ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals

Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the National Cancer Institute (NCI), National Human Genome Research Institute (NHGRI), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), and National Institute of Neurological Disorders and Stroke (NINDS)

Antipsychotics and single-cell activity in the rat superior colliculus

Schizophrenic patients have problems with saccadic eye movements that can be characterized as a loss of control over the saccadic system. Preliminary clinical results suggest that antipsychotics can either disrupt or improve saccadic performance. The brain mechanism through which antipsychotics might affect saccades is the subject of study. The superior colliculus (SC) is crucially involved in the generation of saccades, Previous experimental studies showed that the substantia nigra reticulata (SNr), a structure with profound inhibitory influence on the SC, is differentially affected by classical and atypical antipsychotics. In this study, we investigated the potential effects of atypical antipsychotics (clozapine, olanzapine, and risperidone) and a classical antipsychotic (haloperidol) on the firing rate of SC cells in the rat. In anesthetized rats, we performed extracellular recordings on spontaneous active neurons in the intermediate and deep layers of the SC. After subcutaneous injection of an antipsychotic drug, changes in firing rate were compared with responses upon saline injection. Olanzapine (1.0 mg/kg), risperidone (0.3 and 1.0 mg/kg), and haloperidol (0.5 mg/kg) did not significantly alter cell activity, but clozapine (10.0 mg/kg) induced a short-lasting but significant decrease. Except for clozapine, the effects of antipsychotics on the SC were nonsignificant and therefore independent of the effects in the SNr. Our results support the notion that clozapine is different from the other atypical antipsychotics. (C) 2001 Elsevier Science Inc. All rights reserved

Acute and chronic effects of citalopram on postsynaptic 5-hydroxytryptamine(1A) receptor-mediated feedback:a microdialysis study in the amygdala

Microdialysis was used to assess the involvement of postsynaptic 5-hydroxytryptamine(1A) (5-HT1A) receptors in the regulation of extracellular 5-HT in the amygdala. Local infusion of the 5-HT1A receptor agonist flesinoxan (0.3, 1, 3 muM) for 30 min into the amygdala maximally decreased 5-HT to 50% of basal level. Systemic administration of citalopram (10 mu mol/kg) increased 5-HT to 175% of basal revel. Local infusion of 1 muM of the 5-HT1A receptor antagonist WAY 100.635 into the amygdala augmented the effect of citalopram to more than 500% of basal 5-HT level. 5-HT1A receptor responsiveness after chronic citalopram treatment was determined in two ways. First, by local infusion of 1 muM flesinoxan for 30 min into the amygdala, which showed a significant 63% reduction in response (area under the concentration-time curve; AUC) for the citalopram group compared to the saline group. Second, by systemic administration of citalopram (10 mu mol/kg), which increased 5-HT to 350% of basal level. The effect was larger than in untreated animals, but more important, local infusion of 1 muM WAY 100.635 into the amygdala now failed to augment the effect of citalopram. Both the flesinoxan and WAY 100.635 data suggest an involvement of postsynaptic 5-HT1A receptor-mediated feedback in the amygdala, which diminishes following chronic citalopram treatment.</p

Desensitisation of 5-HT autoreceptors upon pharmacokinetically monitored chronic treatment with citalopram

Rats were chronically treated with the selective serotonin re-uptake inhibitor citalopram [1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phtalancarbonitril], by means of osmotic minipumps. Using an infusion concentration of 50 mg/ml citalopram, steady-state plasma concentrations of approximately 0.3 mu M citalopram were maintained for 15 days. Citalopram plasma levels dropped below pharmacologically active concentrations 48 h after removal of the minipumps. Although chronic treatment with citalopram did induce an attenuated response by extracellular levels of 5-hydroxytryptamine (5-HT) after systemic administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), no effect of chronic citalopram treatment was observed when 5-HT1B receptor function was evaluated with a local infusion of 5-HT1B/D receptor agonist, sumatriptan (3-[2-dimethylamino]ethyl-N-methyl-1 H-indole-5methane sulphonamide). Controversially, no augmentation of the increase of 5-HT levels was observed upon systemic administration of citalopram It is concluded that, although chronic treatment with citalopram does induce desensitisation of 5-HT1A receptors, the absence of augmented effects of citalopram on 5-HT levels indicates that other mechanisms compensate for the loss of autoreceptor control. (C) 2000 Elsevier Science B.V. All rights reserved