properties related to the interactions between dopamine and its receptors, but also reduces the chemical stability of molecules bearing it. The catechol group is highly oxidizable, meaning that electrons are readily withdrawn by other molecules or by catalytic surfaces. Exposure of a catechol to an electric field with a potential difference of one volt causes an oxidation reaction in which four electrons are transferred to the surface of the electrode, with the production of an oxidized quinone molecule.

This book is timely and will prove useful for many researchers interested not only in the specific topic, “Imaging Dopamine,” but also in more general aspects of dopamine. In neurotransmitter research, dopamine has served a spearhead function ever since its discovery in the brain half a century ago. Dopamine has also played a key role in molecular imaging research; the imaging of dopamine receptors started very early in the history of positron emission tomography.

Although this book has its focus on imaging, the full utilization of imaging techniques depends on the background knowledge gained from other methodologies, a theme that has been duly considered by the author. Thus, the various aspects of dopamine, dealing, for example, with its synthesis, storage, release, and metabolism, as well as with the enzymes and transporter proteins involved in these processes, are treated in sufficient detail to provide a well-integrated and reasonably complete picture of the very complex dopamine transmission machinery.

It should go without saying that the growth of knowledge regarding the various aspects of neurotransmission has not taken place without intervals of considerable disagreement and controversy. In the course of the past half century's intense research, many issues have been resolved, whereas others are still being debated. I am pleased to find that the author has devoted some space to historical aspects, starting out with a scheme of the dopamine nerve terminal published by me in 1966.

This book is a biography of dopamine, as illuminated by classical neurochemical methods and especially by molecular imaging with positron emission tomography (PET), or single photon emission tomography (SPET), a closely related technology.

Since the early 1980s, molecular imaging has become indispensable for the study of normal physiology, disease processes, and novel therapeutics. Using external detection with PET or SPET, the uptake and metabolism or binding of radioligands is monitored and quantified in living brain. This book summarizes the state of knowledge of the half-dozen molecular targets in the dopamine system, which have been investigated by imaging techniques. A key advantage of molecular imaging is that aspects of the life of dopamine can be studied in living brain, both in preclinical studies and in humans afflicted with neurodegenerative or psychiatric disorders in which dopamine is implicated. A key disadvantage is presented by the type of knowledge obtained by molecular imaging, which can be only indirectly informative of the step of the pathway for dopamine neurotransmission under investigation. Thus, the interpretation of molecular imaging results must always be grounded in basic aspects of the biochemistry of dopamine and the pharmacology of its binding sites.

Although several groups of dopamine neurons are found in the brain, the entire emphasis here is to be placed on the mesencephalic dopamine systems, which innervate the extended striatum and specific limbic structures of the forebrain.

Molecular biology and enzymology

Basic aspects of the biochemistry of TH have been investigated in considerable detail. Alternative post-transcriptional splicing of the cloned cDNA for human TH gives rise to four distinct messages (Kaneda et al. 1987). Of these, the TH type I resembles in sequence most closely the single transcript expressed in rat (Grima et al. 1987). When purified from tissue, the TH enzyme is associated with dopamine and possesses a bright blue-green color due to the complex between iron(III) and the catecholamine. Purified in the absence of catecholamines from transgenic bacteria, the enzyme is light green due to the complex between iron(III) and several histidine residues close to the active site (Ramsey, Hillas, & Fitzpatrick 1996). When purified to homogeneity, human TH type I expressed in Escherichia coli is a tetrameric protein of subunits with molecular mass of about 60 kDa (Nakashima et al. 1999), consistent with the native tetramer from rat, human, and bovine sources (Oka et al. 1982; Rosenberg & Lovenberg 1983).

The catalytic cycle for TH requires the reduction of iron(III), which has a half-life of 1 s in the presence of reduced biopterin (Ramsey, Hillas, & Fitzpatrick 1996), also known as tetrahydrobiopterin (BH4). Tyrosine hydroxylation requires the reaction between equimolar amounts of molecular oxygen and BH4, or certain synthetic reducers such as 2-amino-4-hydroxy-6,7-dimethyltetrahydropterin (DMPH4) and 6-methyltetrahydropterin (6MPH4). Indeed, the reaction rate is faster for 6MPH4 than for the endogenous compound, BH4 (Lazar et al. 1982; Lazar, Mefford, & Barchas 1982).