Dopamine D receptors

The GRK4 SNPs include Arg65Len, Alal42Val, and Ala486Val. Dopamine D, receptor-mediated cAMP production is reported to be markedly impaired by these variants. Expression of these SNPs is also associated with increased basal phosphorylation of the dopamine Dj receptor. This suggests that increased basal phosphorylation of the dopamine Dj receptor by GRK4 may be associated with the decreased responsiveness of the dopamine Dj receptor in hypertension (187,188). 

In vitro studies suggest that the GRK4 SNPs impair the function of receptors, increase blood pressure, and impair the diuretic and natriuretic effects of dopamine Dj-like agonist stimulation. Inappropriate desensitization of the dopamine D, receptor in renal proximal tubules in hypertension may result in the decreased ability of the kidney to eliminate a sodium chloride load—a key risk factor in the development of hypertension. 

The dopamine D -like receptor polymorphisms include SNPs, variable-number tandem repeats (VNTRs), and splice variants (58,59). The polymorphic forms of the dopamine D receptor, for example, manifest as variable numbers of 48-bp repeat sequences (denoted D j to D., ) (49). 

Similar associations have been reported between dopamine D receptor variants with Tourette s syndrome, obesity (87-89), and alcohol dependence (90-93), although these findings are still the subject of debate in the literature. From the point of view of pharmacogenetics, the TaqlA polymorphism of the dopamine D receptor is associated with the development of tardive dyskinesia (88,94,95). While the results of these association studies vary (3,12), these data clarify our under-... 

Ng, G. Y., Trogadis, J., Stevens, J., Bonvier, M., O Dowd, B. F., and George, S. R. (1995) Agonist-induced desensitization of dopamine D receptor-stimnlated adenylyl cyclase activity is temporally and biochemically separated from D receptor internalization. Proc. Natl. Acad. Sci. U. S. A. 92, 10157-10161. 

Hwang, R., Shinkai, T., De, L., et al. (2006) Association study of four dopamine D receptor gene polymorphisms and clozapine treatment response. J. Psychopharmacol. 16,248-259. 

Kaiser, R., Konneker, M., Henneken, M., et al. (2000) Dopamine D receptor 48-bp repeat polymorphism no association with response to antipsychotic treatment, but association with catatonic schizophrenia. Mol. Psychiatry. 5, 418-424. 

Laucht, M., Becker, K., Blomeyer, D., and Schmidt, M. H. (2007) Novelty seeking involved in mediating the association between the dopamine D receptor gene exon III polymorphism and heavy drinking in male adolescents results from a high-risk community sample. Biol. Psychiatry. 61, 87-92. 

Hori, H., Ohmori, O., Shinkai, T., Kojima, H., and Nakamura, J. (2001) Association between three functional polymorphisms of dopamine D receptor gene and tardive dyskinesia in schizophrenia. Am. J. Med. Genet. 105, llA-11. ... 

The mechanism of action of neuroleptics is not sufficiently clear. However, it is believed that they are antagonists of dopamine and dopaminomimetics, and that their effect is connected in some way with the blockage of dopamine D receptors, which results in changes of behavioral reactions. Moreover, it is possible that they also block action on the serotonin receptors and M-choline receptors. It also is possible that antipsychotic agents disrupt the process of the release and return neuronal uptake of a number of biogenic amines. 

Ahlenius, S. (1999) Clozapine dopamine D, receptor agonism in the prefrontal cortex as the code to decipher a Rosetta Stone of antipsychotic drugs. Pharmacology Toxicol 84 193—196. 

Many researchers have come to believe that schizophrenia is a complex disease, possibly with a number of different causes or courses. PET studies of schizophrenia have found possible contributions of other receptors, including the dopamine D receptor as well as receptors for other neurotransmitters such as glutamate. Genetic researchers are searching for the genes involved in the expression and regulation of these receptors, any or all of which may be involved in some number of patients. 

Calvocoressi L, Lewis B, Harris M, et al Family accommodation in obsessive compulsive disorder. Am J Psychiatry 152 441-443, 1995 Cameron DL, Williams JT Dopamine D, receptors facilitate transmitter release. Nature 366 344-347, 1993... 

Whitworth P, Kendall DA Effects of lithium on inositol phospholipid hydrolysis and inhibition of dopamine D, receptor-mediated cyclic AMP formation by carbachol in rat brain slices. J Neurochem 53 536-541, 1989 Whybrow PC The therapeutic use of triiodothyronine and high dose thyroxine in psychiatric disorder. Acta Med Austriaca 21 44-47, 1994 Whybrow PC Update on thyroid axis approaches to treatment of rapid cycling bipolar disorder. Paper presented at the annual meeting of the New Clinical Drug Evaluations Unit (NCDEU), Boca Raton, EL, May 30, 1996... 

It causes antiemetic action by blocking dopamine (D receptors and it also increases gastric motility. It is absorbed orally but bioavailability is 15% due to first pass metabolism. It is completely biotransformed and metabolites are excreted in urine. It is used in nausea and vomiting in postoperative period, drug induced, radiation, uraemia, hepatitis, peptic ulcer. It is also useful in reflex oesophagitis. 

Van Tol HHM, Bunzow JB, Guan H-C, et al. Cloning of the gene fora human dopamine D receptor with high affinity for the antipsychotic clozapine [Letter], Nature 1991 350 610-614. 

Fenoldopam is a peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension. It acts primarily as an agonist of dopamine D receptors, resulting in dilation of peripheral arteries and natriuresis. The commercial product is a racemic mixture with the (R)-isomer mediating the pharmacologic activity. 

H3 receptor activation selectively inhibits dopamine D receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata. Neuroscience 80 241-249. 

Dimitriadou V, Rouleau A, Trung Tuong MD, Newlands GJ, Miller HR, Luffau G, Schwartz JC, Garbarg M (1997) Functional relationships between sensory nerve fibers and mast cells of dura mater in normal and inflammatory conditions. Neuroscience 77 829-39 Dolezal V, Jackisch R, Hertting G, AUgaier C (1992) Activation of dopamine D] receptors does not affect D2 receptor-mediated inhibition of acetylcholine release in rabbit striatum. Naunyn Schmiedeberg s Arch Pharmacol 345 16-20... 

A typical method was described by Kim et al. (1999). for the determination of a dopamine D receptor antagonist in rat plasma. 0.2 mL volume of plasma was diluted with 1.5 mL of 0.25 M potassium phosphate buffer, pH 8, followed by the addition of 20 xL of the internal standard (1000 ng/mL in methanol), which was a methyl analog of the analyte. The diluted sample was slowly applied on a 1 mL disposable ethyl cartridge which had been successively prewashed... 

Aiso M, Shigematsu K, Kebabian JW, Potter WZ, Cruciani RA, Saavedra JM (1987) Dopamine D receptor in rat brain a quantitative autoradiographic study with 125I-SCH 23982. Brain Res 408. 281-285. 

McMahon CD, Chapin LT, Lookingland KJ, Tucker HA (1998) Stimulation of dopamine D, receptors increases activity of periventricular somatostatin neurons and suppresses concentrations of growth hormone. Dom Anim Endocrinol 75 257-265. 

Figure 19.7. Competition curves for two compounds versus a known radioligand. (Top) These data represent the competition of two compounds with a known radioligand (in this case a radioligand that labels the dopamine D receptor, a member of the G protein-coupled superfamily). It is important to note not only the left-right difference between Compound A and Compound B, but also the difference in the shape of their competition curves. (Bottom) A Hill plot [based on Eq. (19.20)] of the competition curves shown in the top figure provides two pieces of data. First, the slopes of the lines are different (Compound A = -1.0 Compound B = -0.6), which has important mechanistic meaning that is discussed in Section 19.3.4b. Hill plots also allow more precise estimation of IC50s. By definition, at 50% inhibition, the Hill coefficient is 0. As shown, one can estimate the IC50 for each compound from this plot.

Van Kampen JM, Hagg T, Robertson HA (2004) hiduction of neurogenesis in die adult rat subventi icular zone and neostriatum following dopamine D receptor stimulation. Eur J Neurosci 19 2377-2387. 

The newer atypical psychotropics vary widely in their receptor binding profiles. Olanzapine and quetiapine bear resemblance to the profile of clozapine in that their therapeutic effects appear to derive from action on different receptors and transmitter systems. All atypicals (except amisulpride) exhibit greater antagonism of SHT -receptors than Baroceptors compared with the classical agents. Atypical drugs that do antagonise dopamine D -receptors appear to have affinity for those in the... 

Atypical antpipsychotics provoke fewer extra-pyramidal effects (less blockade of dopamine D -receptors in the nigrostriatal pathway). Nevertheless, extrapyramidal effects are seen, notably with high dose of risperidone (8-12 mg per day) and olanzapine (> 20 mg/day). 

Combinations, e.g. benzodiazepine plus dexamethasone, plus a 5-HTj (ondansetron) or dopamine D -receptor blocker (metoclopramide) are often more effective than a single drug. 

Dopamine Low dose (0.5-3.0 xg/min per kg body weight) Stimulation of the dopamine D, receptors on intrarenal vessels Dilatation of renal arterioles leading to a selective increase in RBF Increases urine excretion of Na and water May increase GFR Constant i.v. infusion required Close patient monitoring required (in hospital treatment) May induce cardiac arrhythmias Greater risk of inducing arrhythmias... 

Dopamine has been used for several decades for the treatment of human patients with oliguric ARF (Denton et al 1996, Dishart Kellum 2000). A constant low-dose i.v. infusion (0.5 to 3.0(jLg/ kg/min) produces a dose-dependent increase in the RBF and increases the excretion of sodium and water. Some studies have also reported increases in the GFR but this response is less consistent. A dose-dependent increase in the RBF has also been documented in normal horses (Trim et al 1989). Low doses of dopamine augment the RBF primarily by inducing renal arteriolar vasodilatation by stimulating dopamine D receptors in the intrarenal blood vessels. This effect is typically greater in afferent than in efferent glomemlar arterioles and is the mechanism by which dopamine may also promote an increase in the GFR. A secondary role is the stimulation of D2 receptors on presynaptic sympathetic nerve terminals, which inhibits norepinephrine release. Intermediate doses... 

On the basis of structural, pharmacological, functional and distributional similarities, all dopamine receptor subtypes fall into one of the two initially recognised receptor categories, here designated dopamine D,- or dopamine D2-like receptors. Dopamine D5 receptors share extensive similarities with dopamine D, receptors, while dopamine D3 and D4 receptors more closely conform to the features of dopamine D2 receptors. The properties of the two subfamilies closely resemble those of the dopamine D, and D2 receptor subtypes as originally defined by Kebabian and Caine.9 The most important characteristics of the cloned human dopamine receptor subtypes are summarised in Table 1.1. 

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