Prepulse inhibition (PPI) is a measure of sensorimotor gating and an endophenotype of schizophrenia. We have previously shown that estrogen treatment prevents disruption of PPI by the 5-HT(1A)/5-HT(7) receptor agonist, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT). The aim of the present study was to examine the role of dopamine D(1) and D(2), 5-HT(1A), 5-HT(2A) and 5-HT(7) receptors in these effects. Part 1 of this study investigated the ability of estrogen treatment to reverse a PPI disruption induced by 8-OH-DPAT or the dopamine D(1)/D(2) receptor agonist, apomorphine. Part 2 of this study aimed to compare these effects to the ability of various antagonists in reversing the action of 8-OH-DPAT and apomorphine on PPI. Female Sprague-Dawley rats were ovariectomized (OVX) and, where appropriate, received silastic implants containing either a low- (E20) or high-dose of estrogen (E100). Two weeks later, PPI was assessed using automated startle boxes. The disruption of PPI by either treatment with 8-OH-DPAT (0.5 mg/kg) or apomorphine (0.3 mg/kg) was similarly prevented by E100 treatment. 8-OH-DPAT-induced PPI disruption was reversed by pre-treatment with the 5-HT(1A) receptor antagonist, WAY 100,635 (1 mg/kg) and the typical antipsychotic and dopamine D(2) receptor antagonist, haloperidol (0.25 mg/kg), but not the dopamine D(1) receptor antagonist, SCH 23390 (0.1 mg/kg), 5 HT(2A/2C) receptor antagonist, ketanserin (2 mg/kg) or 5-HT(7) receptor antagonist, SB-269970 (10 mg/kg). Apomorphine-induced disruptions of PPI were reversed by haloperidol and SCH 23390 only. Estrogen may prevent disruptions of PPI induced by both 8-OH-DPAT and apomorphine, by an action on dopamine D(2) receptors downstream of 5-HT(1A) receptors. less...

Tryptophan depletion techniques are effective in reducing central serotonergic function and have been used to investigate its role in mood and cognition. In the present study a tryptophan-free diet was fed to Lister-hooded male rats chronically for 21 days to investigate the effect of lowering central serotonin concentration on cognition using the novel object recognition paradigm. Chronically tryptophan-depleted rats had impaired object recognition memory; this was accompanied by a reduction in central serotonin of 40-50% in the hippocampus, frontal cortex and striatum. In a subsequent experiment, the atypical antipsychotic, risperidone (0.2mg/kg), but not the typical antipsychotic, haloperidol (0.1mg/kg), administered i.p. 30minutes prior to the retention test, significantly attenuated the chronic tryptophan depletion impairment. These data show that chronic lowering of central serotonin is associated with impaired cognitive performance, and that this can be reversed by the atypical antipsychotic, risperidone. less...

Neboglamine is a functional modulator of the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Dysfunction of this receptor has been associated with negative and cognitive symptoms in schizophrenia. Thus, we tested the hypothesis that neboglamine behaves as a potential antipsychotic. We compared the effects of neboglamine, D-serine, clozapine, and haloperidol on the expression of Fos-like immunoreactivity (FLI), a marker of neuronal activation, in rat forebrain. We also studied the effects of these agents on phencyclidine (PCP)-induced behaviour in rats, a model predictive of potential antipsychotic activity. Neboglamine, like haloperidol and clozapine, significantly increased the number of FLI-positive cells in the prefrontal cortex, nucleus accumbens, and lateral septal nucleus (3.2-, 4.8-, and 4.5-fold over control, respectively). Haloperidol dramatically increased FLI (390-fold over control) in the dorsolateral striatum, a brain region in which neboglamine and clozapine had no effect. The pattern of FLI induced by neboglamine closely matched that of D-serine, an endogenous agonist at the glycine site of NMDA receptors. Consistent with this finding, neboglamine restored NMDA-mediated neurotransmitter release in frontal cortex punches exposed to the NMDA antagonist PCP. In the behavioural model, all test compounds significantly inhibited PCP-induced hyperlocomotion. Unlike haloperidol and clozapine, neither neboglamine nor D-serine affected the basal levels of locomotor activity. Moreover, oral neboglamine dose-dependently inhibited both the hyperlocomotion and the frequency of rearing behaviour induced by PCP. These results, while confirming that the NMDA glycine site is a feasible target for activating the frontostriatal system, support the clinical evaluation of neboglamine as a treatment for schizophrenia. less...

Abstract Background: Nitric oxide (NO) is known to be a signaling molecule with many physiogical functions including apoptotic process regulation. Since apoptosis may contribute to the pathophysiology of schizophrenia, this study was undertaken to determine the plasma concentrations of NO in schizophrenics. Methods: Nitrite/nitrate (NO(2)(-)/NO(3)(-)) concentrations were measured in plasma from 40 patients with schizophrenia, and 36 age- and gender-matched healthy persons using a colorimetric test. Results: Plasma NO(2)(-)/NO(3)(-) concentrations were significantly higher in patients with schizophrenia (102.8+/-34.7 mumol/L, p<0.0001) than in controls (69.2+/-13.2 mumol/L). Also, mean NO(2)(-)/NO(3)(-) values in female patients and controls were significantly higher (118.2+/-44.7 mumol/L, p<0.001; 74.8+/-16.1 mumol/L, p<0.05, respectively) compared to males (94.7+/-25.3 mumol/L, 67.6+/-10.8 mumol/L). Significant correlation was seen between plasma NO(2)(-)/NO(3)(-) concentrations and heredity, number of episodes and peripheral blood mononuclear cell (PBMC) caspase-3 activity, which was significantly higher in patients than in controls (p<0.05). There was no significant difference in NO(2)(-)/NO(3)(-) concentrations between patients with different Positive and Negative Syndrome Scale (PANSS) scores or between patients treated with haloperidol (97.2+/-31.2 mumol/L) and those treated with other atypical antipsychotic drugs (109.8+/-33.7 mumol/L). Both parameters showed no significant differences between smokers and non-smokers. Conclusions: This study showed that plasma NO(2)(-)/NO(3)(-) concentrations were significantly increased in patients with schizophrenia, being significantly higher in female than male patients, and showing a significant correlation with heredity, number of episodes and PBMC caspase-3 activity. These results suggest that NO could be considered an inducer or regulator of apoptosis in patients with schizophrenia. Clin Chem Lab Med 2010;48:89-94. less...

This article provides an overview of present knowledge regarding the relationship between the cholinergic system and sigma-1 receptors, and discusses potential applications of sigma-1 receptor agonists in the treatment of memory deficits and cognitive disorders Sigma-1 receptors, initially considered as a subtype of the opioid family, are unique ligand-regulated molecular chaperones in the endoplasmatic reticulum playing a modulatory role in intracellular calcium signaling and in the activity of several neurotransmitter systems, particularly the cholinergic and glutamatergic pathways. Several central nervous system (CNS) drugs show high to moderate affinities for sigma-1 receptors, including acetylcholinesterase inhibitors (donepezil), antipsychotics (haloperidol, rimcazole), selective serotonin reuptake inhibitors (fluvoxamine, sertraline) and monoamine oxidase inhibitors (clorgyline). These compounds can influence cognitive functions both via their primary targets and by activating sigma-1 receptors in the CNS. Sigma-1 agonists show powerful anti-amnesic and neuroprotective effects in a large variety of animal models of cognitive dysfunction involving, among others (i) pharmacologic target blockade (with muscarinic or NMDA receptor antagonists or p-chloroamphetamine); (ii) selective lesioning of cholinergic neurons; (iii) CNS administration of ss-amyloid peptides; (iv) aging-induced memory loss, both in normal and senescent-accelerated rodents; (v) neurodegeneration induced by toxic compounds (CO, trimethyltin, cocaine), and (vi) prenatal restraint stress. less...

A critical appraisal of the FIN-11 study. Compared to the general population, people with schizophrenia are at risk of dying prematurely due to suicide and due to different somatic illnesses. The potential role of antipsychotic treatment in affecting suicide rates and in explaining the increased mortality due to somatic disorders is highly debated. A recent study of death registers in Finland compared the cause-specific mortality in 66,881 patients versus the total population (5.2million) between 1996 and 2006, suggesting that antipsychotic use decreased all-cause mortality compared to no antipsychotic use in patients with schizophrenia, and that clozapine had the most beneficial profile in this regard (Tiihonen et al., 2009). The benefits of clozapine were conferred by significant protective effects for suicide compared to perphenazine, whereas, a mixed group of 'other' antipsychotics, haloperidol, quetiapine and risperidone were reported to be associated with significantly higher all-cause mortality than perphenazine. By contrast, despite known differences in effects on cardiovascular risk factors, there were no significant differences between any of the examined antipsychotics regarding death due to ischemic heart disease. A number of methodological and conceptual issues make the interpretation of these findings problematic, including incomplete reporting of data, questionable selection of drug groups and comparisons, important unmeasured risk factors, inadequate control for potentially confounding variables, exclusion of deaths occurring during hospitalization leading to exclusion of 64% of deaths on current antipsychotics from the analysis, and survivorship bias due to strong and systematic differences in illness duration across the treatment groups. Well designed, prospective mortality studies, with direct measurement of and adjustment for all known relevant risk factors for premature mortality, are needed to identify risk and protective medication and patient factors and to, ultimately, inform clinical practice. less...

Difficulties initiating and maintaining sleep as well as circadian rhythm disorders are very common in schizophrenia. Sleeping disorders occur as early signs of the first manifestation of illness as well as early signs of relapse. They bear a relation to positive symptoms and disorganisation of thought. Polysomnographic investigations with schizophrenic patients typically demonstrate a prolonged sleep-onset latency and a decrease in sleep efficiency and slow wave sleep. In particular, distortions of deep sleep can affect neocortical plasticity and cognition negatively. The considerable sleeping disorders are often not sufficiently taken into account in clinical routine. Particularly older antipsychotic medication like Haloperidol can affect the circadian and sleep-wake rhythms negatively. Therefore, pathophysiological changes of sleep within the scope of schizophrenic disorders and their potential implications are discussed in this outline. Regarding therapy, psychoeducative approaches are discussed as well as the administration of antipsychotic medication in accordance with the recommendations of sleep medicine professionals. less...

OBJECTIVE: To examine the prevalence, psychometric validity and response to antipsychotic drugs of DSM-IV catatonia signs and criteria in patients with a first-episode psychotic disorder. METHODS: Two-hundred antipsychotic-naive patients with a DSM-IV nonaffective psychosis were assessed for catatonia signs and criteria using the Modified Rogers Scale, and the psychometric validity of the 12 DSM-IV catatonia signs and diagnostic criteria was examined. Treatment response of catatonia was assessed in 173 patients who completed one-month trial with haloperidol (n=23), risperidone (n=93) or olanzapine (n=57). RESULTS: Sixty-two patients (31%) endorsed at least one catatonia sign and 24 (12%) met DSM-IV criteria for catatonia. DSM-IV catatonia signs showed an excellent convergent validity (r>0.8) with other rating scales, and DSM-IV criteria showed moderate to fair concordance with other criteria (kappa from 0.57 to 0.77). The total number of signs reflected catatonia severity and demonstrated excellent diagnostic performance against alternative diagnostic criteria. The presence of at least any three signs accurately identified patients with catatonia. Three catatonia domains were identified (hyperkinesia, volitional and hypokinesia), which showed a different association pattern with external variables. Overall, catatonia ratings were particularly related to both dyskinesia and disorganization symptoms and lacked diagnostic specificity for schizophrenia. Patients with catatonia responded well to antipsychotic medication irrespective of the type of antipsychotic drug used, although treatment response was dependent upon the remission of psychotic symptoms. CONCLUSIONS: These results may inform the DSM-V development on diagnosis and classification of catatonia, and indicate that catatonia signs and syndromes are highly responsive to antipsychotic drugs. less...

Abnormalities of amount and function of presynaptic terminals may have an important role in the mechanism of illness in schizophrenia. The SNARE proteins (SNAP-25, syntaxin, and VAMP) are enriched in presynaptic terminals, where they interact to form a functional complex to facilitate vesicle fusion. SNARE protein amounts are altered in the cortical regions in schizophrenia, but studies of protein-protein interactions are limited. We extended these investigations to the striatal regions (such as the nucleus accumbens, ventromedial caudate (VMC), and dorsal caudate) relevant to disease symptoms. In addition to measuring SNARE protein levels, we studied SNARE protein-protein interactions using a novel ELISA method. The possible effect of antipsychotic treatment was investigated in parallel in the striatum of rodents that were administered haloperidol and clozapine. In schizophrenia samples, compared with controls, SNAP-25 was 32% lower (P=0.015) and syntaxin was 26% lower (P=0.006) in the VMC. In contrast, in the same region, SNARE protein-protein interactions were higher in schizophrenia (P=0.008). Confocal microscopy of schizophrenia and control VMC showed qualitatively similar SNARE protein immunostaining. Haloperidol treatment of rats increased levels of SNAP-25 (mean 24%, P=0.003), syntaxin (mean 18%, P=0.010), and VAMP (mean 16%, P=0.001), whereas clozapine increased only the VAMP level (mean 13%, P=0.004). Neither drug altered SNARE protein-protein interactions. These results indicate abnormalities of amount and interactions of proteins directly related to presynaptic function in the VMC in schizophrenia. SNARE proteins and their interactions may be a novel target for the development of therapeutics.Neuropsychopharmacology advance online publication, 13 January 2010; doi:10.1038/npp.2009.228. less...

Tardive dyskinesia (TD) is characterized by repetitive, involuntary, and purposeless movements that develop in patients treated with long-term dopaminergic antagonists, usually antipsychotics. By a genome-wide association screening of TD in 50 Japanese schizophrenia patients with treatment-resistant TD and 50 Japanese schizophrenia patients without TD (non-TD group) and subsequent confirmation in independent samples of 36 treatment-resistant TD and 136 non-TD subjects, we identified association of a single nucleotide polymorphism, rs2445142, (allelic p=2 x 10(-5)) in the HSPG2 (heparan sulfate proteoglycan 2, perlecan) gene with TD. The risk allele was significantly associated with higher expression of HSPG2 in postmortem human prefrontal brain (p<0.01). Administration of daily injection of haloperidol (HDL) for 50 weeks significantly reduced Hspg2 expression in mouse brains (p<0.001). Vacuous chewing movements (VCMs) induced by 7-week injection of haloperidol-reserpine were significantly infrequent in adult Hspg2 hetero-knockout mice compared with wild-type littermates (p<0.001). Treatment by the acetylcholinesterase inhibitor, physostigmine, was significantly effective for reduction of VCMs in wild-type mice but not in Hspg2 hetero-knockout mice. These findings suggest that the HSPG2 gene is involved in neuroleptic-induced TD and higher expression of HSPG2, probably even after antipsychotic treatment, and may be associated with TD susceptibility.Neuropsychopharmacology advance online publication, 13 January 2010; doi:10.1038/npp.2009.220. less...