UMLS:C0036341 - FACTA Search

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Understanding the action of atypical antipsychotics is useful in exploring the pathophysiology of schizophrenia and in synthesizing drugs that improve various domains of psychopathology without unwanted side effects. In animal models, atypical antipsychotic drugs appear to have a preferential action in the limbic dopaminergic system. Regionally specific action has been studied by measuring the amount of Fos protein produced in a particular brain region as a consequence of a drug's effects on the c-fos gene. Evidence suggests that the atypical and typical antipsychotic drug-induced increases in Fos levels in the nucleus accumbens are related to improvements in positive symptoms, whereas Fos increases in the prefrontal cortex, with the atypical antipsychotics only, correlate with negative symptom improvement. The extrapyramidal effects seen with typical antipsychotics are thought to be related to Fos increases in the striatonigral pathway. However, studies of Fos levels in specific brain regions reveal only the site of action, not the mode of action. The finding that atypicality is related to surmountable D2 dopamine receptor blocking provides another venue to define and explore atypical antipsychotic drug action.
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PMID:How do the atypical antipsychotics work? 1176 6

Administration of typical antipsychotic drugs (APDs) is often accompanied by extrapyramidal side-effects (EPS). Treatment with atypical APDs has a lower incidence of motor side-effects and atypical APDs are superior to typical APDs in treating the negative symptoms of schizophrenia. Although typical APDs strongly induce the immediate-early gene c-fos in the striatum while atypical APDs do so only weakly, it is possible that the effects of atypical APDs are more pronounced within certain regions of the striatum. The striatum contains two histochemically defined compartments, the striosome (patch) and the matrix. These compartments have been well characterized anatomically but their functional attributes are unclear. We therefore examined the effects of typical and atypical APDs on Fos expression in the striosome and matrix of the rat. Typical and atypical APDs were distinguished by the pattern of striatal compartmental activation they induced: the striosome : matrix ratio of Fos-li neurons was greater in rats treated with atypical APDs. Pretreating animals with selective antagonists of receptors that atypical APDs target with high affinity did not increase the striosome : matrix Fos ratio of typical APD-treated rats and thus did not mimic the ratio seen in response to atypical APDs. However, pretreatment with the atypical APD clozapine did recapitulate the characteristic compartmental Fos pattern seen in response to typical APDs. These data suggest that some characteristics of atypical APDs, such as the lower EPS liability and greater reduction of negative symptoms, may be linked to the coordinate regulation of the striatal striosome and matrix.
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PMID:Differential effects of typical and atypical antipsychotic drugs on striosome and matrix compartments of the striatum. 1188 51

Otsuka Pharmaceuticals in collaboration with Bristol-Myers Squibb is developing aripiprazole, a dual dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist, for the potential treatment of psychoses including schizophrenia [281327], [340364]. A regulatory filing for schizophrenia in the US was submitted at the end of 2001 [340364]. The compound entered phase III trials in Japan in 1995 [192966]. Although presynaptic dopamine autoreceptor agonists may be efficacious in the treatment of schizophrenia, they may also potentially increase the risk for exacerbation of psychosis through stimulation of postsynaptic dopaminergic receptors [245791], [350478], [350479]. However, earlier neuropharmacology studies have shown that aripiprazole can act as a presynaptic D2 agonist while displaying an antagonistic effect at the postsynaptic D2 receptors [281327], [337126], [350479], [424587], [424588]. In animal models, aripiprazole inhibits the apomorphine-induced stereotypy, without causing catalepsy [281327], [337126]. Moreover, in contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in expression of the c-fos mRNA in the striatum, in agreement with the low risk for extrapyramidal side effects (EPS) during aripiprazole treatment [245781], [262096], [350481], [350483]. Collectively, aripiprazole is an important atypical antipsychotic candidate with a favorable safety profile. Moreover, the mechanism of action of aripiprazole differentiates it from both typical and atypical antipsychotics and hence, may provide important leads for pharmacotherapy of schizophrenia and other psychotic disorders. In January 2000, Lehman Brothers predicted peak sales of aripiprazole could reach US $500 million [357788]. In February 2001, Credit Suisse First Boston predicted sales of US $403 million in 2005 [399484].
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PMID:Aripiprazole (Otsuka Pharmaceutical Co). 1205 61

Both human schizophrenia and the effects of isolation rearing in rats produce deficits in hippocampal and cortical functioning. This study was concerned with identifying changes associated with altered neuronal function in the rat hippocampus following isolation rearing. Rats were isolated from weaning at 21 days postnatal for 6 weeks and the hippocampal sensitivity to isolation rearing and stress were studied using c-fos immunohistochemistry and in vivo microdialysis. Isolation rearing altered neuronal activity measured by Fos-like immunoreactivity in the specific brain areas as measured by either increased or reduced expression. Basal neuronal activity in the ventral CA1 hippocampus in isolation-reared rats was notably higher compared to group-reared rats but markedly lower Fos-like immunoreactivity was found in the central and basolateral nuclei of the amygdala. Exposure to stress produced differential effects on neuronal activity in isolation-reared rats between the dorsal and ventral hippocampus, with increased Fos-like immunoreactivity in the dorsal hippocampus but lower Fos-like immunoreactivity in the ventral hippocampus compared to group-reared rats. These results indicate that isolation rearing may alter the relationship between hippocampal neuronal function in the dorsal and ventral hippocampus. An in vivo microdialysis study showed that systemically administered parachloroamphetamine (2.5 mg/kg, i.p.) enhanced extracellular 5-hydroxytryptamine (5-HT) in the dorsal hippocampus in group-reared but not in isolation-reared rats. Restraint stress had no effect on hippocampal extracellular 5-HT in group-reared rats but reduced levels in isolation-reared rats during the period of restraint. Inescapable mild footshock produced a marked increase in extracellular hippocampal 5-HT in group-reared but not isolation-reared rats. Overall the results provide extensive evidence that isolation rearing alters presynaptic 5-HT hippocampal function and that the neuronal response to stress is altered by isolation. Isolation rearing in the rat alters hippocampal function, including the serotonergic system, leading to changes in neurotransmitter systems in other brain areas. These changes may model aspects of human neurodevelopmental disorders such as schizophrenia.
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PMID:Isolation rearing in the rat disrupts the hippocampal response to stress. 1207 11

Sydnocarb [(phenylisopropyl)N-phenylcarbamoylsydnonimine; SYD] was introduced to clinical practice in Russia as a psychostimulant drug used for the treatment of asthenia and apathy, which accompany schizophrenia and manic depression. It has been described as a psychostimulant with addiction liability and toxicity less than amphetamine (AMPH). The precise cellular mechanisms by which sydnocarb elicits its psychostimulant effect are still unclear. At present its neurochemical and neurotoxic effects are compared to those of AMPH in the striatum, the main input structure of the basal ganglia. The expression of c-fos protein in striatal neurons was much more increased after a single injection of D-AMPH (5 mg/kg) than after an equimolar concentration of SYD (23.8 mg/kg) in both the anterior and the posterior part of the striatum. Using in situ hybridization on striatal slices, we observed that AMPH increased the striatal levels of preprodynorphin (PPDYN) mRNAs in both parts of the striatum, while SYD did not affect basal levels of PPDYN mRNAs. Furthermore, AMPH and SYD increased striatal preprotachykinin (PPT-A) and preproenkephalin (PPE) mRNA levels. The effects of AMPH and SYD on PPT-A-mRNA levels were similar. A differential effect of AMPH and SYD was observed only on the PPE-mRNA levels measured in the anterior striatum where SYD increased these levels more than AMPH. The acute neurotoxicity of these two psychostimulants was analyzed by measuring their effects on the parameters of oxidative stress, such as nitric oxide (NO) generation, as well as specific indices of lipid peroxidation (i.e., thiobarbituric acid reactive substances; TBARS), while, on the other hand, the alpha-tocopherol level was taken as an index of antioxidant defense processes. Measuring generation of NO directly by electron paramagnetic resonance, it was observed that AMPH shows a more pronounced increase in comparison to SYD, in the striatum and in cortex. TBARS levels in the striatum and cortex were significantly less enhanced than AMPH after a single injection of SYD. Similarly, the alpha-tocopherol level was decreased only by AMPH in the striatum, and neither AMPH nor SYD had any effect in the cortex. Results show that a single injection of a high dose of AMPH is able to induce several neurotoxic effects. The study also demonstrates that SYD has mild neurochemical effects as well as fewer neurotoxic properties than AMPH.
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PMID:Neurochemical changes and neurotoxic effects of an acute treatment with sydnocarb, a novel psychostimulant: comparison with D-amphetamine. 1210 94

By using double in situ hybridization performed with proenkephalin and H3-receptor riboprobes on the same sections from rat brain, we show that histamine H3 receptors are expressed within striatopallidal neurons of the indirect movement pathway. The majority ( approximately 70%) of striatal enkephalin neurons express H3-receptor mRNAs. This important degree of coexpression of proenkephalin and H3-receptor mRNAs prompted us to explore the effect of H3-receptor ligands on the regulation of enkephalin mRNA expression in the striatum. Acute administration of ciproxifan, a H3-receptor antagonist/inverse agonist, did not modify the expression of the neuropeptide by itself but strongly increased the upregulation of its expression induced by haloperidol. This potentiation (1) was suppressed by the administration of (R)-alpha-methylhistamine, a H3-receptor agonist, (2) occurred both in the caudate-putamen and nucleus accumbens, and (3) was also observed with a similar pattern on c-fos and neurotensin mRNA expression. Similarly, whereas it was devoid of any motor effect when used alone, ciproxifan strongly potentiated haloperidol-induced locomotor hypoactivity and catalepsy, two behaviors in which striatal neurons are involved. The strong H3-receptor mRNA expression in enkephalin neurons suggests that the synergistic neurochemical and motor effects of ciproxifan and haloperidol result from direct H3/D2-receptor interactions, leading to an enhanced activation of striatopallidal neurons of the indirect movement pathway. The potentiation of the effects of haloperidol by ciproxifan strengthens the potential interest of H3-receptor antagonists/inverse agonists to improve the symptomatic treatment of schizophrenia.
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PMID:Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat. 1217 22

Atypical antipsychotic drugs, such as clozapine, show many differences in their actions as compared to typical antipsychotic drugs, such as haloperidol. In particular, the neuroanatomical substrates responsible for the superior therapeutic profile of clozapine are unknown. In order to identify regions of the CNS which are affected either differentially or in parallel by clozapine and haloperidol, we have used 2-deoxyglucose autoradiography to monitor local cerebral glucose utilisation (LCGU), in parallel with in situ hybridisation to monitor the expression of five immediate-early genes (c-fos, fos B, fra 1, fra 2 and zif 268). Clozapine (20 mg/kg i.p.) caused a reduction in LCGU in many areas of the psychosis-related corticolimbothalamic and Papez circuits, such as the anterior cingulate and retrosplenial cortices and the mammillary body. Haloperidol (1 mg/kg i.p.) showed less ability to modulate LCGU in these regions. Clozapine also increased immediate-early gene expression in these limbic circuits, although the pattern of induction was different for each gene, and also differed from the pattern of effects on LCGU. The only region which displayed similar effects with both antipsychotics was the anteroventral thalamus, with LCGU and c-fos mRNA expression being altered similarly by both drugs. This further supports the hypothesis of the thalamus being a common site of antipsychotic action. Since the Papez circuit has been implicated in emotive learning, and to be involved in mediating the negative symptoms associated with schizophrenia, the greater action of clozapine on regions within this circuit may also provide clues to the atypical antipsychotic's superior efficacy against negative symptoms. This is one of the first studies which provides a direct comparison of regional activity as assessed by LCGU and by a panel of IEGs. The results emphasise the necessity of monitoring a number of different parameters of regional activity in order to identity the neuroanatomical substrate for actions of a drug in the CNS.
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PMID:Induction of differential patterns of local cerebral glucose metabolism and immediate-early genes by acute clozapine and haloperidol. 1224 69

N-methyl-D-aspartate receptor hypofunction has been suggested to play a role in the pathophysiology of schizophrenia. New glutamatergic mechanisms involving metabotropic receptors have been recently proposed to further expand this hypothesis. "Homer" is a family of postsynaptic density proteins functionally and physically attached to glutamate metabotropic receptors. We investigated the activation of the early gene form of Homer after acute treatment with typical or atypical antipsychotic drugs alone or with the adjunction of D-cycloserine. This activation was compared with that of c-fos, considered a putative molecular marker of brain regions activated by antipsychotics. Male Sprague-Dawley rats were treated intraperitoneally with haloperidol (0.8 mg/Kg) or clozapine (15 mg/Kg) alone or with the adjunction of D-cycloserine (20 mg/Kg). Rats were sacrificed ninety minutes after injection and the brains were processed for quantitative in situ hybridization histochemistry. Haloperidol induced a statistically significant increase of Homer both in caudate-putamen and nucleus accumbens compared with controls; clozapine induced Homer significantly only in the accumbens. The adjunction of D-cycloserine attenuated the haloperidol-induced increase of Homer expression in caudate-putamen and nucleus accumbens and attenuated the clozapine-induced increase in the accumbens. The c-fos gene expression was potently induced by haloperidol in caudate-putamen and nucleus accumbens, and by clozapine only in the accumbens. The adjunction of D-cycloserine enhanced c-fos expression only for clozapine in both regions of the forebrain. These results demonstrate a differential involvement of glutamatergic metabotropic system in gene expression modulation induced by typical or atypical antipsychotic drugs and may suggest new molecular basis for the augmentation strategy by a glycine site partial agonist.
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PMID:Homer 1a gene expression modulation by antipsychotic drugs: involvement of the glutamate metabotropic system and effects of D-cycloserine. 1246 47

In the cerebellar vermis of schizophrenic patients, our previous studies have revealed alterations in the mitogen-activated protein (MAP) kinase signaling cascade and downstream transcription factors within the c-fos promoter. Since the proteins of the Fos and Jun families of immediate-early genes dimerize to form activating protein (AP)-1, the present study was conducted to examine the expression of Jun transcription factors in schizophrenic and control subjects. Using Western blot analysis, we determined the protein levels of c-Jun, Jun B, and Jun D as well as the levels of c-jun mRNA by relative RT-PCR in post-mortem samples from cerebellar vermis. The expression of c-Jun protein and c-jun mRNA was significantly increased in the cerebellar vermis of patients with schizophrenia, whereas no significant differences were found in the expression of Jun B or Jun D proteins. Studies in rats indicated that the abnormal expression of c-Jun transcription factor observed in schizophrenic patients was not related to post-mortem intervals or chronic treatment with antipsychotic medications. This study provides new insights into cerebellar abnormalities of schizophrenia at the level of expression of c-Jun that target key genes associated with the MAP kinase cascade.
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PMID:Increased expression of c-Jun transcription factor in cerebellar vermis of patients with schizophrenia. 1279 14

Lesions of the entorhinal cortex are now an accepted model for mimicking some of the neuropathological aspects of schizophrenia, since evidence has accumulated for the presence of cytoarchitectonic abnormalities within this cortex in schizophrenic patients. The present study was undertaken to address the functional consequences of bilateral entorhinal cortex lesions on antipsychotic-induced c-fos expression. After a 15-day recovery period, the effect of a typical antipsychotic, haloperidol (1 mg/kg), on c-fos mRNA expression was compared with that of an atypical one, olanzapine (10 mg/kg), in both sham-lesioned and entorhinal cortex-lesioned rats. In sham-lesioned rats, both haloperidol and olanzapine induced c-fos expression in the caudal cingulate cortex, dorsomedial and dorsolateral caudate-putamen, nucleus accumbens core and shell and lateral septum. In addition, olanzapine, but not haloperidol, increased c-fos expression within the central amygdala. In entorhinal cortex-lesioned rats, haloperidol-induced c-fos expression was markedly reduced in most areas. In contrast, the olanzapine-induced c-fos expression was not altered in the nucleus accumbens shell and lateral septum of the lesioned rats. These findings reveal that entorhinal cortex lesions affect c-fos expression in a compound- and regional-dependent manner. Our results further emphasize the importance of the exploration of the mechanisms of action of antipsychotic drugs in the context of an associated cortical pathology.
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PMID:Bilateral lesions of the entorhinal cortex differentially modify haloperidol- and olanzapine-induced c-fos mRNA expression in the rat forebrain. 1284 25

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