Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sex steroid hormones influence the dopaminergic systems of the hypothalamus as well as the extrahypothalamic regions of the brain in controlling movement and behavior in both humans and animals. This review focuses on the effects of sex steroids on dopaminergic activity in extrahypothalamic brain areas. Among sex steroids, estrogens have been most extensively investigated, and many studies report that estrogens affect behaviors mediated by the basal ganglia, such as in humans suffering from extrapyramidal disorders. Epidemiological and clinical evidence also suggests an influence of estrogens on the vulnerability threshold for schizophrenia and sex differences in the clinical expression of this disease. Clinical observations point to a role of androgenic hormones in Gilles de la Tourette's syndrome. In normal humans, sex steroids were also shown to influence motor and cognitive performance. Biochemical and behavioral studies in animals have also shown the effect of sex steroids on dopaminergic activity in the basal ganglia; however, both activating and inhibiting effects have been reported. This may partly be explained by effects of the dose, duration of treatment, interval between steroid administration and testing the behavior measured, and the part of the basal ganglia from which the behavior is elicited. In view of the numerous variables that influence net dopaminergic response to steroids, focus will be on the literature using similar experimental conditions to assess the effect of in vivo chronic steroid treatment, acute short-term steroid treatment and the estrous cycle as well as in vitro effects of steroids on dopamine receptors. These experimental paradigms point to two general mechanisms of action of steroids: a rapid short-term non-genomic membrane effect and a slower long-term possibly genomic effect of steroids on dopamine systems. Combining dopaminergic drugs with sex steroids could improve efficacy or reduce side effects associated with these drugs. Examples of such combined treatments in rats and monkeys are presented for delta 9-tetrahydrocannabinol, cocaine, neuroleptics, apomorphine and L-DOPA. A better understanding of steroid-dopamine interactions and the possible isolation of conditions to have only pro or anti dopaminergic activity could then be used to develop combined therapies or to optimize drug treatments that would take into account the patient's sex and endocrine status.
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PMID:Modulation of brain dopamine transmission by sex steroids. 801 4

Chronic administration (21 days) of haloperidol (HAL) (IP, 1.0 mg/kg/day) induced a behavioral supersensitivity (stereotypic sniffing) to dopamine (DA) agonists (apomorphine) and upregulation (increased Bmax for sulpiride-inhibitable [3H]spiroperidol binding) of striatal and limbic D2 DA receptors (DAr). Coadministration of cyclo(leucyl-glycyl) (CLG; 8mg/kg, SC; every third day, every other day, but not every day) with HAL attenuated the behavioral supersensitivity. D2-DAr binding assays showed 1) that CLG-induced changes in Bmax parallel these behavioral changes and 2) that the biphasic CLG dose-response curve may involve CLG failure at high cumulative doses to lower Bmax. CLG also reversed an already established D2 DAr supersensitivity/upregulation (i.e., when CLG was injected daily for four days after the withdrawal of HAL). CLG alone did not alter behavior or binding. CLG's ability to both prevent and reverse D2 DAr upregulation/supersensitivity in animal models suggests that CLG may be useful, within a therapeutic window, in clinical disorders that are thought to involve upregulated DAr (e.g., tardive dyskinesia, L-DOPA-induced dyskinesias, and schizophrenia).
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PMID:Prevention and reversal of dopamine receptor supersensitivity by cyclo(leucyl-glycyl) (CLG): biphasic dose-response curves. 811 15

A large body of experimental evidence supports the hypothesis that dopamine is a functional neuromodulator at many levels of the visual system. Intrinsic dopaminergic neurons were characterized in most mammalian retina, including man. These neurons give rise to a dendritic plexus covering the retina. Thus, dopamine seems to be involved in the organization of the ganglion cell and the bipolar cell receptive fields and modulates physiological activity of photoreceptors, both processes which underlie sensitivity and spatial selectivity of visual processing in the early stage of the visual system. Moreover, few data are now available concerning the functional significance of dopaminergic modulation of visual sensitivity in man. Parkinson's disease is a specific disorder of central dopaminergic systems. Abnormalities in the pattern-evoked potentials and electroretinogram have been found in parkinsonian patients. Contrast sensitivity, a useful tool for measuring visual spatio-temporal sensitivity in man, has also been shown to be modified due to this affection. Dynamic contrast sensitivity is primarily decreased in these patients, distinguishing them from the normal aging process. Because these modifications in shape of the contrast sensitivity function are reversed by L-Dopa, and that neuroleptic administration could reproduce them in schizophrenia patients, it was suggested that dopamine might tune the contrast sensitivity function in man. We have recently shown that subcutaneous apomorphine induces changes in contrast sensitivity in healthy volunteers, which preferentially affect motion sensitivity. These dopaminergic sensitive modifications in the shape of the contrast sensitivity function might reflect a change in the range of sensitivity of the visual system, both in dynamic and spatial properties. This could be explained by a modification in the spatial and dynamic properties of the ganglion cell responses in the retina. Moreover, we suggest both from our results and from the review of the literature that human psychophysical data confirm the hypothesis that dopamine may be involved in light retinal adaptation, as light-induced and dopamine-induced modifications in the shape in the contrast sensitivity function are quite similar.
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PMID:Dopaminergic modulation of visual sensitivity in man. 829 83

The dopamine transporter (DAT) is the carrier protein that transports dopamine across the presynaptic membrane. The DAT terminates the action of dopamine (DA) in the synapse via reuptake and thus regulates DA neurotransmission. The transporter has been studied by direct binding techniques using a variety of ligands which are inhibitors of DA transport. DAT binding, both in vivo (positron emission tomography) and in vitro (post mortem) may serve as a presynaptic marker to measure altered DA innervation in several neuropsychiatric diseases such as idiopathic Parkinson's disease, Tourette's disease, schizophrenia or cocaine addiction. In Parkinson's disease, a reduction in the density of binding sites could be due either to a degeneration of the terminal dopaminergic projections or to a compensatory readjustment in the level of dopamine synaptic transmission. This dopaminergic cell specific marker could also aid in attempts to elucidate the rate at which dopaminergic cells are lost in this disease. MPTP (a neurotoxin which induces a parkinsonian-like syndrome after conversion in MPP+) uses DAT to enter the neuron and exert its toxic effect which may be prevented by pretreatment with DA uptake blockers. In cocaine abuse, DAT mediates the addictive properties of cocaine. Cocaine binding sites on the carrier may be distinct from DA binding sites allowing the development of medication sparing the DA function but impairing the cocaine effects. In schizophrenia, functional DA uptake was reported to be increased in the striatum in post mortem brains, whereas the kinetic parameters of the uptake sites were unchanged using different transporter labeling ligands. Thus, this marker does not provide any evidence for the dopaminergic hypothesis, but an impairment of the DAT itself could possibly be involved in the etiology of schizophrenia. However, the possible interaction of drugs such as L-Dopa or neuroleptic treatment with transporter binding may be taken into account in the results analysis. Finally, the DAT gene is also an important candidate gene for psychiatric diseases such as schizophrenia or cocaine abuse.
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PMID:[The dopamine transporter: characterization and physiopathologic implications]. 867 69

Catechol-O-methyltransferase (COMT) inactivates catecholamines and catechol drugs such as L-DOPA. A common genetic polymorphism in humans is associated with a three-to-four-fold variation in COMT enzyme activity and is also associated with individual variation in COMT thermal instability. We now show that this is due to G-->A transition at codon 158 of the COMT gene that results in a valine to methionine substitution. The two alleles can be identified with a PCR-based restriction fragment length polymorphism analysis using the restriction enzyme Nla III. The identification of a gentic marker associated with significant alterations in enzyme activity will facilitate the analysis of a possible role for the COMT gene in neuropsychiatric conditions in which abnormalities in catecholamine neurotransmission are believed to occur, including mood disorders, schizophrenia, obsessive compulsive disorder, alcohol and substance abuse, and attention deficit hyperactivity disorder. In addition, this polymorphism may have pharmacogenetic significance in that it will help make it possible to identify patients who display altered metabolism of catechol drugs.
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PMID:Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. 880 64

The dopaminergic hypothesis of schizophrenia postulates increased brain dopaminergic activity. Two previous studies reported increased 18F-DOPA uptake with positron emission tomography in schizophrenic patients (n = 5, n = 7). In the present study, striatal dopaminergic function was assessed in vivo in six untreated schizophrenics and seven control subjects, comparable for age and sex. The 18F-fluoro-L-DOPA (18F-DOPA) uptake rate constant Ki was determined in the caudate and putamen using coregistered positron emission tomography and magnetic resonance imaging. No difference between groups for mean Ki was found. The variability of the 18F-DOPA uptake values was higher in the caudate (p < 0.01) and in the putamen (p < 0.001) in schizophrenic patients than in control subjects, suggesting that schizophrenia is a disorder involving heterogeneous states of the striatal presynaptic dopaminergic function.
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PMID:Presynaptic dopaminergic function in the striatum of schizophrenic patients. 906 12

The D3 dopamine receptor, a D2-like receptor, is selectively expressed in the ventral striatum, particularly in the shell of nucleus accumbens and islands of Calleja, where it is found in medium sized substance P neurons. The latter co-express the D1 receptor whose interaction with the D3 receptor was studied by treating rats with selective agonists and antagonists. In agreement with the opposite cAMP response, they mediate in cultured neuroblastoma cells, the D1 and D3 receptors exerted opposite influences on c-fos expression in islands of Calleja. However, in agreement with the synergistic influence of cAMP on D3 receptor-mediated mitogenesis on the same cultured cells, D1 and D3 receptor stimulation in vivo synergistically enhanced preprotachykinin mRNA in the shell of accumbens. This indicates that the two receptor subtypes may affect neurons in either synergy or opposition according to the cell or signal generated. Levodopa-induced behavioral sensitization in hemiparkinsonian rats is another example of D1/D3 receptor interaction. Hence repeated levodopa administration induces the ectopic appearance of the D3 receptor in substance P/dynorphin, striatonigral neurons of the dorsal striatum. This induction is secondary to D1 receptor stimulation in neurons of the denervated side and fully accounts for the sensitization, i.e. the increased behavioral responsiveness to levodopa. During brain development, a similar process could operate to control the late appearance of the D3 receptor in D1-receptor bearing neurons of the ventral striatum at a time at which they start to be innervated by dopamine neurons. Finally, taking into account a variety of genetic, developmental, neuroimaging and pharmacological data, we postulate that imbalances between the levels of D1 and D3 receptors in the same neurons could be responsible for schizophrenic disorders.
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PMID:Functional implications of multiple dopamine receptor subtypes: the D1/D3 receptor coexistence. 965 37

We investigated the availability of dopamine reuptake sites in the striata of two patients with productive symptoms and neuroleptic therapy as well as progressive parkinsonism using the new dopamine transporter ligand [123I]N-(3-iodopropen-2-yl)-2beta-carbo-methoxy-3beta- (4-chlorophenyl)tropane (IPT) and single photon emission computed tomography (SPECT). Normal specific binding in the caudate nucleus was 8.6 +/- 1.2 and in the putamen 6.5 +/- 1.3 (mean +/- S.D.; n = 8; mean age, 56.7 years; range 41-67 years). Patient 1 (age 43) was admitted to our clinic at age 38 because of left-sided parkinsonism. At age 40, she developed paranoid psychosis without change after cessation of L-DOPA and lisuride treatment for 3 months. She was diagnosed as a schizophrenic, paranoid subtype (DSM-III-R). IPT-SPECT showed a loss of dopaminergic nerve terminals (right caudate/putamen, 5.16/2.0; left caudate/putamen, 5.92/2.66). Patient 2 (age, 61 years) had a history of paranoid psychosis for approx. 30 years. He experienced progressive right-sided parkinsonism since age 57 when treated with clozapine. IPT-SPECT showed a marked reduction of striatal dopamine transporter binding (right caudate/putamen, 5.06/1.65; left caudate/putamen, 3.8/1.12). Our findings indicate that patients may suffer contemporaneously from Parkinson's disease and schizophrenia. In these patients, the proof of a nigrostriatal dopaminergic deficit justifies treatment with neuroleptics and dopaminergic drugs. Imaging of dopamine transporters with SPECT and IPT or a related compound represents an attractive alternative to the more complex measurements of fluorodopa uptake with positron emission tomography (PET).
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PMID:Reduced striatal dopaminergic innervation shown by IPT and SPECT in patients under neuroleptic treatment: need for levodopa therapy? 975 2

The objective was to examine effects of galaninrat on forebrain monoamine synthesis and on spontaneous locomotor activity in the rat. The rate of monoamine synthesis was estimated by measuring the accumulation of l-DOPA and 5-HTP, following inhibition of cerebral aromatic l-amino acid decarboxylase by means of NSD-1015 (100 mg kg-1 i.p.), after i.c.v. or intracerebral administration of galanin in adult male Wistar rats. Spontaneous locomotor activity was observed in an automated open-field arena ( approximately 0.5 m2). The i.c.v. administration of galanin (0.5-5.0 nmol bilaterally) produced a dose-dependent, statistically significant, increase in DOPA accumulation throughout the neostriatum, and in the olfactory bulb, indicating an increase in the rate of DA synthesis. No increase was observed in brain areas where noradrenaline is the predominant catecholamine, such as the neocortex or the ventral hippocampus. In addition, there was a tendency for an increase in 5-HTP accumulation in the dorso-lateral neostriatum and in the accumbens. The same i.c.v. administration of galanin produced a dose-dependent, and statistically significant, decrease in spontaneous locomotor activity. The effect on forebrain DA synthesis could also be produced by local bilateral application of galanin (2x1 nmol) into the ventral tegmental area, but not the nucleus accumbens (2x2 nmol). There were no effects on forebrain DOPA or 5-HTP accumulation by the local application of galanin into the locus coeruleus, or into the dorsal raphe nucleus. It is concluded that the neuropeptide galanin modulates forebrain dopaminergic neurotransmission. The effect appears to be mediated at the somato-dendritic level of the meso-neostriatal pathway, and could perhaps be utilized to normalize perturbations ascribed to dysfunction in this neuronal pathway, such as schizophrenia.
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PMID:Suggestive evidence for inhibitory effects of galanin on mesolimbic dopaminergic neurotransmission. 1008 97

Presynaptic dopamine metabolism was studied in a group of patients with schizophrenia and in an age- and gender-matched normal control group using 6-[(18)F]fluoro-L-DOPA ((18)F-DOPA) and positron emission tomography (PET). Nineteen patients, nine drug-free, 10 on neuroleptics, and 13 normal control subjects underwent PET scans using (18)F-DOPA. The neuroleptic-treated patients were taking typical neuroleptics (N=4) or the atypical neuroleptic, clozapine (N=6). The ratio of specific/non-specific activity was calculated for eight cortical and subcortical regions of interest. Medication-free patients had a significant reduction in (18)F-DOPA uptake in the ventral striatum (P=0.04) and significantly increased uptake in the posterior cingulate (P=0.02) compared with normal control subjects. The 18F-DOPA PET technique proved to be useful and sensitive in detecting changes in dopamine metabolism in patients with schizophrenia in vivo. The results of this study provide evidence of an aberrant dopamine system in schizophrenia.
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PMID:6-(18)F-DOPA PET study in patients with schizophrenia. Positron emission tomography. 1109 Jul 20


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