Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopamine via interaction with its receptor is known to be involved in the behavioral and endocrine actions in the mammalian brain. Behavioral effects produced by ethanol appear to be due to its actions on the dopaminergic system. In the present study using in situ hybridization histochemistry and RNase protection assay, the effect of prolonged ethanol intake on the expression of D2 dopamine receptor mRNA was examined in the rat brain. Specific D1 and D2 receptor mRNA signals were detected in the caudate putamen, nucleus accumbens, olfactory tubercle, hippocampus, dentate gyrus, and amygdaloid complex of the rat brain. Within the hypothalamus, the level of receptor mRNA was low in most nuclei with a somewhat higher level in the arcuate nucleus. Only the supurachiasmatic nucleus showed moderate to dense dopamine receptor mRNAs. Prefrontal cortex showed hybridization signals but their intensity was very low. A considerable amount of D2 mRNA was localized in the substantia nigra but D1 mRNA was not. Ethanol (10%) intake for 5 weeks increased both the density of hybridization signal and number of cells expressing D2 dopamine receptor mRNA in the caudate putamen, and nucleus accumbens, but not in the olfactory tubercle. RNase protection assay revealed about a 1.5-fold increase in the D2 dopamine receptor mRNA level in the corpus striatum. These results provide a basis for the involvement of dopamine D2 receptor expression in alcoholism.
Mol Cells 1997 Oct 31
PMID:Prolonged ethanol intake increases D2 dopamine receptor expression in the rat brain. 938 58

The mu opioid receptor is implicated in the reward, tolerance and withdrawal effects of alcohol and other drugs of abuse. This hypothesis is supported by the effects of alcohol on beta-endorphin release, of mu opioid receptor agonists and antagonists on alcohol consumption, and by the activation of the dopaminergic reward system by both alcohol and opiates. In addition, the murine mu opioid receptor locus, Oprm, is implicated as the major quantitative trait locus (QTL) affecting the different levels of morphine consumption between two inbred mouse strains that also exhibit differences in alcohol and cocaine consumption. Detection of genetic variation affecting OPRM1 expression or mu opioid receptor function would be an important step towards understanding the origins of inter-individual variation in response to mu opioid receptor ligands and in diseases of substance dependence. We directly sequenced the human mu opioid receptor locus, OPRM1, to detect natural variation that might affect function and/or be associated with psychiatric phenotypes related to opioid function. Four DNA sequence variants were found: three non-synonymous substitutions (Ala6Val [rare], Asn40Asp, [0.10-0.16], Ser147Cys [rare]) and one intronic variant (IVS2+691G/C [0.55-0.63]). OPRM1 alleles, genotypes and haplotypes from three psychiatrically characterized population samples (US Caucasian [USC, n=100], Finnish Caucasian [FC, n=324] and Southwestern American Indian [SAI, n=367]), were used to perform association and sib-pair linkage analyses with alcohol and drug dependence diagnoses. No significant association of OPRM1 genetic variation to phenotype was observed. This analysis has 80% power to detect a small to moderate effect of OPRM1 variation on alcohol dependence and 100% power to detect effects of the magnitude of the ALDH2*2 variant. While these data do not support a role of the mu opioid receptor in susceptibility to alcohol dependence, the potential relationship between OPRM1 genetic variation and response to endogenous opioids and exogenous opiates can now be investigated.
Mol Psychiatry
PMID:Mu opioid receptor gene variants: lack of association with alcohol dependence. 939 94

Recent in vivo studies have shown low dopamine D2 receptor and dopamine transporter densities among late onset (type 1) alcoholics. We have now studied 6-[18F]-FDOPA (FDOPA) uptake in 10 type 1 alcoholics and eight matched controls to test the hypothesis that striatal presynaptic dopamine function is lower among alcoholics. Markedly low FDOPA uptake (Ki) was observed in the left caudate of two alcoholic patients, but the mean striatal uptake values of the patient group were higher than those of the control group. The greatest difference was observed in the mean FDOPA intake in the left putamen, which was 28% higher in the patient group (t = 3.00, P = 0.008, d.f. = 16, independent samples t-test), and in the right caudate (difference 36%, t = 2.87, P = 0.01). The elevated FDOPA uptake in putamen and caudate correlated with poor Wisconsin Card Sorting Test (WCST) performance (error %) among alcoholics (correlation coefficients from 0.49 to 0.56), which suggests that the magnitude of presynaptic dopamine function alteration correlates with the degree of disability to modify one's behavior. The results do not give support to the hypothesis of generally decreased striatal dopamine turnover in type 1 alcoholism, but on the contrary indicate an increased presynaptic dopamine function. This may represent a compensatory mechanism to low postsynaptic DA function. The low presynaptic DA function observed in the left caudate of two patients suggests that type 1 alcoholism may be a heterogeneous disorder.
Mol Psychiatry 1998 Mar
PMID:Striatal presynaptic dopamine function in type 1 alcoholics measured with positron emission tomography. 957 40

The alternatively spliced 8-amino-acid exon for the GABAA receptor gamma2 subunit gene (GABRC2) has been postulated to mediate behavioral actions of alcohol. A rapid search for splice-junction mutations near the 8-amino-acid exon using restriction enzymes which normally recognize sequences near or in the exon gave negative results among 217 alcoholics in four aboriginal groups (Ami, Atayal, Bunun and Paiwan) and Han Chinese in Taiwan. The role of the GABRC2 gene in alcoholism was further assessed by a comparison of allelic frequencies revealed by a NciI RFLP between case and control groups. No significant association of alcohol dependence with GABRC2 alleles was observed. These results suggest that the GABRC2 gene probably does not play an essential role in predisposition to alcoholism in the sample population.
Brain Res Mol Brain Res 1998 May
PMID:Search for mutations near the alternatively spliced 8-amino-acid exon in the GABAA receptor gamma 2 subunit gene and lack of allelic association with alcoholism among four aboriginal groups and Han Chinese in Taiwan. 960 54

Positron emission tomography (PET) studies have revealed significant interindividual variation in dopamine D2 receptor density in vivo in human striatum. Low D2 receptor binding in vivo has been found to associate with alcohol/substance dependence. It has been suggested that the A1 allele of human D2 receptor gene might be associated to a specific type of alcoholism and possibly to a reduced D2 receptor density in vitro. We have determined D2 dopamine receptor-binding density (Bmax), affinity (Kd) and availability (Bmax/Kd) in 54 healthy Finnish volunteers using PET and [11C]raclopride in order to determine whether the A1 allele is associated with a 'baseline' difference in D2 receptor characteristics in vivo. A statistically significant reduction in D2 receptor availability reflecting an alteration in receptor density was observed in the A1/A2 genotype group compared to the A2/A2 group. There was no difference in apparent Kd between the two groups. In conclusion, the association between the A1 allele and low D2 receptor availability in healthy subjects indicates that the A1 allele of the TaqIA polymorphism might be in linkage disequilibrium with a mutation in the promoter/regulatory gene element that affects dopamine D2 receptor expression. This study provides an in vivo neurobiological correlate to the A1 allele in healthy volunteers.
Mol Psychiatry 1998 May
PMID:The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. 967 1

Alcoholism and substance abuse have been associated with a polymorphism in a noncoding region of the D2 receptor gene (the A1 allele of the Taq1 'A' system) in several, but not all studies. In addition, the presence of the A1 allele has been associated with lower density of D2 receptors in the caudate nucleus in one postmortem study. If the Taq1 'A1' allele is in linkage disequilibrium with a mutation that decreases the expression of the D2 receptor gene, it is conceivable that subjects with the A1 allele might be predisposed to behaviors which stimulate dopamine transmission, such as alcoholism or substance abuse. In this study, we attempted to confirm the association between the A1 allele and lower D2 receptor density, and explored a possible association between the B1 allele and D2 receptor expression. Genotypes at the Taq1 'A' and 'B' systems were determined in 70 subjects who underwent in vivo measurement of D2 receptors-binding potential with single photon emission computerized tomography (SPECT) and the selective dopamine D2 receptor radiotracer [123I]IBZM. [123I]IBZM-binding potential was identical in A1 carriers (i.e., subjects heterozygous or homozygous for that allele) (230 +/- 85 ml g-1, n = 27) and A1 noncarriers (231 +/- 70 ml g-1, n = 43). Similarly, we found no effect of the B1 allele on [123I]IBZM-binding potential. In conclusion, the results of this study failed to replicate the previously reported association between A1 allele and lower D2 receptor expression.
Mol Psychiatry 1998 May
PMID:D2 receptors binding potential is not affected by Taq1 polymorphism at the D2 receptor gene. 967 2

Fluoxetine is used in the treatment of a variety of clinical disorders including depression and obesity, and of cocaine detoxification or alcoholism. It is generally believed that fluoxetine exerts its clinical effects because it selectively blocks 5-hydroxytryptamine (5HT) reuptake into nerve terminals. In here we describe that fluoxetine antagonized the neuronal homomeric alpha 7 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes, with an IC50 of 43 microM, when fluoxetine was coapplied with ACh, and of 1.6 microM when the oocytes were pretreated briefly with fluoxetine. A similar block occurred in oocytes expressing L247T alpha 7 mutant nAChR. Furthermore, blockage of mutant alpha 7 receptors appeared non-competitive and was stronger with cell membrane hyperpolarization. Cell-attached single channel recordings in oocytes expressing L247T alpha 7 mutant nAChR showed that the voltage-dependence of the blockage by fluoxetine could be due to a drastic decrease in channel opening frequency accompanied by marked channel flickering and reduced channel conductance. We conclude that fluoxetine behaves as a reversible blocker of both wild and mutant alpha 7 receptors; and that the Leu-247T mutation in the channel domain renders the blockage of alpha 7 nAChR by fluoxetine voltage-dependent. These effects of fluoxetine on alpha 7 receptors may be clinically important.
Mol Psychiatry 1998 Jul
PMID:Effects of fluoxetine on wild and mutant neuronal alpha 7 nicotinic receptors. 970 46

Approximately 10% of Japanese alcoholics develop their disease despite having an inactive form of aldehyde dehydrogenase-2 (ALDH2), known as a genetic deterrent of heavy drinking due to adverse reactions after drinking. Such alcoholics are considered to be advantageous in genetic research because they should show reduced heterogeneity and possess genetic factors conferring susceptibility to alcohol dependence. Examination of the -1438 A/G polymorphism of the serotonin 2A (5HT2A) receptor gene in 225 Japanese alcoholics with inactive ALDH2 revealed the presence of significantly more of the G allele than was found in 361 control subjects. The frequency of the G allele in 282 alcoholics with active ALDH2 fell between the G allele frequencies of controls and subjects with inactive ALDH2. These data suggest that although the effect is relatively small, genetic variability in the 5HT2A receptor is involved in the development of alcohol dependence.
Mol Psychiatry 1999 Jan
PMID:Association of a polymorphism of the 5HT2A receptor gene promoter region with alcohol dependence. 1008 15

Chronic alcohol abuse is often associated with reproductive disorders. Sperm monosaccharides play an indispensable role in sperm-egg interactions and fertilization. Ethanol (3 g/kg body weight as 25%, v/v) was given by gastric intubation twice daily for 30 days while in another group, rats which had been treated with ethanol were withdrawn from treatment for a further period of 30 days, in order to assess the reversibility of the ethanol-induced effects. Epididymal ethanol content, sperm monosaccharides and the fertility of ethanol treated and ethanol withdrawn rats were assessed. Ethanol ingestion caused a significant decrease in sperm monosaccharides suggesting defective glycosylation of sperm surface proteins. Sperm monosaccharides and fertility were returned to normal following the withdrawal of ethanol. Ethanol-induced changes in sperm monosaccharides may be one of the reasons for the reduced fertility of ethanol treated rats.
Biochem Mol Biol Int 1999 Jan
PMID:Effects of ethanol ingestion on sperm monosaccharides and fertility. 1009 46

Dopaminergic transmission has been suggested to be a main mechanism mediating reinforcement, withdrawal and craving associated with alcohol addiction. We measured here striatal dopamine (DA) transporter binding from 27 alcoholics within 4 days after cessation of prolonged heavy drinking and after a 4-week period of abstinence with single photon emission computed tomography (SPECT) using a cocaine analogue, iodine-123-beta-CIT. Controls were 29 healthy volunteers. Blind quantitative analyses of the SPECT data revealed markedly lower DA transporter binding in alcoholics on admission for detoxification than in the non-alcoholic controls. After a 4-week period of abstinence DA transporter binding increased significantly in the alcoholics (P<0.0001) reaching the levels of the healthy controls. The most substantial recovery in DA transporter binding occurred during the first 4 days of abstinence. The data indicate that prolonged heavy drinking decreases DA transporter binding and disturbs synaptic dopamine transport. This may sensitize alcoholics to dopaminergic transmission, which may lead to early relapse after ethanol withdrawal.
Mol Psychiatry 1999 Mar
PMID:Dopamine transporters increase in human brain after alcohol withdrawal. 1020 52


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