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)

Alteration in dopamine (DA) and/or cholecystokinin (CCK) transmission in the CNS may be of relevance for schizophrenia. Previous findings in striatal membranes give indications of a modulation of DA D2 receptor affinity by CCKB receptor activation. In the present study receptor binding studies were performed in a mouse fibroblast cell line (L-hD2l/CCK), expressing both human D2 receptors (long form, D2L) and human CCKB receptors, and binding sites for [3H]CCK-8S (sulfated CCK octapeptide), the D2 agonist [3H]NPA and the D2 antagonist [3H]raclopride were found and characterized in saturation and competition experiments. 1 nM of CCK-8 caused a significant 38% increase in the KD value of the D2 agonist [3H]NPA binding sites in the L-hD2l/CCK cell membranes. This change was blocked by the CCKB receptor antagonist PD 134308 (50 nM). Furthermore, 1 nM of CCK-8 increased the KD value of the D2 antagonist [3H]raclopride binding sites by 34% (P < 0.05) in the L-hD2l/CCK cell membranes. Control cells (L-hD2l cells) expressing D2L receptors showed no specific [3H]CCK-8S binding sites and no modulation by CCK-8 of the D2L receptors. These findings indicate a modulation of the D2L receptor affinity by activation of the CCKB receptor also when they are coexpressed in a fibroblast cell line. One possible explanation of these data may include a receptor-receptor interaction between the CCKB and D2L receptors.
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PMID:Regulation of dopamine D2 receptor affinity by cholecystokinin octapeptide in fibroblast cells cotransfected with human CCKB and D2L receptor cDNAs. 896 50

The DA hypothesis of schizophrenia is one of the oldest biological hypotheses of schizophrenia with many revised versions. However, it is unlikely that any single neurotransmitter hypothesis is able to explain the biological basis of such a highly heterogenous disorder as schizophrenia in a satisfactory way. Rather, it is evident that the biological vulnerability factors and the 'acute neurophysiology' of schizophrenic symptoms involve a complex set of imbalances of aberrant connections in neuronal circuits in the brain. Dopamine is likely to be one of the transmitter substances involved, as evidenced by recent neuroimaging studies in neuroleptic-naive schizophrenia. Regardless of whether the DA hypothesis of schizophrenia is true or not, the DA hypothesis of neuroleptic drug action still has a relatively solid basis. The DA D2 receptor blockade remains the best characterized clinically useful mechanism of drug action to alleviate psychotic symptoms. The ongoing and future work on the precise role of DA in schizophrenia should focus on first-episode/admission neuroleptic-naive schizophrenic patients. Such studies represent the best opportunity of finding out specific changes in the dopaminergic pathways and relating them in a meaningful way to various dimensions of psychopathology seen in schizophrenic patients.
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PMID:Dopamine in schizophrenia. 901 15

Although the basis of schizophrenia is not known, evidence indicates a possible overactivity of dopamine pathways. In order to detect any new dopamine receptor-like sites which may be altered in schizophrenia, the present study used a new radioligand, a [3H]benzo[g]quinoline. The receptors were labelled by this ligand in the presence of other drugs to block the known dopamine D1, D2, D3, or D5 receptors (no D4-selective ligands are available to block D4). Using this method, we found that schizophrenia brain striata had elevated levels of a D2-like site not detected in control human postmortem brains or in Alzheimer's, Huntington's, or Parkinson's disease brains. The ligand acted as an agonist at this D2-like site, because binding was abolished by guanine nucleotide. The binding of the ligand to the D4 receptor, however, was not sensitive to guanine nucleotide. The site differed from D2 itself, because S- and R-sulpiride were equally potent at the D2-like site. The D2-like sites were present in rat and mouse brain but were absent in brain slices from transgenic mice where D2 had been knocked out. The abundance of the receptor was not related to premortem use of antipsychotic drugs. Future research should examine the biochemical differences between the D2 dopamine receptor and these D2-like sites in schizophrenia.
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PMID:Dopamine D2-like sites in schizophrenia, but not in Alzheimer's, Huntington's, or control brains, for [3H]benzquinoline. 902 94

D2 dopamine receptor antagonism is postulated to be the key to antipsychotic efficacy in the treatment of schizophrenia. Yet the D1 dopamine family of receptors is far more prevalent in the cortical areas of the brain, such as the prefrontal cortex, which have frequently been implicated in schizophrenia. Moreover, the prefrontal cortical D1 sites have recently been shown to be down-regulated by chronic treatment with several commonly used antipsychotic drugs (Lidow and Goldman-Rakic, 1994). To provide further insight into the pharmacological regulation of the D1 class of dopaminergic receptors, we have now used ribonuclease protection assays to examine the regulation of D1 and D5 dopamine receptor mRNAs in the prefrontal cortex and the neostriatum of nonhuman primates after chronic treatment with eight different drugs representing a wide structural and pharmacological spectrum of antipsychotic medications. The medications were administered for 6 months twice daily at doses that fall within the therapeutic range recommended for human patients. The study also included a substituted benzamide, tiapride, which is a D2 antagonist like the eight aforementioned drugs but reportedly lacks antipsychotic activity. Remarkably, all drugs used in this study, including tiapride, down-regulated the levels of both D1 and D5 mRNAs in the prefrontal cortex by 30% to 60% compared with a vehicle control group, whereas mRNAs in the neostriatum were not affected. This observation indicates that a reduction in the levels of prefrontal cortical dopamine receptors of the D1 class may be an obligatory consequence of D2 receptor antagonism and thus may be a pharmacological property of antipsychotic drugs.
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PMID:Down-regulation of the D1 and D5 dopamine receptors in the primate prefrontal cortex by chronic treatment with antipsychotic drugs. 910 49

In a previous study of 10 drug-naive schizophrenic patients, the density of D2 dopamine receptors was found to be elevated in the caudate nucleus. The study raised questions about the influence of the age of the patients, the relationship of receptor density to psychosis, and the accuracy of the method used to obtain this evidence. Using positron emission tomography and constrained analysis of the brain uptake of the radioligand N-[11C]methyl-spiperone ([11C]NMSP), we tested four questions: Were the assumptions underlying the quantitation valid? Is there an age decline of the density of D2-like dopamine receptors in drug-naive schizophrenia and bipolar illness? If so, is it different from that observed in normal aging? Are D2-like dopamine receptors elevated at any age in either drug-naive schizophrenic or psychotic bipolar illness patients? NMSP and haloperidol partition volumes and plasma protein fractions were not significantly different among patient groups and normal volunteers. The model-derived assay of radioligand metabolites in plasma was confirmed by high-performance liquid chromatography in the patient groups. D2-like dopamine receptors declined with age, and the slope did not differ significantly between the schizophrenic patients, bipolar affective illness patients, and normal controls. Taking the effect of age into account, increases in D2 dopamine receptor density were found in seven psychotic patients with bipolar affective illness compared with seven nonpsychotic patients and 24 control subjects as well as in 22 drug-naive schizophrenic patients compared with the 24 control subjects.
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PMID:Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness. 911 6

Schizophrenia is a serious and often debilitating neuropsychiatric disease of worldwide importance. Current therapy relies on the use of typical antipsychotic medications, which specifically inhibit binding of ligand at the D2 dopamine receptor, and atypical medications which display little activity for this receptor interaction. While atypical antipsychotic agents have been shown to variably inhibit other neuroreceptor-ligand interactions, the exact mechanisms for the therapeutic efficacy of these medications have not been completely defined. Clozapine, an atypical antipsychotic, and nine of its metabolites were studied in vitro for possible antiviral activity against a model of a human neurotropic virus, human immunodeficiency virus type 1 (HIV-1). In an assay for inhibition of virus-induced cytopathic effect (CPE) two metabolites demonstrated antiviral activity (ID50 = 37-85 micrograms/ml) (119-289 microM), while other atypical or novel antipsychotics as well as typical medications had no effect. Based on an ELISA, four chemically similar metabolites inhibited the production of p24, the major internal antigen of HIV (ID50 = 11.6-15.7 micrograms/ml) (38-51 microM). These data suggest that the therapeutic efficacy of some antipsychotics may be due in part to an ability to inhibit viral replication. Antiviral agents may prove to be effective adjuncts in the treatment of schizophrenia.
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PMID:Metabolites of the antipsychotic agent clozapine inhibit the replication of human immunodeficiency virus type 1. 917 28

Alcoholism is one of a group of common psychiatric diseases which are well-defined clinically and strongly influenced genetically, but which are likely to be highly heterogeneous in causation, genetically and otherwise. Dopamine is a key neurotransmitter in drug-mediated reinforcement. Based on association studies with the Taq1A downstream marker, the D2 dopamine receptor has been proposed to be the "Reward Deficiency Syndrome Gene." Ser311Cys, a naturally occurring variant which largely inactivates transduction after D2 receptor activation, was abundant (0.16) in a Southwestern American Indian population we studied. Therefore, we were able to provide a critical test of the D2 hypothesis of vulnerability to alcoholism by evaluating Ser311Cys and also the intron-2 STR and Taq1A markers at this locus in a total of 459 subjects, including 373 sib pairs, from large families. The result is that neither alcoholism, substance use disorders nor schizophrenia show a relationship to Ser311Cys genotype, even when the 15 Cys311/Cys311 homozygous individuals are compared to others. Furthermore, sib pair analysis incorporating information across all three sib pair categories: concordant affected, discordant and concordant unaffected revealed no effect of DRD2 genotype or haplotype on alcoholism or substance use disorder.
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PMID:Linkage and association of a functional DRD2 variant [Ser311Cys] and DRD2 markers to alcoholism, substance abuse and schizophrenia in Southwestern American Indians. 1049 Jul 20

There is considerable evidence for the involvement of brain dopaminergic and serotonergic systems in schizophrenia pathology. However, post-mortem studies have been limited by difficulties in separating the effects of chronic exposure to antipsychotics from that of the disease process. Our recent studies directly explored this by comparing groups that were free from antipsychotic treatment for up to a year prior to death and that were maintained on antipsychotics. We have used this approach to identify that there are prominent effects of both disease and of antipsychotic treatment. There appears to be a high association for schizophrenics between elevations of D3 receptors in target regions of the mesolimbic dopamine (DA) system and elevated numbers of 5-HT(1A) receptors in prefrontal cortex (PFc). Antipsychotic treatment was correlated with a reduction of D3 receptors in the ventral striatum and its output structures. It also led to a reduction in the number of 5-HT2 receptors in some regions of the PFc without modifying the concentration of 5-HT(1A) receptors. The limbic loop interconnecting the PFc and ventral striatum may be the site of antipsychotic regulation of certain symptoms in schizophrenia, particularly anhedonia and depression. The positive symptoms of schizophrenia are more likely to be associated with disturbances in the temporal lobe. However, dopaminergic systems in the temporal lobe have historically been thought to be underdeveloped compared to that in the basal ganglia and unlikely to be the target of antipsychotics. Our studies of the expression of the DA D2 receptor in the temporal lobe has shown a complex organization in the perirhinal and temporal cortices that is disrupted in schizophrenia. The disturbances, which might be of neurodevelopmental origin and are unrelated to antipsychotic treatment, include altered laminar distribution of the D2 receptor and modified modular organization of D2 receptors in the superior temporal gyrus. We hypothesize that modified expression of D2 receptors in these regions play a key role in the genesis of hallucinations. Treatment with antipsychotics leading to D2 receptor blockade in temporal cortex may reduce the presence of positive symptoms.
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PMID:Limbic circuits and monoamine receptors: dissecting the effects of antipsychotics from disease processes. 927 86

Recent studies have described a left lateralized striatal asymmetry of D2 dopamine receptors in male patients with schizophrenia. To replicate this finding and to explore its potential functional consequences, we investigated the D2 dopamine receptor system in 23 drug-naive patients with schizophrenia using single photon emission computed tomography (SPECT). Patients were examined in the drug-naive state and 72 h after completing a standardized neuroleptic treatment with benperidol (12-16 mg/day) for 25 days. Each SPECT examination comprised two scans: the first scan was taken 2 h after intravenous injection of 185 MBq [123I]iodobenzamide. After completion of the first scan, patients received benperidol (8 mg) intravenously. The second scan was started 20 min later. For analysis, basal ganglia to frontal cortex ratios were calculated. Fifteen of the 23 patients originally recruited completed the study on day 28. When compared to female patients, male patients showed a left lateralized asymmetry of striatal D2 dopamine receptor binding in the drug-naive state with an almost significant (P = 0.07) sex x hemisphere interaction. In the male patients, benperidol challenge led to a reversal of asymmetry patterns. These findings support previous reports of a left lateralized striatal D2 receptor binding in drug-naive male patients with schizophrenia and suggest that this asymmetry may affect the binding of conventional neuroleptics such as benperidol at the D2 dopamine receptor.
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PMID:Gender differences in D2 dopamine receptor binding in drug-naive patients with schizophrenia: an [123I]iodobenzamide single photon emission computed tomography study. 935 93

Dopaminergic axons in the prefrontal cortex synapse with interneurons as well as pyramidal cells. Electrophysiological data suggest that dopamine depolarizes certain gamma-aminobutyric acid (GABA)-containing interneurons in the cortex. We investigated the dopaminergic regulation of extracellular GABA levels in the prefrontal cortex using in vivo microdialysis. Systemic administration of the mixed D1/D2 dopamine receptor agonist apomorphine increased extracellular GABA levels in the prefrontal cortex, but did not increase levels of glycine; the apomorphine-elicited increase in GABA levels was blocked by tetrodotoxin infusion into the prefrontal cortex. Local administration of the D2 agonist quinpirole into the cortex via the dialysis probe resulted in a dose-dependent increase in extracellular GABA levels. In contrast, administration of the D1 agonist SKF 38393 did not alter GABA levels. The ability of systemic apomorphine to increase extracellular GABA levels in the prefrontal cortex was blocked by local administration of the D2-like antagonist sulpiride to the cortex, but was not attenuated significantly by local perfusion of the D1 antagonist SCH 23390. Similarly, the ability of local infusion of the D2 agonist quinpirole to enhance extracellular GABA levels was blocked by sulpiride but not by SCH 23390. These data suggest that dopamine agonists increase the release of GABA in the prefrontal cortex through a D2-like receptor. In view of posited changes in prefrontal cortical dopamine and GABA systems in schizophrenia, it is possible that changes in GABAergic function in the cortex in schizophrenia are secondary to changes in cortical dopamine function.
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PMID:Dopaminergic regulation of extracellular gamma-aminobutyric acid levels in the prefrontal cortex of the rat. 953 31


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