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)

The mechanism by which stimulation of somatodendritic and/or postsynaptic 5-hydroxytryptamine (5-HT, serotonin)-1A receptor could attenuate acute Parkinsonian-like effects of typical antipsychotics is investigated by comparing the anticataleptic and neurochemical effects of 8-hydroxy-2-di-n-propylaminotetralin (8-OH-DPAT) and buspirone in rats injected with haloperidol. Cataleptic effects of a submaximal dose (1 mg/kg) of haloperidol were attenuated more by prior administration of 8-OH-DPAT (0.25 mg/kg) than buspirone (1 mg/kg). Striatal 5-HT metabolism decreased more in buspirone- than 8-OH-DPAT-injected animals. Administration of haloperidol did not alter 5-HT metabolism in saline-, 8-OH-DPAT- or buspirone-injected animals. Dopamine decreased and its metabolite homovanillic acid (HVA) increased in the striatum of rats injected with buspirone. Effects of 8-OH-DPAT on dopamine metabolism were not significant. Haloperidol-induced increases of dopamine metabolites were attenuated by prior administration of 8-OH-DPAT, but not buspirone. The mechanism by which stimulation of somatodendritic as well as postsynaptic 5-HT-1A receptors could attenuate haloperidol-induced catalepsy is discussed. The findings have potential implications in the treatment of schizophrenia and motor behavior.
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PMID:Somatodendritic and postsynaptic serotonin-1A receptors in the attenuation of haloperidol-induced catalepsy. 1558 59

Since H3 receptor (H3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on therapy in the treatment of schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of haloperidol-induced catalepsy by ciproxifan, an imidazole-containing H3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M., Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat, J Neurosci, 22 (2002) 7272-80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another imidazole and two non-imidazole H3R antagonists. The results indicate that ciproxifan significantly augmented the effects of haloperidol and risperidone on catalepsy. Another imidazole H3R antagonist, thioperamide, also potentiated the effect of risperidone on catalepsy. In contrast, no catalepsy-enhancing effects were observed when selective non-imidazole H3R antagonists, ABT-239 and A-431404, were coadministered with haloperidol and/or risperidone. As ciproxifan and thioperamide are inhibitors of cytochrome P450 enzymes, responsible for metabolizing risperidone and haloperidol, the possibility that the augmentation of antipsychotics by imidazoles resulted from drug-drug interactions was tested. A drug metabolism study revealed that an imidazole, but not a non-imidazole, potently inhibited the metabolism of haloperidol and risperidone. Furthermore, ketoconazole, an imidazole-based CYP 3A4 inhibitor, significantly augmented risperidone-induced catalepsy. Together, these data suggest the potentiation of antipsychotic-induced catalepsy may result from pharmacokinetic drug-drug interactions and support the potential utility of non-imidazole H3R antagonists in treatment of cognitive impairment in schizophrenia without increased risk of increased EPS in patients.
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PMID:Lack of cataleptogenic potentiation with non-imidazole H3 receptor antagonists reveals potential drug-drug interactions between imidazole-based H3 receptor antagonists and antipsychotic drugs. 1591 Jul 72

Knoll is developing belaperidone, an antipsychotic agent, as a potential new treatment for schizophrenia. Phase II trials have commenced in Germany [200089,333710]. The compound is regarded as an atypical antipsychotic, similar in profile to clozapine, with potential to help patients whose illness has become difficult or impossible to treat. In rats, cumulative doses of belaperidone (0.128 to 32.768 mg/kg) reversed inhibition of the firing rate in the substantia nigra dopaminergic neurons induced by iv quinpirole. The ED50 value for the inhibition was 1.66 mg/kg, which is twice as potent as clozapine and 40-fold less potent than haloperidol. The drug did not produce catalepsy [346021]. In addition to possessing high affinity for 5-HT2 receptors (Ki = 3.3 nM), belaperidone selectively antagonizes the dopamine D4 (Ki = 3.1 nM) receptor, in preference to the D2 (Ki = 105 nM) subtype [247874]. It also has very low muscarinic affinity (Ki > 200 nM) [289024], [333710].
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PMID:Belaperidone (Knoll AG). 1610 43

FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene] is a potential novel antipsychotic with high affinity for dopamine D2 (Ki= 6.3 nM), 5-HT(2A) (Ki= 7.3 nM), and 5-HT6 (Ki= 8.0 nM) human recombinant receptors and lower affinity for histamine H1 (Ki= 30 nM) and 5-HT2C (Ki= 102 nM) human recombinant receptors than olanzapine. Oral administration of FMPD increased rat nucleus accumbens 3,4-dihyroxyphenylacetic acid concentrations (ED200 = 6 mg/kg), blocked 5-HT2A agonist-induced increases in rat serum corticosterone levels (ED50= 1.8 mg/kg), and inhibited the ex vivo binding of [125I]SB-258585 [4-iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide] to striatal 5-HT6 receptors (ED50= 10 mg/kg) but failed to inhibit ex vivo binding of [3H]pyrilamine to hypothalamic histamine H1 receptors at doses of up to 30 mg/kg. In electrophysiology studies, acute administration of FMPD selectively elevated the number of spontaneously active A10 (versus A9) dopamine neurons and chronic administration selectively decreased the number of spontaneously active A10 (versus A9) dopamine neurons. FMPD did not produce catalepsy at doses lower than 25 mg/kg p.o. In Fos-induction studies, FMPD had an atypical antipsychotic profile in the striatum and nucleus accumbens and increased Fos expression in orexin-containing neurons of the hypothalamus. FMPD produced only a transient elevation of prolactin levels. These data indicate that FMPD is an orally available potent antagonist of dopamine D2, 5-HT2A, and 5-HT6 receptors and a weak antagonist of H1 and 5-HT2C receptors. FMPD has the potential to have efficacy in treating schizophrenia and bipolar mania with a low risk of treatment-emergent extrapyramidal symptoms, prolactin elevation, and weight gain. Clinical trials are needed to test these hypotheses.
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PMID:Preclinical pharmacology of FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: a potential novel antipsychotic with lower histamine H1 receptor affinity than olanzapine. 1614 69

Recent clinical studies have shown that the anticonvulsant drug topiramate may improve negative symptoms in schizophrenia when added to a stable regimen of neuroleptic medication. It has also been shown that addition of topiramate to neuroleptics might be beneficial in treatment-resistant schizophrenia. Clinically effective doses of antipsychotic drugs (APDs) have been found to suppress conditioned avoidance response behavior (CAR), a preclinical test of antipsychotic activity with high predictive validity, in rats. Therefore, we investigated the putative antipsychotic-like activity of topiramate when added to the selective dopamine (DA) D2 receptor antagonist raclopride, using the CAR model in the rat. Extrapyramidal side effect liability of the drug combination was evaluated in parallel by means of the catalepsy test. We also examined the effect of this drug treatment on DA release in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis in freely moving animals. Topiramate (40 mg/kg), while ineffective when given alone, significantly augmented the antipsychotic-like effect of raclopride (0.075 mg/kg) on CAR without any concomitant catalepsy. Addition of topiramate to rats treated with raclopride generated a large increase in DA output in the mPFC, whereas no additional effect on the raclopride-induced DA release in the NAC was obtained. These data support the adjunctive use of topiramate in schizophrenia to ameliorate negative symptoms and suggest that this treatment may increase the efficacy, but not the extrapyramidal side effect liability, of the APDs used.
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PMID:Topiramate augments the antipsychotic-like effect and cortical dopamine output of raclopride. 1628 83

A 21-year-old female presented excitement, auditory hallucination, monologue, and insomnia. After 1 week of risperidone administration, she showed hyperthermia, salivation, and muscle rigidity. Risperidone was discontinued, but stupor, convulsions, and respiratory distress developed. In the intensive care unit where she was transferred, catatonic symptoms such as stupor or excitement, catalepsy, and negativism were prominent. In addition, severe bronchorrhea causing respiratory failure was observed. Her catatonic symptoms, hyperthermia, and bronchorrhea resolved by ECT. After recovery, affective flattening, alogia, and avolition remained. The final diagnosis was MC associated with schizophrenia. This report suggests that MC may be complicated by severe bronchorrhea, but this condition responds to ECT.
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PMID:Malignant catatonia with severe bronchorrhea and its response to electroconvulsive therapy. 1667 86

Development of antipsychotics with slight/no extra-pyramidal symptoms (EPS) and/or other side effects is one of the exploring fields of drug research. Haloperidol is a high potency typical neuroleptic used in the treatment of schizophrenia but produces muscles related side effects commonly known as EPS. These effects are not produced following the administration of atypical neuroleptics such as clozapine. A severe side effect of clozapine treatment is however, agranulocytosis. This involves investigation on the mechanism by which a typical neuroleptic acting via serotonergic mechanism tends to produce less or no EPS. The present study was, therefore, designed to determine the effect of serotonin precursor tryptophan and a large neutral amino acid other than tryptophan (valine) on the modulation of haloperidol induced catalepsy and akinesia. Cataleptic effects of the drug and activity reducing effects were monitored on inclined surface and in an activity box or open field respectively. The results are discussed in the context of a role of tryptophan and valine induced changes of brain serotonin in modifying the extrapyramidal and monoaminergic effects of the typical neuroleptic haloperidol. In the present study administration of TRP and valine decreased activity in rats, haloperidol-induced catalepsy' was not modulated by prior administration of tryptophan or valine. Brain serotonin levels were elevated by haloperidol treatment and correlated very well with the behavioral response. These findings suggest a possible serotonergic involvement in neuroleptic induced tardive dyskinesia and an amelioration of the disorder through TRP supplementation.
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PMID:Effects of tryptophan and valine administration on behavioral pharmacology of haloperidol. 1643 94

The therapeutic properties of typical antipsychotic drugs (APDs) such as haloperidol in schizophrenia treatment are mainly associated with their ability to block dopamine D2 receptors. This blockade is accompanied by side effects such as extrapyramidal symptoms (EPS). Atypical APDs such as risperidone have superior therapeutic efficacy possibly due to their activity at multiple receptors (in particular 5-HT2A receptors). Although the risk of EPS is significantly lower in atypical than in typical APDs, it is not negligible. To investigate and compare the behavioural profile and EPS-asssociated side effects of haloperidol and risperidone APD treatment we applied a multi-tiered, comprehensive behavioural phenotyping approach. Sprague-Dawley rats were treated chronically (28 days) with supratherapeutic EPS-inducing doses of haloperidol and risperidone using osmotic minipumps. Domains such as motor activity, exploration, memory, and anxiety were analysed together with EPS assessment ("early onset" vacuous chewing movements and catalepsy). Both APDs produced diminished motor activity and exploration, impaired working memory performances, and increased anxiety levels. These effects were more pronounced in haloperidol-treated animals. Chronic APD treatment also caused a time-course dependent elevation of EPS-like symptoms. Risperidone-treated animals showed a catalepsy-like phenotype, which differed to that of haloperidol-treated rats, indicating that processes other than the anticipated dopaminergic mechanisms are underlying this phenomenon. These EPS-related phenotypes are consistent with reported EPS-inducing D2 receptor occupancies of around 80%. Differences in the behavioural profile of haloperidol and risperidone, which were revealed by a comprehensive phenotyping strategy, are likely due to the unique receptor activation profiles of these APDs.
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PMID:Behavioural effects of chronic haloperidol and risperidone treatment in rats. 1669 60

Adjunctive treatment with the selective alpha2 adrenoceptor antagonist idazoxan augments the effect of conventional antipsychotics in treatment-resistant schizophrenics comparing favourably with clozapine. Clozapine has high affinity for alpha2 adrenoceptors. Previously, we found that adjunctive idazoxan treatment to the dopamine (DA) D2/3 antagonist raclopride enhanced raclopride-induced effects in an animal model of antipsychotic activity (conditioned avoidance response, CAR) and, similarly to clozapine, reversed the disruption of working memory induced by N-methyl-D-aspartate receptor blockade in rats with a concomitant increase in prefrontal DA efflux. To further investigate the significance of alpha2 adrenoceptor affinity for antipsychotic efficacy, we here investigated, in rats, the effects of adjunctive idazoxan treatment to low doses of a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug, both lacking appreciable alpha2 adrenoceptor affinity, on (i) CAR; (ii) catalepsy; and (iii) DA output in the prefrontal cortex and the nucleus accumbens using microdialysis. Adjunctive treatment with idazoxan to haloperidol or olanzapine enhanced suppression of CAR to a level predicting sufficient antipsychotic activity, increased DA output preferentially in the prefrontal cortex, and reversed haloperidol-induced catalepsy. Our data confirm and extend our previous findings as well as clinical observations, and suggest that adjunctive alpha2 adrenoceptor blockade both typical and atypical antipsychotic drugs, lacking appreciable affinity for the alpha2 adrenoceptor, may contribute to a more advantageous therapeutical profile of these drugs in schizophrenia treatment, allowing for reduced DA D2 occupancy and reduction of unwanted side-effects.
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PMID:Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive alpha2 adrenoceptor blockade: experimental evidence. 1670 32

Experimental and clinical evidence points to a role of central histaminergic system in the pathogenesis of schizophrenia. The present study was designed to study the effect of histamine H(3)-receptor ligands on neuroleptic-induced catalepsy, apomorphine-induced climbing behavior and amphetamine-induced locomotor activities in mice. Catalepsy was induced by haloperidol (2 mg/kg p.o.), while apomorphine (1.5 mg/kg s.c.) and amphetamine (2 mg/kg s.c.) were used for studying climbing behavior and locomotor activities, respectively. (R)-alpha-methylhistamine (RAMH) (5 microg i.c.v.) and thioperamide (THP) (15 mg/kg i.p.), per se did not cause catalepsy. Administration of THP (3.75, 7.5 and 15 mg/kg i.p.) 1 h prior to haloperidol resulted in a dose-dependent increase in the catalepsy times (P < 0.05). However, pretreatment with RAMH significantly reversed such an effect of THP (15 mg/kg i.p.). RAMH per se showed significant reduction in locomotor time, distance traveled and average speed but THP (15 mg/kg i.p.) per se had no effect on these parameters. On amphetamine-induced hyperactivity, THP (3.75 and 7.5 mg/kg i.p.) reduced locomotor time, distance traveled and average speed (P < 0.05). Pretreatment with RAMH (5 microg i.c.v.) could partially reverse such effects of THP (3.75 mg/kg i.p.). Climbing behavior induced by apomorphine was reduced in animals treated with THP. Such an effect was, however, reversed in presence of RAMH. THP exhibited an antipsychotic-like profile by potentiating haloperidol-induced catalepsy, reducing amphetamine-induced hyperactivity and reducing apomorphine-induced climbing in mice. Such effects of THP were reversed by RAMH indicating the involvement of histamine H(3)-receptors. Findings suggest a potential for H(3)-receptor antagonists in improving the refractory cases of schizophrenia.
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PMID:Antipsychotic-like profile of thioperamide, a selective H3-receptor antagonist in mice. 1686 21


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