Serotonin 1A receptor availability in patients with schizophrenia and schizo-affective disorder: a positron emission tomography imaging study with [11C]WAY 100635

Background Postmortem and positron emission tomography (PET) studies have reported several alterations in serotonin 1A receptor (5-HT_1A) binding parameters in patients with schizophrenia. This study examines 5-HT_1A availability in vivo in individuals with schizophrenia and schizo-affective disorder.Materials and methods Twenty-two medication-free individuals with schizophrenia or schizo-affective disorder and 18 healthy subjects underwent PET scans with [¹¹C]WAY 100635. Regional distribution volumes (V _T, in milliliters per gram) were derived using a two-tissue compartment kinetic model. Outcome measures for 5-HT_1A availability included binding potential (BP) and the specific to nonspecific equilibrium partition coefficient (V ₃″). Eleven brain regions with high density of 5-HT_1A were included in the analysis.Results No significant differences were observed in regional BP or V ₃″ between patients and controls. No significant relationships were observed between regional 5-HT_1A availability and symptom severity.Conclusion The postmortem literature reports increased 5-HT_1A binding in the prefrontal cortex in schizophrenia. This study did not detect differences in 5-HT_1A binding. Whereas in two recently published PET studies, one reports increased binding in the temporal lobe while the other reports decreased binding in the amygdala. These inconsistencies suggest that the alterations demonstrated in postmortem studies cannot be reliably detected at the resolution achieved with PET. This raises the question as to whether major changes in the level of expression of the 5-HT_1A receptor play a role in the pathophysiology of schizophrenia.Dr. Lombardo participated in this work while at Columbia University but subsequently has moved to Pfizer Inc., 235 east 42nd Street MS 10/33, New York, NY 10017, USA.     

The manganese superoxide dismutase Ala16Val dimorphism modulates both mitochondrial import and mRNA stability

A genetic dimorphism incorporates either alanine (Ala) or valine (Val) in the mitochondrial targeting sequence (MTS) of manganese superoxide dismutase (MnSOD). The Ala-MTS confers a 40% higher MnSOD activity than the Val-MTS after import into isolated mitochondria in vitro. The present study aimed to characterize functional consequences in whole cells. HuH7 human hepatoma cells were transfected with vectors encoding for the human Ala- or Val-MnSOD variants fused to a Myc-His-tag. The Ala-variant resulted in four-fold higher levels of the mature exogenous protein and MnSOD activity than the Val-variant. Studies with a proteasome inhibitor indicated that precursor proteins are either imported into the mitochondria or degraded by the proteasome. Despite identical levels 8 h after transfection, mRNA levels at 36 h were two-fold higher for the Ala-encoding mRNA than the Val-mRNA. Decreasing the mitochondrial membrane potential decreased both MnSOD mitochondrial import and its mRNA levels. Much larger differences in the activity of the human Val- and Ala-MnSOD variants are observed in whole cells rather than after import experiments performed in vitro. First, the slowly imported Val-MnSOD is degraded by the proteasome in cells. Second, the slower mitochondrial import of the Val-variant may be associated with decreased mRNA stability, possibly due to impaired cotranslational import.     

Imaging the high-affinity state of the dopamine D2 receptor in vivo: Fact or fiction?

Positron Emission Tomography (PET) has been used for more than three decades to image and quantify dopamine D2 receptors (D2R) in vivo with antagonist radioligands but in the recent years agonist radioligands have also been employed. In vitro competition studies have demonstrated that agonists bind to both a high and a low-affinity state of the D2Rs, of which the high affinity state reflects receptors that are coupled to G-proteins and the low-affinity state reflects receptors uncoupled from G-proteins. In contrast, antagonists bind with uniform affinity to the total pool of receptors. Results of these studies led to the proposal that D2Rs exist in high and low-affinity states for agonists in vivo and sparked the development and use of agonist radioligands for PET imaging with the primary purpose of measuring the proportion of receptors in the high-affinity (activating) state. Although several lines of research support the presence of high and low-affinity states of D2Rs and their detection by in vivo imaging paradigms, a growing body of controversial data has now called this into question. These include both in vivo and ex vivo studies of anesthesia effects, rodent models with increased proportions of high-affinity state D2Rs as well as the molecular evidence for stable receptor-G-protein complexes. In this commentary we review these data and discuss the evidence for the in vivo existence of D2Rs configured in high and low-affinity states and whether or not the high-affinity state of the D2R can, in fact, be imaged in vivo with agonist radioligands.     

Pericardial effusion in severe hypothyroidism in children

Pleural and pericardial effusion is a rare complication of severe hypothyroidism in children but can be present in 10 to 30% of adults. Most pediatric cases have been in children with Down syndrome. In this report, six cases of pericardial effusion in children with severe hypothyroidism with and without trisomy 21 are presented. In all patients, the pericardial effusion was managed successfully without pericardiocentesis. The effusions resolved completely in 2 to 12 months after initiation of thyroxin replacement. In conclusion, hypothyroidism should be considered in any child with unexplained pericardial or pleural effusions. Early recognition and treatment with thyroid hormone replacement could eliminate the need for unnecessary diagnostic procedures and invasive treatment measures and reduce the risk of progression to cardiac tamponade.