Pharmacological Manipulation of D1-Dopamine Receptor Function in Schizophrenia Göran C
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Pharmacological Manipulation of D1-Dopamine Receptor Function in Schizophrenia Göran C. Sedvall, M.D., Ph.D., and Per Karlsson, M.D. The most widely accepted hypothesis concerning the trial of SCH 39166, a selective D1-dopamine receptor pathophysiology of schizophrenia, the dopamine hypothesis, antagonist, showed no evidence of antipsychotic activity in suggests that the symptoms of schizophrenia are mediated schizophrenic patients. Instead, it appeared that selective in part by a functional hyperactivity in the dopamine D1-receptor antagonism may have aggravated symptoms. system in the brain, primarily at D2-dopamine receptors. Although these findings do not support the prediction that Recent data suggest that D1-dopamine receptors may also selective D1-dopamine receptor antagonism produces play a major role in the pathophysiology of schizophrenia. antipsychotic effects, they do not preclude the possibility Using positron emission tomography (PET), increased that combined D1- and D2-receptor antagonism may act variability and reduced D1-receptor binding have been synergistically to ameliorate symptoms in schizophrenia. In observed in the basal ganglia and frontal cortex of drug- addition, clinical evaluation of D1 agonists in schizophrenia naive schizophrenia patients. Such alterations have also should be undertaken. [Neuropsychopharmacology been found in some in vitro studies. These results suggest 22:S181–S188, 1999] © 1999 American College of that the ratio of D1- over D2-regulated dopamine signaling Neuropsychopharmacology. Published by Elsevier in some brain regions is reduced in schizophrenia. A clinical Science Inc. KEY WORDS: Schizophrenia; Dopamine; D1 receptor; D2 tral dopamine receptor subtypes (D1, D2, D3, D4, and D5) receptor; Positron emission tomography (PET); (Sunahara et al. 1993). The D1-dopamine receptor Autoradiography subfamily consists of two subtypes, D1 and D5, and the Dopamine receptors have been divided into two major D2-receptor subfamily is composed of D2-, D3-, and D4- receptor subtypes (Lachowicz and Sibley 1997). These families, D1 and D2, based primarily on pharmacologi- cal and biochemical criteria (Sunahara et al. 1993). receptors are distinguished based on their primary However, recent advances in the molecular biology of structure, chromosomal location, mRNA size and tissue the dopamine receptor system have led to the identifi- distribution, and biochemical and pharmacological dif- cation and characterization of at least five distinct cen- ferences (Sunahara et al. 1993). For example, D1-like re- ceptors activate adenylate cyclase; whereas, D2-like re- ceptors have no effect on or inhibit adenylate cyclase (Lachowicz and Sibley 1997). From the Department of Clinical Neuroscience, Karolinska Insti- Historically, development of pharmacologic treat- tute, Stockholm, Sweden. Address correspondence to: Göran C. Sedvall, M.D., Ph.D., ments for schizophrenia has been dominated by the Department of Clinical Neuroscience, Karolinska Institute, Psychia- dopamine hypothesis, which states that the symptoms try Section, Karolinska Hospital, SE-17176 Stockholm, Sweden. Tel.: of schizophrenia are produced by excess activity in cen- 146 8 517 7 4445. Fax: 146 8 346 5 63. E-mail: goran.sedvall@ neuro.ks.se tral dopaminergic systems, primarily at D2 receptors. Received June 24, 1999; accepted July 28, 1999. Evidence for dopaminergic dysfunction was based on NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. S6 © 1999 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(99)00104-9 S182 G.C. Sedvall and P. Karlsson NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. S6 observations that the effective antipsychotics are potent of receptor ligands in the living human brain (Sedvall et antagonists at D2-dopamine receptors (Creese et al. al. 1986). Furthermore, it is possible to examine not only 1976; Seeman et al. 1976), and drugs that increase the distribution of receptors but also some quantitative dopamine release produce psychotomimetic effects aspects of receptor function and drug–receptor interac- (Lieberman et al. 1987). The results of more recent stud- tions in vivo (Sedvall et al. 1990; Wiesel et al. 1990). ies suggest that D1-dopamine receptors also may play a Following the classification of dopamine receptors major role in the pathophysiology of schizophrenia. into the D1- and D2-receptor subfamilies, the pharma- Understanding of the etiology of schizophrenia has cology of the D2 receptor was well characterized be- increased in the past two decades, in part because of the cause of the existence of a number of selective D2-recep- development of more sophisticated brain-imaging and tor antagonists and agonists (Seeman 1980). More histological techniques and selective radioligands that recently, the development of selective antagonists and allow visualization of abnormalities in brain chemistry agonists has enabled the evaluation of the D1 receptor. (Sedvall et al. 1986). Questions related to laterality and Farde et al. (1987) conducted a PET study in three regional specificity of alterations of dopamine signaling healthy male subjects and two male drug-treated necessitate the simultaneous recording of dopamine- schizophrenic patients injected with tracer doses of the 11 regulated mechanisms in a vast number of brain re- D1-receptor antagonist, [ C]SCH 23390 and the selec- 11 gions. This can be achieved at low resolution using tive D2-receptor antagonist [ C]raclopride. In healthy positron emission tomography (PET) with suitable ra- subjects, a high accumulation of radioactivity in the dioligands, which bind to specific components of striatum (caudate nucleus and putamen) was observed dopamine signaling pathways, such as receptors and with both [11C]SCH 23390 and [11C]raclopride; the ra- transporters. Using autoradiography in postmortem dioactive accumulation in the striatum was several-fold brain tissue from humans and in situ hybridization his- higher than the accumulation observed in any other tochemistry, visualization of receptor binding sites and brain region. This finding is similar to the accumulation areas of gene expression can be achieved with a much of [11C]SCH 23390 observed in the striatum of monkey higher resolution. These new chemical methods, in brain (Halldin et al. 1986). In contrast to the accumula- combination with computer graphics for image presen- tion of both D1- and D2-receptor antagonists in the stria- tation, allow the construction of three-dimensional (3- tum, [11C]SCH 23390, but not [11C]raclopride, showed a D) computed information banks of human brain anat- noticeable localization of radioactivity in the neocortex, omy. Information banks will help define the neuronal indicating the relative predominance of D1 receptors circuitry of the human brain and identify relevant neu- over D2 receptors in this region (Farde et al. 1987). This rochemical aberrations in the pathophysiology of result is consistent with studies in monkeys showing schizophrenia (Sedvall and Farde 1995). D1-receptor prominence in major cortical areas (Gold- This review summarizes the current state of under- man-Rakic et al. 1990; Lidow et al. 1991). The localiza- standing regarding dopamine receptor distribution in tion of a very low density of D2 receptors in the human the brain based on autoradiographic studies of receptor neocortex has also been observed with [11C]raclopride. binding in postmortem tissue and in vivo PET studies, In humans, [11C]SCH 23390 does not appear to accumu- as well as in studies of dopamine-receptor mRNA ex- late in the cerebellum, indicating a negligible density pression identified by in situ hybridization. Evidence is of D1 receptors (Farde et al. 1987); the ratio of recep- presented implicating the D1-dopamine receptor in the tor binding in the putamen (a dopamine-rich structure) pathophysiology of schizophrenia. In addition, this re- to receptor binding in the cerebellum (a region with a view focuses on emerging evidence concerning the effi- negligible density of D1-dopamine receptors) was 3.0 cacy of pharmacological manipulation of D1-receptor (Table 1). function in the treatment of schizophrenia. Although SCH 23390 is a D1-receptor antagonist, it also has affinity for other binding sites, such as 5-HT re- ceptors (McQuade et al. 1988; Yamamoto and Kebabian 1989). SCH 39166, a benzonaphthazepine, has been DOPAMINE RECEPTOR DISTRIBUTION characterized both in vitro and in vivo as a potent and selective D -dopamine antagonist (Chipkin et al. 1988). PET Studies 1 SCH 39166 has a lower affinity for 5-HT receptors, and 11 In PET, high-affinity C-labeled ligands are adminis- is thus a more selective D1 antagonist than SCH 23390 tered intravenously to the subject, and the accumula- (Taylor et al. 1991). PET studies with [11C]SCH 39166 in tion of radioactive ligand is measured in various sec- cynomolgus monkeys demonstrated accumulation of tions of the brain. The positron camera records the radioactivity in the striatum (Halldin et al. 1991; Sedvall gamma radiation produced upon disintegration of 11C- et al. 1991) and neocortex (Sedvall et al. 1991). In labeled atoms. PET provides data on the relative distri- healthy human subjects, [11C]SCH 39166 rapidly passed bution of receptors and specific binding characteristics the blood–brain barrier and accumulated in the stria- NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. S6 D1 Receptor Function in Schizophrenia S183 Table 1. Radioactivity