Dopamine D2-like sites in schizophrenia, but not in Alzheimer's, Huntington's, or control brains, for [3H]benzquinoline

Abstract

Although the basis of schizophrenia is not known, evidence indicates a possible overactivity of dopamine pathways. In order to detect any new dopamine receptor-like sites which may be altered in schizophrenia, the present study used a new radioligand, a [3H]benzo[g]quinoline. The receptors were labelled by this ligand in the presence of other drugs to block the known dopamine D1, D2, D3, or D5 receptors (no D4-selective ligands are available to block D4). Using this method, we found that schizophrenia brain striata had elevated levels of a D2-like site not detected in control human postmortem brains or in Alzheimer's, Huntington's, or Parkinson's disease brains. The ligand acted as an agonist at this D2-like site, because binding was abolished by guanine nucleotide. The binding of the ligand to the D4 receptor, however, was not sensitive to guanine nucleotide. The site differed from D2 itself, because S- and R-sulpiride were equally potent at the D2-like site. The D2-like sites were present in rat and mouse brain but were absent in brain slices from transgenic mice where D2 had been knocked out. The abundance of the receptor was not related to premortem use of antipsychotic drugs. Future research should examine the biochemical differences between the D2 dopamine receptor and these D2-like sites in schizophrenia.

Cloning, expression, functional coupling and pharmacological characterization of the rat dopamine D 4 receptor

“…At the rat dopamine D 4 receptor, these compounds acted as partial agonists (relative efficacy around 30%). Here again, although all three have been presented as antagonists (Patel et al 1997;Seeman et al 1997;Tallman et al 1997), we have found evidence that they can behave, at least under some circumstances, as partial agonists at the human dopamine D 4 receptor (Gazi et al 1998(Gazi et al , 1999a(Gazi et al , 1999b. For example, an increase in the expression of human dopamine 562 Fig.…”

Schizophrenia: An Epigenetic Puzzle?

“…Although it is known that chronic administration of neuroleptics results in increased dopamine D2-like receptor sites in the brain (Muller and Seeman 1977; Owen et al 1980), neuroleptics do not seem to be the main cause of the increased density of D2-like receptors. The density of D2-like receptors was also found to be higher in a number of studies of the brains from never-medicated patients (Cross et al 1981; Seeman et al 1984, 1997; Wong et al 1986). Several experimental designs have been suggested to identify the specific dopamine receptor that accounts for the increased density of D2-like receptors in schizophrenia.…”

Case–control association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population

“…2 Postmortem and in vivo neuroimaging studies indicate increased dopamine D2 receptor density and binding affinity in the striatum of schizophrenic patients. 11,19,20 Enhanced expression of DRD2 in the caudate nucleus was implicated in the cognitive dysfunction of affected individuals. 2 Furthermore, common antipsychotic medications are capable of affecting the positive symptoms of the disease 2 as a result of antagonistic or partially agonistic interactions with the dopamine D2 receptor, whereas dopamine agonists, such as amphetamines, provoke schizophrenia-like psychosis.…”

“…2 Furthermore, common antipsychotic medications are capable of affecting the positive symptoms of the disease 2 as a result of antagonistic or partially agonistic interactions with the dopamine D2 receptor, whereas dopamine agonists, such as amphetamines, provoke schizophrenia-like psychosis. 2,11,21 The dopamine receptor genes comprise a large superfamily that encodes G-protein-coupled receptors important for regulation of some higher functions, such as locomotion, cognition and emotions. [22][23][24] Five human dopamine receptors are described and classified into two major groups, dopamine 1-like (D1) and dopamine 2-like (D2), in accordance with their transcriptional and pharmacological properties.…”