dopamine receptor D4

There are two families of dopamine (DA) receptors, called D1 and D2, respectively. The D1 family consists of D1- and D5-receptor subtypes and the D2 family consists of D2-, D3-, and D4-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a large superfamily of receptors with seven transmembrane domains, which are coupled to their

The pharmacological profiles of D1- and D2-like dopamine receptors were investigated for native brain receptors in the leopard frog, Rana pipiens, using direct binding assays, which characterize functional receptors rather than assess total receptor protein. We used homogenate assays of R. pipiens fore- and midbrains to determine, via saturation isotherms, that the dissociation constant, Kd, for (3)H-SCH-23390 binding to the D1-like receptors was 0.29 nM, and the maximal receptor density, Bmax, was 40 fmoles/mg protein. This compares with the more than 10-fold higher density of D1 sites in rat striatum. Specific binding for the D2-like receptors was measurable using these methods with (3)H-spiperone as the ligand. However, saturation of binding was not achieved. This contrasts with the > 400 fmoles/mg protein Bmax in rat striatum. Pharmacological profiles (rank order of potency of displacing drugs) for each receptor type were determined. We used non-radioactive SCH-23390, SKF-38393, sulpiride, and spiperone to displace (3)H-SCH-23390 and (3)H-spiperone at D1 and D2 receptors, respectively. Parallel displacement assays were performed with rat striatal controls. Results indicated that the relative rank order displacements in anuran dopamine receptors were characteristic of D1- and D2-like receptors. However, the rank orders were not identical to those in mammals. The rank order for affinity at D1-like receptors in both rats and frogs was SCH-23390 > SKF-38393 > spiperone > sulpiride. The rank order for affinity at D2-like receptors was spiperone > SCH-23390 > sulpiride > SKF-38393 in frogs, and spiperone > sulpiride > SCH-23390 > SKF-38393 in rats. SKF-38393 and spiperone had similar affinities for the 'D1' receptors in both species. SCH-23390 had a slightly lower affinity for the D1-like receptors in Rana, whereas sulpiride had a significantly lower affinity for Rana D1-like receptors compared to rat D1 receptors. In Rana D2-like receptors, spiperone and sulpiride were significantly less potent compared to rat. However, SCH-23390 and SKF-38393 were equally potent for the D2-like receptors in both species. The results indicate that amphibian brain dopamine receptors fall into two classes similar to the mammalian D1 and D2 subfamilies, but with binding characteristics slightly different from those typically described in mammals. This work represents the first pharmacological characterization of native brain dopaminergic receptors in an anuran amphibian. Because direct binding assays measure the initial aspect of the functional interaction between transmitter and receptor, these data provide an important complement to studies using cell expression systems.

Planaria represents the most primitive example of centralization and cephalization of nervous system. Previous reports indicate that planaria shows specific behavioral patterns, analogous to mammalian stereotypes, in response to drugs acting on acetylcholine or dopamine transmission. Here we further characterized these responses, and investigated the interactions between cholinergic and dopaminergic systems by means of behavioral methods. Exposure to cholinergic agonists physostigmine or nicotine produced hypokinesia with 'bridge-like' and 'walnut' positions, respectively. Blockade of muscarinic receptors by atropine produced 'screw-like' hyperkinesia. Exposure to dopamine agonists (nomifensine, apomorphine) produced marked hyperkinesia with 'screw-like' movements. Finally, exposure to dopamine antagonists produced immobility or 'bridge-like' position. Pre-exposure to physostigmine blocked the behavioral effects of nomifensine and reduced and ...

Background: Since treatment approaches thought to be useful for mania are presumably suitable for hypomania as well, little systematic research has been done on the treatment of hypomanic episodes and their long-term outcome. As systematic trials have shown that the atypical antipsychotic risperidone may be effective and safe in the treatment of acute mania, we decided to conduct an open-label study of its effectiveness and tolerability in hypomania associated with bipolar II. Methods: Forty-four DSM-IV bipolar II patients with Young Mania Rating Scale (YMRS) scores above 7 were included and followed-up for 6 months. Efficacy was measured by means of the YMRS and the Clinical Global Impression for Bipolar Disorder (CGI-BD). Treatment-emergent depression was measured by the Hamilton Depression Rating Scale (HDRS-17), and the Udvalg for Kliniske Undersøgelser (UKU) subscale was used for neurological/extrapyramidal side-effects. Results: Thirty-four patients completed the trial. The mean dose of risperidone at endpoint was 2.8 mg/day. Last observation-carried-forward analysis showed significant reduction of YMRS scores from the first week of treatment, which continued until the endpoint (P<0.0001). At 6-month follow-up, 60% of patients were assymptomatic according to the CGI. The 32% who received risperidone in monotherapy seemed to respond equally well. Risperidone, as used in this study, appeared to be most protective against hypomanic than depressive recurrences. Nine patients (12%) had a depressive relapse during 6-month follow-up, one patient (2%) had an hypomanic relapse and another (2%) had both. No patients developed tardive dyskinesia during the duration of the study. Although most patients received risperidone in combination with standard mood-stabilizers, only three patients discontinued risperidone because of other side-effects. Limitations: In the absence of a placebo arm, it is uncertain to what extent the foregoing results could be ascribed to spontaneous remission of bipolar II disorder. Conclusions: Risperidone, either in combination with mood-stabilizers or alone was well-tolerated in bipolar II patients, who presented in a hypomanic state, and appeared efficacious. Further controlled research on the role of atypical antipsychotics in the treatment of less-than-manic forms of bipolar illness is warranted.

In the current study we tested whether the dopamine receptor D4 (DRD4) genotype moderates the association of experienced parental problems during childhood (e.g., parental depression, marital discord) with unresolved loss or trauma during the Adult Attachment Interview. To test the specificity of this moderation the role of the serotonin transporter gene promoter (5-HTTLPR) was also examined. Subjects were 124 adopted adults (mean age 39 years). Participants with the DRD4-7 repeat (7R) allele who experienced parental problems had the highest scores for unresolved loss or trauma whereas participants with DRD4-7R who did not experience parental problems showed the lowest ratings. Among participants without DRD4-7R, the parental problems during childhood did not make a difference. 5-HTTLPR did not moderate the relation between parental problems and unresolved loss or trauma. Our study shows heightened susceptibility to environmental influences for carriers of the DRD4-7R allele, and suggests that the interplay between specific dopamine-related genes and family contexts leads to more or less successful coping with adverse childhood experiences.

Role of basal ganglia: Vesalius and Piccolomini distinguished subcortical nuclei from cortex and white matter in the 16th century. Willis&#39; mistaken concept in the late 17th century that the corpus striatum was the seat of motor power persisted for 200 years and formed the basis of mid-19th-century localizations of movement disorders to the striatum (chorea by Broadbent and Jackson, and athetosis by Hammond). By the late 19th century, many movement disorders were described but for most no pathologic correlate was known. Tremor: Descriptions of tremors progressed from Galen&#39;s definition in the 2nd century; to Galileo&#39;s physiologic tremor in 1610; separation of involuntary movements during action and at rest in the 17th and 18th centuries by de la Boë Sylvius and van Sweiten; description of Parkinson&#39;s disease by Parkinson, discrimination of the rest tremor of Parkinson&#39;s disease from the intention tremor of multiple sclerosis by Charcot, and recognition of familial...

All current drugs approved to treat schizophrenia appear to exert their antipsychotic effects through blocking the dopamine D2 receptor. Recent meta-analyses and comparative efficacy studies indicate marginal differences in efficacy of newer atypical antipsychotics and the older drugs, and little effects on negative and cognitive symptoms. This review integrates findings from postmortem, imaging, and drug-challenge studies to elucidate a corticolimbic &quot;pathologic circuit&quot; in schizophrenia that may be particularly relevant to the negative symptoms and cognitive impairments of schizophrenia. Potential sites for pharmacologic intervention targeting glutatatergic, GABAergic, and cholinergic neurotransmission to treat these symptoms of schizophrenia are discussed.

The purpose of the present study was to understand the tissue specificity of DNA methylation and the relationship between methylation and expression of genes with essential roles in neurodevelopment and brain function. We chose dopamine receptor genes (DRD1 and DRD2), NCAM, and COMT as examples of genes with CpG islands around the promoter region, and serotonin receptor genes (HTR2A and HTR3A), HCRT, and DRD3 as genes without CpG islands. Methylation states were investigated in fetal brain, fetal liver, placenta, and in adult peripheral leukocytes from three individuals by Southern blot and bisulfite-modified DNA sequencing. A repetitive sequence, human endogenous retrovirus (HERV)-K was also examined. All genes examined were almost completely unmethylated in brains. The genes with CpG islands were unmethylated regardless of their expression state. In contrast, genes without CpG islands showed various methylation patterns, which did not necessarily reflect the transcriptional activity of the genes. Most HERV-K loci were methylated, but some loci showed relatively low methylation in the placenta and liver. Interestingly, we found inter-individual differences in methylation levels in HTR2A and HCRT in the placenta and in some loci of HERV-K in the placenta and liver. The sample with the lowest methylation levels in the two unique genes showed higher methylation of HERV-K loci than the other samples. These results provide detailed information about the methylation states of the genes analyzed and evidence for inter-individual variations in methylation in both unique and repetitive sequences.

Positron emission tomography (PET) studies have shown decreased glucose metabolism in brain regions of detoxified alcoholics and cocaine abusers. However, it is not clear whether this decrease is due to chronic drug abuse or a pre-existing condition. Molecular genetic studies have found an association of the D2 dopamine receptor (DRD2) A1 allele with alcoholism and drug abuse. Moreover, reduced central dopaminergic function has been suggested in subjects who carry the A1 allele (A1+) compared with those who do not (A1-). In the present study, using 18F-deoxyglucose, regional glucose metabolism was determined in healthy nonalcohol/nondrug-abusing subjects with the A1+ or A1- allele. The mean relative glucose metabolic rate (GMR) was significantly lower in the A1+ than the A1- group in many brain regions, including the putamen, nucleus accumbens, frontal and temporal gyri and medial prefrontal, occipito-temporal and orbital cortices. Decreased relative GMR in the A1+ group was also found in Broca&amp;#39;s area, anterior insula, hippocampus, and substantia nigra. A few brain areas, however, showed increased relative GMR in the A1+ group. Since polymorphism of the DRD2 gene is commonly observed in humans, the importance of differentiating A1+ and A1- alleles subjects in PET studies is suggested.