Schizophrenia: elevated mRNA for dopamine D2(Longer) receptors in frontal cortex.

Because dopamine D2 receptors are the primary targets for antipsychotic drugs, including clozapine and quetiapine, and because some studies have found D2 receptors to be elevated in schizophrenia, we examined the mRNA of three forms of the D2 receptor, particularly the new form of the dopamine D2 receptor, D2(Longer), in post-mortem brains from patients who died with schizophrenia. Using quantitative competitive RT-PCR (reverse transcriptase-polymerase chain reaction), the D2(Longer) mRNA was higher in the frontal cortex, compared to control tissues. The mRNA concentration of D2(Long) and D2(Short) was also higher in the frontal cortex, compared to control tissues.

Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis.

Objective: Although atypical antipsychotics are becoming the treatment of choice for schizophrenia, what makes an antipsychotic "atypical" is not clear. This article provides a new hypothesis about the mechanism of action of atypical antipsychotics.

Method: Published data regarding the molecular, animal model, neuroimaging, and clinical aspects of typical and atypical antipsychotics were reviewed to develop this hypothesis.

Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study.

Rationale: Dopamine D2 receptor upregulation in the striatum is regularly seen in response to the administration of traditional antipsychotics in animal experiments. This is associated with hyperactivity and, for this reason, D2 receptor upregulation has long been postulated as central to tardive dyskinesia (TD).

Objective: Using positron emission tomography (PET), the present study attempted to determine whether antipsychotic-induced D2 receptor up-regulation also occurs in humans.

Schizophrenia: elevated mRNA for calcium-calmodulin-dependent protein kinase IIbeta in frontal cortex.

Because amphetamine releases two to three times more dopamine in schizophrenia patients than in control subjects, and because calcium-calmodulin-dependent protein kinase II has a key role in the enhanced action of amphetamine-induced dopamine release in rats, the synaptic content of calcium-calmodulin-dependent protein kinase IIbeta mRNA was measured (by quantitative competitive RT-PCR; reverse transcriptase-polymerase chain reaction) in seven frontal cerebral cortices of post-mortem brains from patients who had schizophrenia and in seven control tissues. The results indicate that the mRNA of this kinase is elevated in the schizophrenia frontal cortex.

Dopamine D(2) receptor blockade by haloperidol. (3)H-raclopride reveals much higher occupancy than EEDQ.

Two techniques are commonly used to measure antipsychotic induced dopamine D(2) occupancy in animals: competition with a reversible radioligand (3H-raclopride) or with an irreversible receptor inactivator (EEDQ). While both of these techniques have been used in the past, there is no direct and systematic comparison. In the first direct comparison of these two methods we find that the dose of haloperidol required for blocking 50% of the dopamine D(2) receptors was 0.

Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP): reliable detection of the CMT1A duplication and HNPP deletion using 8 microsatellite markers in 2 multiplex PCRs.

Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsies (HNPP) are the most frequent inherited disorders of the peripheral nervous system. They are clinically and genetically heterogeneous. A submicroscopic tandem duplication of 1.

A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy.

Background: Quetiapine is a new atypical antipsychotic medication. As such, relatively little has been published regarding its in vivo effects at the dopamine type 2 (D2) and serotonin type 2a (5-HT2a) receptor systems. The following study was undertaken to explore these effects across the clinical dose range and relate this information to its clinical profile.

The human dopamine D2(Longer) receptor has a high-affinity state and inhibits adenylyl cyclase.

Brain dopamine D2 receptors are the main targets for antipsychotic and anti-Parkinsonian drugs. The dopamine D2 receptor has three forms, D2(Short), D2(Long) and D2(Longer). D2(Longer) is a newly found splice variant which contains two additional amino acids (valine and glutamine) in the third cytoplasmic loop of the receptor.

Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action.

Rationale And Objective: While the blockade of dopamine D2 receptors are necessary for antipsychotic action, antipsychotic agents differ nearly a thousand-fold in their affinity for the D2 receptor. This affinity is determined by the rate at which the antipsychotic agent binds to (kon) and the rate at which it dissociates from (koff) the D2 receptors. The objective of this study was to determine the relationship between kon, koff and the affinity (Ki) of antipsychotic agents for the D2 receptors, with particular reference to typical and atypical antipsychotic agents.

Simple PCR amplification of the entire glucocerebrosidase gene (GBA) coding region for diagnostic sequence analysis.

Mutations in the human glucocerebrosidase gene (GBA) may lead to Gaucher disease-an autosomal recessive, lysosomal storage disease. In about 15-25% of Caucasian patients with Gaucher disease yet the disease-causing mutations remain to be identified. There exists 16kb downstream from the functional GBA gene (chromosome 1q21) a highly homologous transcribed pseudogene (GBAP) with some sequence differences to GBA.

New dopamine receptor, D2(Longer), with unique TG splice site, in human brain.

Brain dopamine receptor agonists alleviate the signs of Parkinson's disease, while dopamine receptor antagonists alleviate hallucinations and delusions in psychosis. The dopamine type 2 receptor (or D2) is blocked by antipsychotic drugs, including even the "atypical" drugs such as clozapine or remoxipride, in direct relation to their clinical potencies. Compared to the long form of the D2 receptor (D2(Long)), the short form (D2(Short)) may be three times more sensitive to benzamide antipsychotic drugs.

Cloning and characterization of additional members of the G protein-coupled receptor family.

A search of the expressed sequence tag (EST) database retrieved a human cDNA sequence which partially encoded a novel G protein-coupled receptor (GPCR) GPR26. A human genomic DNA fragment encoding a partial open reading frame (ORF) and a rat cDNA encoding the full length ORF of GPR26 were obtained by library screening. The rat GPR26 cDNA encoded a protein of 317 amino acids, most similar (albeit distantly related) to the serotonin 5-HT(5A) and gastrin releasing hormone BB2 receptors.

Clozapine pre-treatment enhances raclopride catalepsy.

The clinical replacement of clozapine by another antipsychotic sometimes causes extrapyramidal signs, including dystonia, to appear suddenly. The present study was done, therefore, to test whether clozapine pre-treatment of rats could affect raclopride-induced catalepsy. Clozapine, at 5 mg/kg, given 2 h before a catalepsy-threshold dose of 0.

Rapid release of antipsychotic drugs from dopamine D2 receptors: an explanation for low receptor occupancy and early clinical relapse upon withdrawal of clozapine or quetiapine.

Objective: In an attempt to understand the basis of early relapse after antipsychotic withdrawal, the objective of this study was to determine whether the low occupancy of dopamine D2 receptors by clozapine and by quetiapine, as seen by brain imaging, could arise from a rapid release of some of the D2-bound clozapine or quetiapine by the brain imaging compounds and by the action of a physiological concentration of dopamine.

Method: Human cloned D2 receptors were first pre-equilibrated with the [3H]antipsychotic drug, after which raclopride, iodobenzamide, or dopamine (at the physiological concentration in the synapse) was added, and the time course of release of the [3H]antipsychotic from the D2 receptor was measured.

Results: Within 5 minutes, low concentrations of raclopride and iodobenzamide displaced appreciable amounts of [3H]clozapine and [3H]quetiapine from the D2 receptors but, during the course of 1 hour, did not displace any of the other antipsychotic [[3H]ligands.

Dopamine D2 receptor dimers in human and rat brain.

In order to determine whether dimers of dopamine D2 receptors can occur in mammalian brain, rat and human brain striatal membranes were photolabelled with two radioactive photoaffinity compounds selective for dopamine D2 receptors, [125I]azidophenethylspiperone and [125I]-4-azido-5-iodonemonapride. It was found that [125I]azidophenethylspiperone only labelled the D2 monomer, while [125I]-4-azido-5-iodonemonapride labelled both D2 monomers and dimers, despite the fact that very high concentrations (6 nM) of both radiocompounds were used. In addition, human cloned D2 receptors were probed with a D2-specific antibody, revealing multiple bands indicating the existence of trimers, tetramers and pentamers of D2 receptors.

A transmembrane domain-derived peptide inhibits D1 dopamine receptor function without affecting receptor oligomerization.

In this study, we show that a peptide based on the sequence of transmembrane domain 6 of the D1 dopamine receptor (D1DR) specifically inhibited D1DR binding and function, without affecting receptor oligomerization. It has been shown that an analogous peptide from the beta2-adrenergic receptor disrupted dimerization and adenylyl cyclase activation in the beta2-adrenergic receptor (Hebert, T. E.

The human serotonin-7 receptor pseudogene: variation and chromosome location.

We report a variation of the pseudogene for the serotonin-7 receptor in human DNA. Human genomic DNA was amplified, using the polymerase chain reaction method and degenerate oligonucleotide primers for serotonin receptor-like genes. A novel gene DNA sequence of 1325 bp was found.

Anti-hyperactivity medication: methylphenidate and amphetamine.

How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? These apparent paradoxes are the focus of this brief review on the mechanism of action of stimulant medications used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for attention deficit hyperactivity disorder.

Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors.

This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor.

A human serotonin-7 receptor pseudogene.

Although the serotonin-7 receptor was cloned several years ago, its localization in brain tissues remains confusing because of the existence of a related expressed pseudogene, the sequence of which has not hitherto been reported. During the course of searching for related receptor genes, we also searched for this pseudogene to determine its sequence. Human genomic DNA was screened for dopamine and serotonin receptor-like genes, using the polymerase chain reaction method and degenerate oligonucleotide primers based on the similar sequences in the transmembrane-6 and -7 regions of the serotonin-5A, the serotonin-7, and the dopamine D2, D3 and D4 receptors.

A serotonin-4 receptor-like pseudogene in humans.

During a search for new G-protein-linked receptors for dopamine and serotonin, we found a serotonin-4 receptor-like pseudogene. This receptor-like pseudogene is intronless, contains an in-frame stop codon following transmembrane-3, and has two one-nucleotide insertions between transmembrane-5 and -6 regions which alter the reading frame. The predicted amino acid sequence of the human pseudogene is about 35% identical with that of the rat serotonin-4 receptor.