Avril Pereira

5-HT2A receptor polymorphism and steady state receptor expression in schizophrenia.

Vol 349 • June 21, 1997 1815 activates Ca-sensitive ion channels leading to saliva formation. Myoepithelial cells are believed to play a central part in the reflex salivary flow by concentration, which may stimulate the release of acinar cell contents and exert some counterpressure during stimulated salivary flow. These results show a new cellular defect of potential pathogenetic importance in an autoimmune disease.

Significant Correlation Between 14C-5-HT Uptake by and 3H-Paroxetine Binding to Platelets from Healthy Volunteers

The lack of correlation between 5-HT uptake by platelets and the ability of platelet membrane to bind antidepressant drugs, particularly imipramine, has been reported. However, more recently it has been suggested that 3H-paroxetine could be a better drug with which to study the platelet 5-HT uptake mechanism in disease states. We have therefore compared the ability of platelet-rich plasma (PRP) from normal individuals to take up 5-HT with the ability of platelet membranes to bind paroxetine. A significant correlation was apparent between the Vmax of 14C-5-HT uptake by PRP and the Bmax of 3H-paroxetine binding to platelet membrane from 30 individuals (r = 0.6468, p = 0.0001). Furthermore, this correlation was highly significant in the 20 female (r = 0.7768, p = 0.00006) but not in the 10 male volunteers. There was also a significant association between Vmax and Bmax and the month of blood sampling but this did not totally account for the correlation between Vmax and Bmax. The simultaneous measurement of 5-HT uptake by PRP and paroxetine binding to platelet membranes from both depressed patients and matched controls should be carried out to confirm and extend these findings.

Neuregulin-1 and schizophrenia in the genome-wide association study era

Clinical and pre-clinical evidence has implicated neuregulin 1 (NRG1) as a critical component in the pathophysiology of schizophrenia. However, the arrival of the genome-wide association study (GWAS) era has yielded results that challenge the relevance of NRG1 in schizophrenia due to the absence of a genome-wide significant NRG1 variant associated with schizophrenia. To assess NRG1s relevance to schizophrenia in the GWAS era, we provide a targeted review of recent preclinical evidence on NRG1s role in regulating several aspects of excitatory/inhibitory neurotransmission and in turn schizophrenia risk. We also present a systematic review of the last decade of clinical research examining NRG1 in the context of schizophrenia. We include concise summaries of genotypic variation, gene-expression, protein expression, structural and functional neuroimaging as well as cognitive studies conducted during this time period. We conclude with recommendations for future clinical and preclinical work that we hope will help prioritize a strategy forward to further advance our understanding of the relationship between NRG1 and schizophrenia.

Potential clozapine target sites on peripheral hematopoietic cells and stromal cells of the bone marrow.

ABSTRACTThe antipsychotic drug clozapine, acts via interaction with selective neurotransmitter receptor systems. Its use however, is associated with life-threatening agranulocytosis. The mechanism by which this occurs and its possible relationship with the drugs atypicality remain unclear. As a first step in identifying mechanistic pathways involved, profiling of neurotransmitter receptors on human neutrophils, mononuclear and bone marrow stromal cells as putative targets for clozapine-mediated toxicity was undertaken. Expression of mRNA encoding dopaminergic d2, d3, d4; serotonergic 5ht2a, 5ht2c, 5ht3, 5ht6, 5ht7; adrenergic α1a, α2; histaminergic h1 and muscarinic m1, m2, m3, m4, m5 receptors was analyzed by reverse transcription-polymerase chain reaction methods. While 5ht2c, 5ht6, m1 and m2 mRNA were undetected, the presence of the other receptors indicates sites at which clozapine could bind and induce toxicity of neutrophils and stromal components which regulate granulopoiesis. The functional significance of differential receptor expression while unknown, may argue for neural regulation of hematopoiesis.

Clozapine induction of ERK1/2 cell signalling via the EGF receptor in mouse prefrontal cortex and striatum is distinct from other antipsychotic drugs.

Treatment resistance remains a major obstacle in schizophrenia, with antipsychotic drugs (APDs) being ineffective in about one third of cases. Poor response to standard therapy leaves the APD clozapine as the only effective treatment for many patients. The reason for the superior efficacy of clozapine is unknown, but as we have proposed previously it may involve modulation of neuroplasticity and connectivity through induction of interconnected mitogenic signalling pathways. These include the mitogen-activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade and epidermal growth factor (EGF)/ErbB systems. Clozapine, distinct from other APDs, induced initial inhibition and subsequent activation of the ERK response in prefrontal cortical (PFC) neurons in vitro and in vivo, an action mediated by the EGF receptor (ErbB1). Here we examine additionally the striatum of C57Bl/6 mice to determine if clozapine, olanzapine, and haloperidol differentially regulate the ERK1/2 pathway in a region or time-specific manner conditional on the EGF receptor. Following acute treatment, only clozapine caused delayed striatal ERK phosphorylation through EGF receptor phosphorylation (tyrosine 1068 site) and MEK that paralleled cortical ERK phosphorylation. Olanzapine induced initial pERK1-specific blockade and an elevation 24-h later in PFC but had no effect in the striatum. By contrast, haloperidol significantly stimulated pERK1 in striatum for up to 8 h, but exerted limited effect in PFC. Clozapine but not olanzapine or haloperidol recruited the EGF receptor to signal to ERK. These in-vivo data reinforce our previous findings that clozapines action may be uniquely linked to the EGF signalling system, potentially contributing to its distinctive clinical profile.

Accelerated Gray and White Matter Deterioration With Age in Schizophrenia

OBJECTIVE Although brain changes in schizophrenia have been proposed to mirror those found with advancing age, the trajectory of gray matter and white matter changes during the disease course remains unclear. The authors sought to measure whether these changes in individuals with schizophrenia remain stable, are accelerated, or are diminished with age. METHOD Gray matter volume and fractional anisotropy were mapped in 326 individuals diagnosed with schizophrenia or schizoaffective disorder and in 197 healthy comparison subjects aged 20-65 years. Polynomial regression was used to model the influence of age on gray matter volume and fractional anisotropy at a whole-brain and voxel level. Between-group differences in gray matter volume and fractional anisotropy were regionally localized across the lifespan using permutation testing and cluster-based inference. RESULTS Significant loss of gray matter volume was evident in schizophrenia, progressively worsening with age to a maximal loss of 8% in the seventh decade of life. The inferred rate of gray matter volume loss was significantly accelerated in schizophrenia up to middle age and plateaued thereafter. In contrast, significant reductions in fractional anisotropy emerged in schizophrenia only after age 35, and the rate of fractional anisotropy deterioration with age was constant and best modeled with a straight line. The slope of this line was 60% steeper in schizophrenia relative to comparison subjects, indicating a significantly faster rate of white matter deterioration with age. The rates of reduction of gray matter volume and fractional anisotropy were significantly faster in males than in females, but an interaction between sex and diagnosis was not evident. CONCLUSIONS The findings suggest that schizophrenia is characterized by an initial, rapid rate of gray matter loss that slows in middle life, followed by the emergence of a deficit in white matter that progressively worsens with age at a constant rate.

The impact of premorbid and current intellect in schizophrenia: cognitive, symptom, and functional outcomes

Background:Cognitive heterogeneity among people with schizophrenia has been defined on the basis of premorbid and current intelligence quotient (IQ) estimates. In a relatively large, community cohort, we aimed to independently replicate and extend cognitive subtyping work by determining the extent of symptom severity and functional deficits in each group.Methods:A total of 635 healthy controls and 534 patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited through the Australian Schizophrenia Research Bank. Patients were classified into cognitive subgroups on the basis of the Wechsler Test of Adult Reading (a premorbid IQ estimate) and current overall cognitive abilities into preserved, deteriorated, and compromised groups using both clinical and empirical (k-means clustering) methods. Additional cognitive, functional, and symptom outcomes were compared among the resulting groups.Results:A total of 157 patients (29%) classified as ‘preserved’ performed within one s.d. of control means in all cognitive domains. Patients classified as ‘deteriorated’ (n=239, 44%) performed more than one s.d. below control means in all cognitive domains except estimated premorbid IQ and current visuospatial abilities. A separate 138 patients (26%), classified as ‘compromised,’ performed more than one s.d. below control means in all cognitive domains and displayed greater impairment than other groups on symptom and functional measures.Conclusions:In the present study, we independently replicated our previous cognitive classifications of people with schizophrenia. In addition, we extended previous work by demonstrating worse functional outcomes and symptom severity in the compromised group.

Quetiapine and aripiprazole signal differently to ERK, p90RSK and c-Fos in mouse frontal cortex and striatum: role of the EGF receptor

BackgroundSignaling pathways outside dopamine D2 receptor antagonism may govern the variable clinical profile of antipsychotic drugs (APD) in schizophrenia. One postulated mechanism causal to APD action may regulate synaptic plasticity and neuronal connectivity via the extracellular signal-regulated kinase (ERK) cascade that links G-protein coupled receptors (GPCR) and ErbB growth factor signaling, systems disturbed in schizophrenia. This was based upon our finding that the low D2 receptor affinity APD clozapine induced initial down-regulation and delayed epidermal growth factor receptor (EGFR or ErbB1) mediated activation of the cortical and striatal ERK response in vivo distinct from olanzapine or haloperidol. Here we map whether the second generation atypical APDs aripiprazole and quetiapine affect the EGFR-ERK pathway and its substrates p90RSK and c-Fos in mouse brain, given their divergent agonist and antagonist properties on dopaminergic transmission, respectively.ResultsIn prefrontal cortex, aripiprazole triggered triphasic ERK phosphorylation that was EGFR-independent but had no significant effect in striatum. Conversely quetiapine did not alter cortical ERK signaling but elevated striatal ERK levels in an EGFR-dependent manner. Induction of ERK by aripiprazole did not affect p90RSK signaling but quetiapine decreased RSK phosphorylation within 1-hour of administration. The transcription factor c-Fos by comparison was a direct target of ERK phosphorylation induced by aripiprazole in cortex and quetiapine in striatum with protein levels in temporal alignment with that of ERK.ConclusionsThese data indicate that aripiprazole and quetiapine signal to specific nuclear targets of ERK, which for quetiapine occurs via an EGFR-linked mechanism, possibly indicating involvement of this system in its action.

Repeated antidepressant drug treatment, time of death and frequency of handling do not affect [3H]paroxetine binding in rat cortex

[3H]Paroxetine binding to the serotonin transporter has been shown to be altered in brain tissue from schizophrenic subjects. Some schizophrenic subjects are treated with antidepressant drugs, some of which bind to the serotonin transporter and their time of death is variable. To determine if these confounding factors could affect [3H]paroxetine binding, [3H]paroxetine binding to cortical membrane from rats treated with the antidepressant drugs for 10 or 28 days and in non-treated rats that were killed at different times of the day was measured. Drug treatment, when compared to injection with 0.9% saline and time of death, did not affect [3H]paroxetine binding. Treatment with imipramine [10 days: mean +/- S.D.: 590 +/- 59 fmol/mg protein (P < 0.05); 28 days: 653 +/- 59 fmol/mg protein (P < 0.01)] or mianserin [10 days: 600 +/- 43 (P < 0.05)] caused a significant decrease in the density of [3H]paroxetine binding compared to that in fluoxetine-treated rats (10 days: 820 +/- 211 fmol/mg protein; 28 days: 764 +/- 100 fmol/mg protein). Thus, overall, these data do not suggest changes in [3H]paroxetine binding reported in the human brain tissue would be due to antidepressant drug treatment or time of death.

Clozapine regulation of p90RSK and c-Fos signaling via the ErbB1-ERK pathway is distinct from olanzapine and haloperidol in mouse cortex and striatum

Treatment of the positive psychotic symptoms of schizophrenia with standard antipsychotic drugs (APDs) is ineffective in a proportion of cases. For these treatment resistant patients the alternative is the APD clozapine which is superior to other agents but carries serious side effects. Why clozapine is uniquely effective is unknown, but we have previously postulated may involve G-protein coupled receptor (GPCR) and epidermal growth factor (EGF) receptor (ErbB1) transactivation signaling to the mitogen-activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade. This was based upon clozapine induced initial down-regulation and delayed ErbB1 mediated activation of the cortical and striatal ERK response in vivo distinct from other APDs. This study investigated if modulation of the ErbB1-ERK1/2 pathway by clozapine, olanzapine and haloperidol affected expression of the ERK substrates p90RSK and c-Fos, factors that regulate transcription of proteins associated with neuroplasticity and synapse formation in C57Bl/6 mice. In cortex and striatum, acute clozapine treatment induced biphasic p90RSK phosphorylation via MEK that paralleled ERK phosphorylation independent of EGF receptor blockade. By contrast, olanzapine and haloperidol caused p90RSK phosphorylation that was not concomitant with ERK signaling over a 24-hour period. For c-Fos, clozapine elevated expression 24h after administration, a timeframe consistent with ERK activation at 8h. Alternatively, haloperidol stimulation of c-Fos levels limited to the striatum was in accord with direct transcriptional regulation through ERK. The unique spatio-temporal expression of downstream nuclear markers of the ErbB1-ERK pathway invoked by clozapine may contribute to its effectiveness in treatment resistant schizophrenia.