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

Sympathetic neural outflow to thermoregulatory cutaneous vascular beds is selectively activated when the individual is aroused, so that cutaneous blood flow is characterized by sudden alerting-related falls to near zero levels ("SCVARs", sympathetic cutaneous vasomotor alerting responses). Our previous work shows that clozapine, an atypical antipsychotic drug used in schizophrenia, profoundly inhibits SCVARs. Clozapine, conventionally assumed to have a dopamine D(2) receptor antagonist action, also increases baseline cutaneous blood flow and lowers body temperature. However dopamine D(2) receptor agonists lower temperature, suggesting that a dopamine D(2)agonist action might also reduce SCVARs. The present study determined whether a dopamine D(2)agonist action contributes to clozapine's SCVAR-inhibiting effect. SCVARs were measured in conscious rats with a Doppler ultrasonic flow probe chronically implanted around the base of the artery, with probe wires passing subcutaneously to a headpiece. Doppler signals were monitored via a flexible connection between the headpiece and a swivel device in the roof of the cage. Apomorphine (0.1-0.5 mg/kg), quinpirole (0.05-0.25 mg/kg) and 7-OH-DPAT (0.02-0.5 mg/kg) dose-dependently reduced SCVARs. Pre-treatment with the dopamine receptor antagonist spiperone (20 microg/kg) but not the D(1) antagonist SCH-23390 or the peripheral dopamine D(2) antagonist domperidone, abolished this effect. Spiperone pre-treatment reduced the SCVAR-inhibiting action of clozapine (0.06-1.0 mg/kg). Chlorpromazine (0.1-10 mg/kg) also dose-dependently inhibited SCVARs, but this effect was not reduced by pre-treatment with spiperone. Mechanisms underlying clozapine's SCVAR-inhibiting effect include dopamine D(2) receptor agonism, not dopamine D(2) receptor antagonism, calling into question the mechanism of the drug's therapeutic action in schizophrenia.
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PMID:Activation of dopamine D2 receptors in the CNS inhibits sympathetic cutaneous vasomotor alerting responses (SCVARs), contributing to clozapine's SCVAR-inhibiting action. 1705 39

Schizophrenia is characterized by attentional deficits possibly associated with glutamate dysfunction. The role of postsynaptic metabotropic glutamate 5 receptors (mGluR5) or presynaptic inhibitory mGluR2/3 on attention is currently unknown. We investigated the effects of the mGluR5 antagonist MPEP (2-methyl-6[phenylethynyl]-pyridine) and the mGluR2/3 antagonist LY341495 on attention in the 5-choice serial reaction time task (5CSRTT), as well as on food intake to evaluate their effects on food motivation. The effects of pre-feeding and the muscle relaxant curare were examined to characterize the effects of alterations in the motivation or ability to perform the task, respectively. MPEP had no effect on accuracy but overall decreased performance in the 5CSRTT, including decreased speed of responding and decreased premature responses. LY341495 had no significant effect on rats' performance in the 5CSRTT. LY341495 decreased food intake in the home cage to a greater extent than MPEP. Curare decreased the speed of correct responding, reflecting motor impairment. Free feeding decreased overall performance, number of trials completed and number of head entries into the feeder, reflecting decreased motivation to perform the task. Thus, blockade of mGluR5, but not mGluR2/3, decreased overall responding without affecting accuracy in the 5CSRTT.
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PMID:The effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on rats' performance in the 5-choice serial reaction time task. 1712 59

There is growing evidence implicating dysfunctional glutamatergic neurotransmission and abnormal interactions between the glutamate and dopamine (DA) systems in the pathophysiology of various neuropsychiatric disorders including schizophrenia. The present study evaluated knockout (KO) mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) GluR1 receptor subunit for a range of behaviors considered relevant to certain symptoms of schizophrenia. KO showed locomotor hyperactivity during exposure to open field and in response to a novel object, but normal activity in a familiar home cage. Open field locomotor hyperactivity in KO was effectively normalized to WT levels by treatment with the DA antagonist and neuroleptic haloperidol, while locomotor stimulant effects of the NMDA receptor antagonist MK-801 were absent in KO. Social behaviors during a dyadic conspecific encounter were disorganized in KO. KO showed deficits in prepulse inhibition of the acoustic startle response. In vivo chronoamperometric measurement of extracellular DA clearance in striatum demonstrated retarded clearance in KO. These data demonstrate behavioral abnormalities potentially pertinent to schizophrenia in GluR1 KO, together with evidence of dysregulated DA function. Present findings provide novel insight into the potential role of GluR1, AMPA receptors and glutamate x DA interactions in the pathophysiology of schizophrenia and other neuropsychiatric conditions.
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PMID:Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and 'schizophrenia-related' behaviors. 1768 98

Prior exposure to subchronic phencyclidine (PCP) produces behaviors argued to model schizophrenia in rats, including alterations in the behavioral responses to stress-inducing stimuli. Prior exposure to a single injection of PCP also produces a number of schizophrenia-like behaviors in rats, suggesting that a single injection of PCP is able to model schizophrenia-like behaviors as well. We examined the effects of prior exposure to either a single injection or subchronic PCP on stress-induced behavior and c-Fos-like immunoreactivity (FLI). Twenty-four hours after a single injection of PCP (15 mg/kg) or subchronic PCP (10 mg/kg for 14 days) or saline, male rats were exposed to either novel environment, forced swim, or left in their home cages. A single injection of PCP produced only small effects on stress-induced behavior and FLI: a drugxtime interaction on the number of cage crossings in the novel environment and a drugxcondition interaction on FLI in the shell of the nucleus accumbens. However, subchronic PCP decreased cage crosses and rears in the novel environment and increased immobility in the forced swim test. The increased immobility in the forced swim test was accompanied by increased striatal FLI. These data suggest that while a single injection of PCP produces only minimal alterations in the response to stressful stimuli, subchronic PCP produces a quantitatively greater effect. In addition, the observation that PCP pretreatment increased striatal FLI induced by forced swim but not novelty suggest that PCP alters the behavioral responses to these stressors via different neurochemical mechanisms.
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PMID:Subchronic phencyclidine exposure potentiates the behavioral and c-Fos response to stressful stimuli in rats. 1769 79

Kynurenic acid is an endogenous neuroactive compound whose unbalancing is involved in the pathogenesis and progression of several neurological diseases. Kynurenic acid synthesis in the human brain is sustained by the catalytic activity of two kynurenine aminotransferases, hKAT I and hKAT II. A wealth of pharmacological data highlight hKAT II as a sensible target for the treatment of neuropathological conditions characterized by a kynurenic acid excess, such as schizophrenia and cognitive impairment. We have solved the structure of human KAT II by means of the single-wavelength anomalous dispersion method at 2.3-A resolution. Although closely resembling the classical aminotransferase fold, the hKAT II architecture displays unique features. Structural comparison with a prototypical aspartate aminotransferase reveals a novel antiparallel strand-loop-strand motif that forms an unprecedented intersubunit beta-sheet in the functional hKAT II dimer. Moreover, the N-terminal regions of hKAT II and aspartate aminotransferase appear to have converged to highly similar although 2-fold symmetry-related conformations, which fulfill the same functional role. A detailed structural comparison of hKAT I and hKAT II reveals a larger and more aliphatic character to the active site of hKAT II due to the absence of the aromatic cage involved in ligand binding in hKAT I. The observed structural differences could be exploited for the rational design of highly selective hKAT II inhibitors.
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PMID:Crystal structure of human kynurenine aminotransferase II, a drug target for the treatment of schizophrenia. 1805 96

Rearing rats in isolation has been shown to produce behavioral and neurochemical alterations similar to those observed in psychoses such as schizophrenia. Also, a dysregulation in both the endocannabinoid and dopaminergic systems has been implicated in schizophrenia. The aim of this study was to determine if there are differences in CB1 receptor and fatty acid amide hydrolase (FAAH) protein expression, as well as D2 dopamine receptor expression in different brain regions in rats reared in different environmental conditions. Twenty-one-day-old male Sprague-Dawley rats were either reared in individual cages (isolated rats) or in group cages of six per cage (group-housed rats) for 8 weeks. Quantitative fluorescence immunohistochemistry was performed on brain slices using antibodies specific to the CB1 or D2 receptor, or the enzyme FAAH. Raising rats in isolation led to a significant decrease in CB1 receptor expression in the caudate putamen and the amygdala, a significant increase in FAAH expression in the caudate putamen and the nucleus accumbens core and shell, and no significant change in D2 receptor expression in any region studied. These results indicate that the endocannabinoid system is altered in an animal model of aspects of psychosis. This implies that rearing rats under different housing conditions may provide new insight into the role of the endocannabinoid system in the development of psychoses.
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PMID:Effect of social isolation on CB1 and D2 receptor and fatty acid amide hydrolase expression in rats. 1808 30

There are experimental evidences indicating that the non-competitive NMDA receptor antagonist MK-801 impairs cognition and produces a series of schizophrenia-like symptoms in rodents (hypermotility, stereotypies and ataxia). The present study was designed to investigate the efficacy of the selective 5-HT(6) receptor antagonist Ro 04-6790 in counteracting these MK-801-induced behavioural effects in the rat. The effects of Ro 04-6790 in antagonizing MK-801-induced memory deficits were assessed using the object recognition task. The ability of this 5-HT(6) receptor antagonist in counteracting hypermotility, stereotypies and ataxia produced by MK-801 were evaluated in a motor activity cage. Post-training administration of Ro 04-6790 (10 and to some extent also 3mg/kg) antagonized MK-801-induced performance deficits in a recognition memory test. In a subsequent study, Ro 04-6790 (3 and 10 mg/kg) reversed hypermotility and ataxia produced by MK-801. This 5-HT(6) receptor antagonist also alleviated MK-801-induced certain stereotypies. Our findings indicate that Ro 04-6790 attenuates behavioural effects related to the hypofunction of the NMDA receptor suggesting that this compound might be involved in the psychotomimetic effects of non-competitive NMDA receptor antagonists.
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PMID:The selective 5-HT(6) receptor antagonist Ro 04-6790 attenuates psychotomimetic effects of the NMDA receptor antagonist MK-801. 1816 78

The suicide rates in Denmark have been declining during the last two decades. The decline was relatively larger among women than among men. All age groups experienced a decline except the very young with stable rates and the very old with increasing rates. The Universal, Selective, Indicated (USI) model recommended by Institute of Medicine was used as a framework for the thesis. Universal preventive interventions are directed toward the entire population; selective interventions are directed toward individuals who are at greater risk for suicidal behaviour; and indicated preventions are targeted at individuals who have already begun self-destructive behaviour. At the universal level, a review was carried out to highlight the association between availability of methods for suicide and suicide rate. There were mostly studies of firearms, and the conclusion of the review was that there was clear indication of restricted access to lethal means was associated with decline in suicide with that specific method, and in many cases also with overall suicide mortality. Restricting access is especially important for methods with high case fatality rate. Our own study indicated a beneficial effect on suicide rates of restrictions in access to barbiturates, dextropropoxyphen, domestic gas and car exhaust with high content of carbon monoxide. Although a range of other factors in the society might also be of importance, it was concluded that restrictions in access to dangerous means for suicide were likely to play an important role in reducing suicide rates in Denmark, especially for women. At the selective level, there are several important risk groups such as psychiatric patients, persons with alcohol and drug abuse, persons with newly diagnosed severe physical illness, all who previously attempted suicide, and groups of homeless, institutionalized, prisoners and other socially excluded persons. The thesis focused on homeless persons and psychiatric patients, especially patients with schizophrenia and related disorders. The thesis contains a review of the risk of suicide in homeless. In all the studies included, increased suicide mortality was found, and in the studies that evaluated suicide risk in different age groups, the excess suicide mortality was most dominant in younger age groups. Our own study revealed an increased risk of suicide, and in univariate analysis, significant predictors for suicide were found to be associated with shortest stay in hostel less than 11 days and more than one stay during one year. The thesis also contains a review of the risk of suicide in first-episode patients with schizophrenia, and it was concluded on the basis of the identified studies that long-term risk of suicide was not 10 percent as previously accepted, but lower. Risk factors for suicide among patients with schizophrenia were evaluated in case control studies, in nested case control studies, and in prospective studies. The following risk factors were the most important and frequently observed predictors: male gender, young age, short duration of illness, many admissions during last year, current inpatient, short time since discharge, previous and recent suicide attempt, co-morbid depression, drug abuse, poor compliance with medication, poor adherence to treatment, high IQ, and suicidal ideations. The results of analyses of psychotic symptoms as risk factor for suicide were contradictory, but a recent meta-analysis concluded that both hallucinations and delusions seemed to be protective; however, there was a non-significant tendency that command hallucinations were associated with higher suicide risk. Prevention of suicide in schizophrenia must especially focus on improving assessment of risk of suicide during inpatient treatment and the first week after discharge, and special attention must be paid to patients with one or more of the identified risk factors. There is a need for large randomised clinical trials evaluating the effect on suicide and suicide attempt of psychosocial and pharmacological treatment in schizophrenia. In our own study, we did not find any effect of integrated treatment on attempted suicide, but there was an effect on hopelessness and a trend toward lower prevalence of depression among patients in the integrated treatment. There were four suicides and one probable suicide (drowning) in standard treatment and one suicide in integrated treatment at two-year follow-up, but the study did not have sufficient power to detect these differences in proportion to who committed suicide; more than one thousand patients should have been in each treatment condition in order for these differences in proportion to be significant. At the indicated prevention level, a literature review was carried out regarding risk of suicide attempt and suicide in short-term, medium-term and long-term follow-up of persons who attempted suicide. It was concluded that the risk of repetition in short- and medium-term follow-up studies was approximately 16 percent, with lower risk among "first-evers" compared to repeaters. There was a large variation in repetition rate. The proportion who committed suicide in medium-term follow-up studies was 2.8 percent and in long-term follow-up studies was 3.5 percent (weighted mean) with clearly higher proportions in the Nordic studies than in the studies from UK. Risk factors for attempted suicide were previous suicide attempt, alcohol and drug abuse, depression, schizophrenia, previous inpatient treatment, self-discharge before evaluation, sociopathy, unemployment, frequent change of address, hostility, and living alone. Several of the predictors are overlapping and most of them were already identified in early studies of factors predictive of repetition of suicide attempt. Predictors of suicide were male gender, increasing age, previous suicide attempt, serious suicide attempt, alcohol and substance abuse, somatic disease, mental illness, and planning of suicide attempt, high suicidal intent score, violent suicide attempt or suicide attempt with severe lethality, and ongoing or previous psychiatric treatment. In our follow-up study from Bispebjerg Hospital, we found that the risk of suicide during a ten-year follow-up period among patients admitted in 1980 after self-poisoning was 30 times greater than in the general population. We also found increased mortality by all other causes of death. Predictors of suicide were several previous suicide attempts, living alone and increasing age. There are not many randomised clinical trials of psychosocial interventions aiming to reduce risk of repetition among suicide attempters. A Cochrane review concluded that evidence was lacking to indicate the most effective forms of treatment for deliberate self-harm patients. A recent randomised controlled trial showed a positive influence of cognitive behavioural therapy on repetition rate. Our own quasi-experimental study of effectiveness of two weeks' inpatient treatment in a special unit of young persons who had severe suicidal thoughts or who had attempted suicide showed that risk of repetition was reduced in the intervention group, and that the intervention group obtained a significantly greater improvement in Beck's Depression Inventory, Hopelessness Scale, Rosenberg Self-Esteem Scale and CAGE-score. The study of emergency outreach indicates that there are many persons in the community that experience a suicidal crisis, and that this group is an important target group for psychiatric emergency outreach. In our study of registration and referral practice in Copenhagen Hospital Cooperation, we conclude that not all suicide attempts were registered as such in the National Patient Register - in fact, only 37 percent. It must be concluded that the quality of the Danish Patient Register must be improved with regard to registration of suicide attempt. We found that psychiatric evaluation was planned in relation to almost all suicide attempts, but that it must be recommended to pay attention to escorting patients to psychiatric emergency in order to ensure that the patient actually attends the planned consultation. We found that patients who were referred after psychiatric evaluation to psychiatric treatment at outpatient facilities only received the planned treatment in approximately two-thirds of the cases; therefore, like Hawton et al. [Hawton et al., 1998; Hawton et al., 1999], we recommend that outpatient facilities adopt an assertive approach to patients who have attempted suicide. Danish suicide research is strong, primarily due to the possibilities for linking complete national registers providing detailed data and large sample sizes for suicide research, which is so far unique for the Nordic countries. This, combined with skilful use of epidemiological methods, had resulted in a remarkable series of papers highlighting risk of suicide in different risk groups, risk factors and protective factors. This activity must continue. In this work it is important to be aware of limitations in naturalistic studies such as the risk of interchanging cause and effect and the necessity to carry out control for confounders. Meta-analysis is a strong tool for summing up results of previous research. Meta-analyses can be used in reporting the evidence for effectiveness of interventions, but also for determining risk or identifying risk factors. A meta-analysis of risk factors of repetition of suicide attempt has not been carried out, and the quality of the identified studies did not allow a formal meta-analysis. Large randomised clinical trials examining the effectiveness of interventions on reducing rate of suicide attempt and suicide should have high priority. Suicide is a major public health problem and should be given high priority with regard to prevention and research. (ABSTRACT TRUNCATED)
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PMID:Prevention of suicide and attempted suicide in Denmark. Epidemiological studies of suicide and intervention studies in selected risk groups. 1820 80

RG-15 (trans-N-[4-[2-[4-(3-cyano-5-trifluoromethyl -phenyl) -piperazine -1 -yl] -ethyl] -cyclohexyl] -3 -pyridinesulfonic amide dihydro-chloride), is a highly selective dopamine D3/D2 receptor antagonist with subnanomolar affinity for the D3 receptor and nanomolar affinity for the D2 receptor. We found that RG-15 showed a good oral bioavailability (54%) and high brain levels (approx. 900 ng/g) in rats and demonstrated antipsychotic efficacy in amphetamine-induced hyperactivity and conditioned avoidance response tests in rats, yielding ED50 (median effective dose) values of 8.6 and 12 mg/kg orally, respectively. At six- to eightfold higher doses, RG-15 blocked spontaneous motor activity, while a 30 mg/kg dose of the compound caused an increase in the home-cage motility of rats. The drug did not produce catalepsy up to 160 mg/kg oral dose; moreover, it inhibited haloperidol-induced catalepsy in the range 15-60 mg/kg. RG-15 (10 mg/kg orally) restored the impaired learning performance of scopolamine- or diazepam-treated rats in a water-labyrinth paradigm. It is assumed that the motor activating, anticataleptic and cognitive-enhancing properties of RG-15 result from its potent D3 antagonism. In this regard, RG 15 clearly differs from other antipsychotics. Olanzapine, clozapine and amisulpride all showed efficacy against amphetamine-induced hyperactivity and on conditioned avoidance, but compared to RG-15, they proved to be more cataleptogenic and depressed or did not change the home-cage activity of animals. Olanzapine was also inactive in the learning paradigm. Our results suggest that subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity may result in an antipsychotic profile characterised by a lack of extrapyramidal side effects and secondary negative symptoms with simultaneous efficacy on positive and cognitive symptoms of schizophrenia.
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PMID:Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: II. behavioural characterisation of RG-15. 1854 31

The idea that serotonin (5-hydroxytryptamine; 5-HT) is contributed in schizophrenia has long been advocated and alterations in 5-HT neurotransmission has been hypothesized to modulate both the therapeutic and extrapyramidal symptoms (EPS) liability of conventional neuroleptics. The 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a preferential 5-HT(1A) ligand, has been reported to attenuate EPS functions of haloperidol in animals. In view of a possible role of 5-HT(1A) receptors in the management of EPS functions of a neuroleptic drug, the present study was designed to investigate behavioral responses of 8-OH-DPAT at a challenge dose of 0.5mg/Kg in rats with subchronic haloperidol administration at a dose of 5mg/Kg twice daily for 5 days. The intensity of 5-HT syndrome provoked by 8-OH-DPAT was taken as a measure of postsynaptic responses. In the present study administration of haloperidol at a dose of 5mg/Kg twice daily for 5 days decreased locomotion significantly (p<0.01) in familiar (home cage) environment. Subchronic administration of haloperidol at the same dose elicited significant (p<0.01) cataleptic responses in rats when compared with saline treated rats. Results revealed that 8-OH-DPAT-induced hyperlocomotion (p<0.05) and forepaw treading (p<0.1) were significantly smaller in rats pre-treated with haloperidol for 5 days than repeatedly saline injected rats. Conversely, the other components of the syndrome i.e. flat body posture (p<0.001), hind limb abduction (p<0.001) and straub tail (p<0.01) were significantly greater in repeated haloperidol treated rats when compared with repeated saline injected rats. These findings help to demonstrate a causal link between the upregulation of DA-D(2) receptors and the decrease in the effectiveness of presynaptic 5-HT(1A) receptors following subchronic haloperidol administration and this may further help to yield an antipsychotic agent with an improved profile of efficacy to EPS, thereby widening its therapeutic window.
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PMID:Serotonin(1A) receptor agonism in the expression of behavioral dopaminergic supersensitivity in subchronic haloperidol treated rats. 1893 Aug 64


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