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  • 1
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract A four-site haplotype system at the dopamine D2 receptor locus (DRD2) has been studied in a global sample of 28 distinct populations. The haplotype system spans about 25 kb, encompassing the coding region of the gene. The four individual markers include three TaqI restriction site polymorphisms (RSPs) – TaqI “A”, “B”, and “D” sites – and one dinucleotide short tandem repeat polymorphism (STRP). All four of the marker systems are polymorphic in all regions of the world and in most individual populations. The haplotype system shows the highest average heterozygosity in Africa, a slightly lower average heterozygosity in Europe, and the lowest average heterozygosities in East Asia and the Americas. Across all populations, 20 of the 48 possible haplotypes reached a frequency of at least 5% in at least one population sample. However, no single population had more than six haplotypes reaching that frequency. In general, African populations had more haplotypes present in each population and more haplotypes occurring at a frequency of at least 5% in that population. Permutation tests for significance of overall disequilibrium (all sites considered simultaneously) were highly significant (P〈0.001) in all 28 populations. Except for three African samples, the pairwise disequilibrium between the outermost RSP markers, TaqI “B” and “A”, was highly significant with D’ values greater than 0.8; in two of those exceptions the RSP marker was not polymorphic. Except for those same two African populations, the 16-repeat allele at the STRP also showed highly significant disequilibrium with the TaqI “B” site in all populations, with D’ values usually greater than 0.7. Only four haplotypes account for more than 70% of all chromosomes in virtually all non-African populations, and two of those haplotypes account for more than 70% of all chromosomes in most East Asian and Amerindian populations. A new measure of the amount of overall disequilibrium shows least disequilibrium in African populations, somewhat more in European populations, and the greatest amount in East Asian and Amerindian populations. This pattern seems best explained by random genetic drift with low levels of recombination, a low mutation rate at the STRP, and essentially no recurrent mutation at the RSP sites, all in conjunction with an “Out of Africa” model for recent human evolution.
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  • 2
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The human dopamine D2L (long form) and D2S (short form) receptors were expressed separately in mouse Ltk− fibroblast cells to investigate whether there is a difference in transmembrane signaling of these D2 receptors. Both receptors induced two signals, a phosphatidylinositol-linked mobilization of intracellular calcium and an inhibition of cyclic adenosine 3′-5’monophosphate (cAMP) accumulation, each with similar response magnitudes and identical pharmacology. Both calcium and cAMP signals were sensitive to pretreatment with pertussis toxin (PTX), indicating mediation by coupling to Gi/Go proteins. However, the two forms of D2 receptor were distinguished by acute prior activation of protein kinase C (PKC) with 12-O-tetradecanoyl 4β-phorbol 13-acetate (TPA): TPA blocked the D2S-mediated increase in cytosolic free calcium concentration ([Ca2+]i) in a concentration-dependent manner (between 10 nM and 1 μM), whereas the D2L receptor-induced increase in [Ca2+]i was resistant to TPA and was only partially (60%) inhibited by 100 μM TPA. By contrast, TPA did not alter the inhibition of cAMP accumulation induced by activation of either D2S or D2L receptors. We conclude that, in the L cell system, prior activation of PKC differentially modulates the transmembrane signaling of the D2L and D2S receptors, preferentially inhibiting the D2S receptor-mediated calcium signal but not altering the dopamine-induced inhibitory cAMP signal of either receptor subtype.
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  • 3
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Two important aspects of striatal function, exploratory behaviour and motor co-ordination, require the integrity of the dopamine D4 receptor subtype. These receptors are also implicated in the pathophysiology of certain neuropsychiatric disorders. However, the distribution of D4 receptors in the striatum has not yet been described and this situation impairs our understanding of the anatomical substrate in which D4 receptors function. We developed a D4 receptor-specific anti-body that has permitted us to investigate the regional and cellular localization of the receptor in the neostriatum of the rat, mouse, cat and monkey. The subcellular distribution and the synaptic organization of this receptor were also determined in the rat striatum. We found moderate levels of D4 receptor expression in the caudoputamen and lower levels in the nucleus accumbens. These receptors were expressed in cell bodies and in the neuropil and were heterogeneously distributed among different striatal compartments, being more abundant in striosomes than in the matrix. At the subcellular level, the receptor immunoreactivity was mainly localized to dendritic shafts and spines. The prominent immunoreactivity observed in the striosomes indicates that integrative processes involved in D4-mediated limbic behaviours occurs through the striosomes rather than accumbens, whereas the motor behaviour is based in the striatal matrix.
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  • 4
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract : Presynaptic D2 dopamine (DA) autoreceptors,which are well known to modulate DA release, have recently been shown toregulate DA transporter (DAT) activity. To examine the effects ofD2 DA receptor deficiency on DA release and DAT activity in dorsalstriatum, we used mice genetically engineered to have two(D2+/+), one (D2+/-), or no(D2-/-) functional copies of the gene coding for theD2 DA receptor. In vivo microdialysis studies demonstrated thatbasal and K+-evoked extracellular DA concentrations were similar inall three genotypes. However, using in vivo electrochemistry, theD2-/- mice were found to have decreased DAT function,i.e., clearance of locally applied DA was decreased by 50% relative to that inD2+/+ mice. In D2+/+ mice, but notD2-/- mice, local application of the D2-likereceptor antagonist raclopride increased DA signal amplitude, indicatingdecreased DA clearance. Binding assays with the cocaine analogue[3H]WIN 35,428 showed no genotypic differences in either density oraffinity of DAT binding sites in striatum or substantia nigra, indicating thatthe differences seen in DAT activity were not a result of decreased DATexpression. These results further strengthen the idea that the D2 DA receptor subtype modulates activity of the striatal DAT.
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  • 5
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: According to the dual systems model for opiate reward, dopamine mediates opiate motivation when an animal is in a deprived motivational state (i.e. opiate-dependent and in withdrawal) and not when an animal is in a nondeprived state (i.e. previously drug-naive). To determine the role of the D2 dopamine receptor subtype in mediating opiate motivation, we examined the behaviour of N5 congenic D2 receptor knockout mice and their wild-type siblings in opiate-naive and opiate-dependent and withdrawn place conditioning paradigms. Opiate-naive D2 receptor knockout mice demonstrated acquisition of morphine-conditioned place preference but failed to acquire place preference when conditioned in the deprived state. We propose that D2 receptor function is critical in mediating the motivational effects of opiates only when the animal is in an opiate-dependent and withdrawn motivational state. These findings also underscore the important influence of the genetic background to a given phenotype, as evidenced by the observation that increasing the allelic contribution from the 129/SvJ strain abolishes morphine place preference in C57BL/6 wild-type mice.
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  • 6
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The prefrontal cortex receives a major dopaminergic input from the ventral tegmental area, which plays an important role in the integration of neuronal signals influencing behavioural responses to stressful environmental stimuli. The dopamine D4 receptor (D4R) is expressed at highest levels in the prefrontal cortex and is the predominant D2-like receptor localized in this brain area. To investigate the functional significance of D4Rs in dopamine-mediated responses we have analysed a strain of mice lacking this receptor subtype (Drd4–/–). Wild-type and Drd4–/– mice were challenged in two different approach/avoidance conflict paradigms: the elevated plus maze and the light/dark preference exploration test. By these behavioural measures Drd4–/– mice showed heightened avoidance to the more fear-provoking areas of each maze as demonstrated by reduced exploration of the open arms of the plus maze and longer latencies to explore the illuminated compartment of the light/dark shuttle box. These exaggerated avoidance behaviours were further enhanced by an additional handling stress but completely prevented by anxiolytic agents such as the benzodiazepine midazolam and ethanol. Although Drd4–/– mice displayed heightened anxiety, they exhibited normal ethanol preference and consumption in a two-bottle choice test. Learned fear responses evaluated by contextual, cued and instrumental fear-conditioning tests showed no difference between wild-type and Drd4–/– mice. Taken together these results indicate that the absence of D4Rs increases avoidance behaviour to unconditioned stimuli and does not impair behavioural reactions to Pavlovian fear-conditioning, suggesting that the D4R could play a key role in the dopaminergic modulation of cortical signals triggered by environmental stimuli.
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  • 7
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] The D! and D2 dopamine receptors are G protein-coupled receptors that stimulate and inhibit adenylyl cyclase, respec-tively1'2. Their structures should therefore contain the putative seven transmembrane domains common to G protein-coupled receptors7. The rat D2 receptor was cloned by low-stringency ...
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  • 8
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] Table 1 K{ values (nM) for L-RGB2Zem-l and rat striatum RGB-2 transformed Ltk~ cells Rat striatum (+)Butaclamol 0.83 1.0 (-)Butaclamol 〉 1,000 〉 1,000 Haloperidol 3.0 5.3 Dopamine + GTP 17,000 6,300 Sulpiride high affinity 80 67(87%) low ...
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  • 9
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: We have cloned and expressed a rat brain cDNA, TS11, that encodes a μ-opioid receptor based on pharmacological, physiological, and anatomical criteria. Membranes were prepared from COS-7 cells transiently expressing TS11 bound [3H]diprenorphine with high affinity (KD = 0.23 ± 0.04 nM). The rank order potency of drugs competing with [3H]diprenorphine was as follows: levorphanol (Ki = 0.6 ± 0.2 nM) ≈β-endorphin (Ki = 0.7 ± 0.5 nM) ≈ morphine (Ki = 0.8 ± 0.5 nM) ≈ [d-Ala2, N-Me-Phe4,Gly-ol5]-enkephalin (DAMGO; Ki = 1.6 ± 0.5 nM) ⋙ U50,488 (Ki = 910 ± 0.78 nM) 〉 [d-Pen2,5]-enkephalin (Ki = 3,170 ± 98 nM) 〉 dextrorphan (Ki = 4,100 ± 68 nM). The rank order potencies of these ligands, the stereospecificity of levorphanol, and morphine's subnanomolar Ki are consistent with a μ-opioid binding site. Two additional experiments provided evidence that this opioid-binding site is functionally coupled to G proteins: (a) In COS-7 cells 50 µM 5′-guanylylimidodiphosphate shifted a fraction of receptors with high affinity for DAMGO (IC50 = 3.4 ± 0.5 nM) to a lower-affinity state (IC50 = 89.0 ± 19.0 nM), and (b) exposure of Chinese hamster ovary cells stably expressing the cloned μ-opioid receptor to DAMGO resulted in a dose-dependent, naloxone-sensitive inhibition of forskolin-stimulated cyclic AMP production. The distribution of mRNA corresponding to the μ-opioid receptor encoded by TS11 was determined by in situ hybridization to brain sections prepared from adult female rats. The highest levels of μ-receptor mRNA were detected in the thalamus, medial habenula, and the caudate putamen; however, significant hybridization was also observed in many other brain regions, including the hypothalamus.
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  • 10
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: D1 and D5 dopamine receptor genes, stably expressed in GH4C1 rat somatomammotrophic cells, display identical binding values and stimulate adenylate cyclase. Approximately 60% of D1 receptors were in the agonist high-affinity state and were converted to the low-affinity state by 100 µM guanyl-5′-ylimidodiphosphate [Gpp(NH)p]. Of the 48% of D5 receptors in the high-affinity state, only half were modulated by 100 µM Gpp(NH)p; in the presence of the G protein activator, AlF4−, the high-affinity sites of D5 receptors were abolished by Gpp(NH)p, suggesting tight coupling between D5 receptors and G proteins. The high-affinity sites of D1, but not D5, receptors were reduced after pertussis toxin treatment of cells. Thus, whereas D1 receptors in GH4C1 cells couple to both Gs, the G stimulatory protein, and a pertussis toxin-sensitive G protein, D5 receptors couple to Gs and a pertussis toxin-insensitive G protein. Neither D1 nor D5 receptors were able to stimulate phosphoinositide metabolism in these cells. The ability of D5, but not D1, receptors to couple to novel G proteins may be significant in assigning a functional role for these receptors.
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