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)

On a group of 40 paranoid schizophrenic patients HLA serotypes for HLA--A, B, C antigens a significant increase of Cw4 was observed. It is argued that this finding represents the common denominator for previous data reporting increased A9 and A28 antigen in SCH because these antigens are frequently present on haplotypes bearing Cw4. The possible role of the HLA "central" parts, i.e. the chromosomal segment between HLA--A and HLA--B locus in the pathogenesis of schizophrenia was stressed.
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PMID:HLA--Cw4 in paranoid schizophrenia. 85 Sep 17

The mechanisms by which the atypical neuroleptic clozapine produces its therapeutic effects in the treatment of schizophrenia without causing the extrapyramidal side effects that are characteristic of most antipsychotic drugs remain unclear. Recently, a single injection of the typical antipsychotic haloperidol has been shown to increase c-fos expression in the striatum [Dragunow et al. (1990) Neuroscience 37, 287-294]. C-fos is a proto-oncogene that encodes a 55,000 mol. wt phosphoprotein, Fos, which is thought to assist in the regulation of "target genes" containing an AP-1 binding site. Because a wide variety of physiological and pharmacological stimuli increase c-fos expression, it has been proposed that Fos immunohistochemistry might be useful in mapping functional pathways in the central nervous system. The present experiments examined some potential neuroanatomical differences in the actions of clozapine and haloperidol by comparing their effects on c-fos expression in the medial prefrontal cortex, nucleus accumbens, striatum and lateral septum. The effects of the selective dopamine receptor antagonists SCH 23390 (D1) and raclopride (D2) were also examined. Haloperidol (0.5, 1 mg/kg) and raclopride (1, 2 mg/kg) produced large increases in the number of Fos-containing neurons in the striatum and nucleus accumbens. SCH 23390 (0.5, 1 mg/kg) reduced the number of Fos-positive neurons in the nucleus accumbens and striatum, and had no effect in the other regions. Neither haloperidol nor raclopride increased the number of Fos-positive neurons in the medial prefrontal cortex. Haloperidol, but not raclopride, produced a modest increase in c-fos expression in the lateral septal nucleus. Clozapine (10, 20 mg/kg) was without effect in the striatum; however, it significantly increased the number of Fos-positive neurons in the nucleus accumbens, medial prefrontal cortex and lateral septal nucleus. Destruction of mesotelencephalic dopaminergic neurons with 6-hydroxydopamine abolished the increase in Fos expression in the nucleus accumbens and striatum produced by haloperidol and raclopride, and also blocked the clozapine-induced increase in the nucleus accumbens. However, the inductive effects of clozapine and haloperidol on c-fos expression in the lateral septal nucleus and of clozapine in the medial prefrontal cortex were not affected by the 6-hydroxydopamine lesions. These results suggest that clozapine's unique therapeutic profile may be related to its failure to induce Fos in the striatum as well as its idiosyncratic actions in the lateral septum and medial prefrontal cortex. The effects of clozapine in these latter regions do not appear to be mediated by dopaminergic mechanisms.
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PMID:Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine. 134 6

The neurochemical properties of three novel benzazepine derivatives NNC-112, NNC-687 and NNC-756 were assessed. These compounds inhibited dopamine D1 receptor binding in vitro with low nanomolar to picomolar dissociation constants whereas those for the D2 receptor were in the micromolar range. Contrary to classical neuroleptics, but similar to the atypical neuroleptics, clozapine and fluperlapine, NNC-112, NNC-687 and NNC-756 were relatively more potent in inhibiting dopamine-stimulated adenylyl cyclase than [3H]SCH 23390 binding. Both NNC-112 and NNC-756 had high affinity for the 5-HT2 receptor whereas NNC-687 had low affinity for this receptor. The affinity for other receptors or neurotransmitter transporters was very low. In vivo, the dopamine D1 receptor selective profile of NNC-112, NNC-687 and NNC-756 was evident from the potent inhibition of D1 receptor binding whereas no effect on D2 receptor binding was apparent. In addition, the compounds blocked D1 receptor-mediated rotation in unilaterally 6-hydroxydopamine-lesioned rats, but had no effect on D2-induced rotation. Thus, NNC-112, NNC-687 and NNC-756 are potent and selective dopamine D1 receptor antagonists that may be useful in the treatment of schizophrenia.
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PMID:NNC-112, NNC-687 and NNC-756, new selective and highly potent dopamine D1 receptor antagonists. 139 49

Nicotine potentiates the catalepsy produced by haloperidol. Furthermore, nicotine as an adjunct to haloperidol produces a remarkable improvement in motor tics in Tourette's syndrome (TS) patients. The present experiments (1) compared the ability of nicotine to potentiate the catalepsy produced by haloperidol or the selective D1 dopamine receptor antagonist SCH 23390 and (2) examined the effects of various doses of nicotine (0.1, 0.2, or 0.3 mg/kg) on haloperidol-induced (0.1, 0.2, or 0.4 mg/kg) catalepsy and locomotor hypoactivity. In the first experiment, nicotine produced a five-fold increase in catalepsy following haloperidol but had no effect on the catalepsy produced by SCH 23390. In the second experiment, nicotine potentiated the cataleptic effects of both the 0.2 and 0.4 but not the 0.1 mg/kg dose of haloperidol. Haloperidol (0.1 and 0.4 mg/kg) also produced a dose-related decrease in locomotion that was significantly potentiated by nicotine (0.1 mg/kg). Nicotine alone did not produce catalepsy or any significant changes in locomotion. These results indicated that nicotine's potentiation of haloperidol-induced catalepsy is likely related to striatal D2 receptor mechanisms. Nicotine potentiated the locomotor effects of doses of haloperidol that were previously found to be subcataleptic, indicating that catalepsy testing may actually underestimate the behavioral interaction between haloperidol and nicotine. Nicotine may prove useful for treating neuroleptic responsive disorders such as TS, schizophrenia, and Huntington's disease.
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PMID:Nicotine potentiates the behavioral effects of haloperidol. 177 13

Previous work suggests that the dopamine agonist apomorphine decreases prepulse inhibition (PPI) of the acoustic startle response in rats. To better understand the dopamine substrates of this apomorphine response, we investigated the effects of four pharmacologically distinct dopamine antagonists on the apomorphine-induced loss of PPI. Apomorphine (0.5 mg/kg s.c.) markedly decreased PPI for all prepulse intervals tested. This effect of apomorphine on PPI was reversed by pretreatments with the D2 antagonists spiperone and raclopride but not by pretreatment with the D1 antagonist SCH 23390. The atypical antipsychotic clozapine exhibited an "inverted-U" shaped dose-response curve, reversing the apomorphine-induced loss of PPI at low doses but not at high doses. High doses of both SCH 23390 and clozapine decreased PPI independent of apomorphine treatment. The effects of apomorphine on baseline startle amplitude were also differentially modified by these drugs: apomorphine potentiated startle amplitude in spiperone- and raclopride-pretreated animals, but apomorphine decreased startle amplitude in animals pretreated with SCH 23390 or high doses of clozapine. Prepulse inhibition has been shown to be markedly impaired in humans with schizophrenia. Since our present findings suggest that the activation of D2 dopamine receptors is responsible for the loss of PPI in rats, overactivity of D2 dopamine receptors might also be a substrate for PPI deficits in schizophrenia.
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PMID:Effects of spiperone, raclopride, SCH 23390 and clozapine on apomorphine inhibition of sensorimotor gating of the startle response in the rat. 182 26

SCH 39166 [(-)-trans-6,7,7a,8,9, 13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]naphtho[2, 1b]azepine] has recently been described as a selective D1 antagonist and has entered clinical trials for the treatment of schizophrenia. The tritiated analogue of this compound, [3H]SCH 39166, has now been synthesized and characterized for its in vitro and in vivo binding profiles. [3H]SCH 39166 binds to D1 receptors in a saturable, high-affinity fashion, with a KD of 0.79 nM. In competition studies, D1-selective antagonists like SCH 23390 displaced the binding of [3H]SCH 39166 with nanomolar affinities, whereas antagonists of other receptors exhibited poor affinity. In vivo, [3H]SCH 39166 bound to receptors in rat striatum in a fashion suggestive of D1 selectivity. Further, when the time course for the binding of [3H]SCH 39166 was compared with the behavioral time course of the unlabeled compound, the two durations of action were virtually indistinguishable. Similar studies were performed for SCH 23390 and its tritiated analogue, but the in vivo binding of this radioligand exhibited a duration of action far greater than the behavioral activity of the unlabeled drug. In concert, these data demonstrate that [3H]SCH 39166 selectively labels D1 receptors in vitro and in vivo, and that this drug is superior for in vivo imaging of the D1 receptor.
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PMID:[3H]SCH 39166, a new D1-selective radioligand: in vitro and in vivo binding analyses. 183 1

Amphetamine is known to elicit stereotyped behavior in various species. For a long time, this effect was considered to be an animal model for the positive symptoms of schizophrenia. In addition, amphetamine is known to induce a strong social isolation in socially living monkeys. Both on symptomatologic and pharmacologic grounds, this amphetamine-induced social isolation has been suggested to represent an animal model for the negative symptoms of schizophrenia. To date no effective treatment has been found for these negative symptoms. We now report that the selective D1 dopamine antagonist SCH 23390 is very effective in antagonizing both the stereotyped behavior and the social isolation in Java monkeys induced by amphetamine. Moreover, SCH 23390 is able to reinstate normal behavior in these animals. These results may have important consequences for our understanding of the functional significance of the D1 receptor as well as for the clinical treatment of the positive and negative symptoms of schizophrenia.
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PMID:Are antagonists of dopamine D1 receptors drugs that attenuate both positive and negative symptoms of schizophrenia? A pilot study in Java monkeys. 257 39

Dopamine receptor types D1 and D2 can oppose or enhance each other's actions for electrical, biochemical, and psychomotor effects. We report a D1-D2 interaction in homogenized tissue as revealed by ligand binding. D2 agonists lowered the binding of [3H]raclopride to D2 receptors in striatal and anterior pituitary tissues. Pretreating the tissue with the D1-selective antagonist SCH 23390 prevented the agonist-induced decrease in [3H]raclopride binding to D2 sites in the striatum but not in the anterior pituitary, which has no D1 receptors. Conversely, a dopamine-induced reduction in the binding of [3H]SCH 23390 to D1 receptors could be prevented by the D2-selective antagonist eticlopride. Receptor photolabeling experiments confirmed both these D1-D2 interactions. The blocking effect by SCH 23390 was similar to that produced by a nonhydrolyzable guanine nucleotide analogue, and SCH 23390 reduced the number of agonist-labeled D2 receptors in the high-affinity state. Thus, the D1-D2 link may be mediated by guanine nucleotide-binding protein components. The link may underlie D1-D2 interactions influencing behavior, since the link was missing in over half the postmortem striata from patients with schizophrenia and Huntington disease (both diseases that show some hyperdopamine signs) but was present in human control, Alzheimer, and Parkinson striata.
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PMID:Link between D1 and D2 dopamine receptors is reduced in schizophrenia and Huntington diseased brain. 257 62

The technique of quantitative autoradiography was used to examine the effects of Huntington's disease (HD) and schizophrenia on the organization of striatal dopamine (DA) D1 and D2 receptors. Whereas the striatum of HD cases showed a reduction in the density of D1 ([3H]SCH 23390) and D2 ([3H]spiroperidol) receptors, the patterning of D2 receptor loss did not match that of the D1 receptor loss. The HD loss of D1 D1 receptors (65%) is far greater than the loss of D2 receptors (28%). Whereas there was a dorsal-ventral gradient of effect on both receptor subtypes, the effects of HD on D2 receptors in the ventral putamen (PUT) and nucleus accumben septi (NAS) were minimal. Similarly, muscarinic M1 and M2 receptors demonstrate different patterns of alteration in HD. The M2 subtype, labeled with [3H]N-methylscopolamine (in the presence of excess pirenzepine to occlude M1 sites), was depleted far more than the M1 receptor subtype, labeled with [3H]pirenzepine. Although the effects of HD on [3H]mazindol labeling of DA terminals were more heterogeneous, there appeared to be a relative preservation of this afferent input to the striatum of the HD cases. In the schizophrenic cases, our autoradiographic studies confirm previous reports of an elevation of D2 receptor density in the striata of many schizophrenics. This increase was evident even though two of the three cases were known to have not been treated with neuroleptics, and the third case may also have been drug naive. However, the increase was far greater in the NAS (164%) and ventral PUT (173%) than more dorsally in the striatum (68%). The density of D1 receptors and DA terminals labeled with [3H]mazindol in the striatum of schizophrenics was not significantly different from that of control cases. Thus in both HD and schizophrenia, the ratio of D2/D1 receptors is altered in favor of the D2 population, particularly in the NAS.
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PMID:Organization of dopamine D1 and D2 receptors in human striatum: receptor autoradiographic studies in Huntington's disease and schizophrenia. 297 47

Antipsychotic agents were tested for their ability to antagonize both dopaminergic-induced and non-competitive N-methyl-D-aspartate (NMDA) antagonist-induced behaviors. All of the agents dose-dependently antagonized the apomorphine-induced climbing mouse assay (CMA) and dizocilpine (MK-801)-induced locomotion and falling assay (MK-801-LF) with a CMA/MK-801-LF ratio of less than or equal to 1.6. However, clozapine and its structural analog olanzapine more potently antagonized MK-801-LF (1.1 and 0.05 mg/kg) than the CMA (12.3 and 0.45 mg/kg) and as a result had a CMA/MK-801-LF ratio of 11.2 and 9, respectively. Furthermore, phencyclidine (PCP) (2 mg/kg) can selectively induce social withdrawal in naive rats that were housed in pairs (familiar) for 10 days prior to testing without affecting motor activity. SCH 23390, raclopride, haloperidol, chlorpromazine and risperidone failed to reverse the social withdrawal induced by PCP up to doses which produced significant motor impairment. However, clozapine (2.5 and 5.0 mg/kg) and olanzapine (0.25 and 0.5 mg/kg) significantly reversed this social withdrawal in rats. Therefore, the non-competitive NMDA antagonists PCP and MK-801 can induce behaviors in Rodents which are selectively antagonized by clozapine and olanzapine. Furthermore, assessment of the effects of antipsychotic agents in the CMA, MK-801-LF and PCP-induced social withdrawal assays may provide a preclinical approach to identify novel agents for negative symptoms and treatment resistant schizophrenia.
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PMID:Antipsychotic agents antagonize non-competitive N-methyl-D-aspartate antagonist-induced behaviors. 748 May 37


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