Chronic escitalopram treatment attenuated the accelerated rapid eye movement sleep transitions after selective rapid eye movement sleep deprivation: a model-based analysis using Markov chains

BackgroundShortened rapid eye movement (REM) sleep latency and increased REM sleep amount are presumed biological markers of depression. These sleep alterations are also observable in several animal models of depression as well as during the rebound sleep after selective REM sleep deprivation (RD). Furthermore, REM sleep fragmentation is typically associated with stress procedures and anxiety. The selective serotonin reuptake inhibitor (SSRI) antidepressants reduce REM sleep time and increase REM latency after acute dosing in normal condition and even during REM rebound following RD. However, their therapeutic outcome evolves only after weeks of treatment, and the effects of chronic treatment in REM-deprived animals have not been studied yet.ResultsChronic escitalopram- (10 mg/kg/day, osmotic minipump for 24 days) or vehicle-treated rats were subjected to a 3-day-long RD on day 21 using the flower pot procedure or kept in home cage. On day 24, fronto-parietal electroencephalogram, electromyogram and motility were recorded in the first 2 h of the passive phase. The observed sleep patterns were characterized applying standard sleep metrics, by modelling the transitions between sleep phases using Markov chains and by spectral analysis.Based on Markov chain analysis, chronic escitalopram treatment attenuated the REM sleep fragmentation [accelerated transition rates between REM and non-REM (NREM) stages, decreased REM sleep residence time between two transitions] during the rebound sleep. Additionally, the antidepressant avoided the frequent awakenings during the first 30 min of recovery period. The spectral analysis showed that the SSRI prevented the RD-caused elevation in theta (5 inverted question mark9 Hz) power during slow-wave sleep. Conversely, based on the aggregate sleep metrics, escitalopram had only moderate effects and it did not significantly attenuate the REM rebound after RD.ConclusionIn conclusion, chronic SSRI treatment is capable of reducing several effects on sleep which might be the consequence of the sub-chronic stress caused by the flower pot method. These data might support the antidepressant activity of SSRIs, and may allude that investigating the rebound period following the flower pot protocol could be useful to detect antidepressant drug response. Markov analysis is a suitable method to study the sleep pattern

Luminescent Tris(8-hydroxyquinolates) of Bismuth(III)

Luminescent homoleptic bismuth(III) complexes have been synthesized by adding several functionalized 8-hydroxyquinolate ligands to bismuth(III) chloride in a 3:1 mole ratio in either ethanol or tetrahydrofuran (THF) solvent. These complexes have been characterized by single-crystal X-ray diffraction (XRD) analysis, UV-vis spectroscopy, fluorescence spectroscopy, and density functional theory (DFT) calculations to determine their structures and photophysical properties. Reversible dimerization of the mononuclear tris(hydroxyquinolate) complexes was observed in solution and quantified using UV-vis spectroscopy. The fluorescence spectra show a blue shift for the monomer compared with homoleptic aluminum(III) hydroxyquinolate compounds. Four dimeric compounds and one monomeric isomer were characterized structurally. The bismuth(III) centers in the dimers are bridged by two oxygen atoms from the substituted hydroxyquinolate ligands. The more sterically hindered quinolate complex, tris(2-(diethoxymethyl)-8-quinolinato)bismuth, crystallizes as a monomer. The complexes all exhibit low-lying absorption and emission spectral features attributable to transitions between the HOMO (π orbital localized on the quinolate phenoxide ring) and LUMO (π* orbital localized on the quinolate pyridyl ring). Excitation and emission spectra show a concentration dependence in solution that suggests that a monomer-dimer equilibrium occurs. Electronic structure DFT calculations support trends seen in the experimental results with a HOMO-LUMO gap of 2.156 eV calculated for the monomer that is significantly larger than those for the dimers (1.772 and 1.915 eV). The close face to face approach of two quinolate rings in the dimer destabilizes the uppermost occupied quinolate π orbitals, which reduces the HOMO-LUMO gap and results in longer wavelength absorption and emission spectral features than in the monomer form

Control of 5-hydroxytryptamine release in the dorsal raphe nucleus by the noradrenergic system in rat brain. Role of alpha-adrenoceptors

The interactions between the brainstem serotonergic (5-hydroxytryptamine, 5-HT) and noradrenergic (NA) systems are important for the pathophysiology and treatment of affective disorders. We examined the influence of -adrenoceptors on 5-HT and NA release in the rat dorsal raphe nucleus (DR) using microdialysis. 5-HT and NA concentrations in DR dialysates were virtually suppressed by TTX and increased by veratridine. The local and systemic administration of the 1-adrenoceptor antagonist prazosin reduced the DR 5-HT output but not that of NA. The maximal 5-HT reduction induced by local prazosin administration (-78% at 100 M) was more marked than by its systemic administration (-43% at 0.3 mg/kg). The local application of NA and desipramine, to increase the tone on DR 1-adrenoceptors, did not enhance 5-HT release. The local (100 M) or systemic (0.1–1 mg/kg s.c.) administration of clonidine reduced 5-HT and NA release (-48 and -79%, respectively, at 1 mg/kg), an effect reversed by RX-821002, which by itself increased both amines when given systemically. DSP-4 pretreatment prevented the effects of clonidine on 5-HT, suggesting the participation of 2-adrenoceptors on NA elements. Moreover, the systemic effect of clonidine on 5-HT (but not NA) was cancelled by lesion of the lateral habenula and by anesthesia, and was slightly enhanced by cortical transection. These data support the view that 1-adrenoceptors in the DR tonically stimulate 5-HT release, possibly at nearly maximal tone. Likewise, the 5-HT release is modulated by 2-adrenoceptors in NA neurons and in forebrain areas involved in the distal control of 5-HT neurons.Peer reviewe

The mechanism of action of doxofylline is unrelated to HDAC inhibition, PDE inhibition or adenosine receptor antagonism

Xanthines such as theophylline have been used in the treatment of lung diseases since the early 1900's, but have a major drawback of a very narrow therapeutic window and many drug/drug interactions. This means that plasma levels have to be measured regularly and can make the use of theophylline problematic. With the increasing availability of other classes of drugs for the treatment of respiratory diseases, this has limited the use of xanthines, despite their clear clinical benefit in the treatment of patients with asthma and COPD. Doxofylline is a xanthine molecule having both bronchodilator and anti-inflammatory activity with an improved therapeutic window over conventional xanthines such as theophylline. However, the mechanistic basis of this improved therapeutic window is not understood. The present study has investigated some pharmacological activities of doxofylline in comparison with theophylline. Doxofylline does not directly inhibit any of the known HDAC enzymes, and did not inhibit any POE enzyme sub types or act as an antagonist at any of the known adenosine receptors, except for PDE2A(1), and adenosine Am and only at the highest tested concentration (10(-4) M). These results may explain the improved tolerability profile of doxofylline compared with theophylline. (C) 2011 Published by Elsevier Ltd

(−)Tertatolol is a potent antagonist at pre- and postsynaptic serotonin 5-HT1A receptors in the rat brain

The potential 5-HT1A antagonist properties of the ß-antagonist tertatolol were assessed using biochemical and electrophysiological assays in the rat. (±) Tertatolol bound with high affinity (Ki = 38 nM) to 5-HT1A sites labelled by [3H]8-OH-DPAT in hippocampal membranes. The (–)stereoisomer (Ki = 18 nM) was about 50-fold more potent than the (+)stereoisomer (Ki = 864 nM) to inhibit the specific binding of [3H]-8-OHDPAT. As expected of a 5-HT1A antagonist, (–)tertatolol prevented in a concentration-dependent manner (Ki = 24 nM) the inhibitory effect of 8-OH-DPAT on forskolin-stimulated adenylate cyclase activity in rat hippocampal homogenates. Furthermore in vivo pretreatment with (–)tertatolol (5 mg/kg s.c.) significantly reduced the inhibitory influence of 8-OH-DPAT (0.3 mg/ kg s.c.) on the accumulation of 5-hydroxytryptophan in various brain areas after the blockade of aromatic L-amino acid decarboxylase by NSD-1015 (100 mg/kg i.p.). In vitro (in brainstem slices; Ki 50 nM) and in vivo (in chloral hydrate anaesthetized rats; ID50 0.40 mg/kg i.v.), (–)tertatolol prevented the inhibitory effects of the 5-HT1A receptor agonists 8-OH-DPAT, ipsapirone and lesopitron on the firing rate of serotoninergic neurones within the dorsal raphe nucleus. In about 25% of these neurones, the basal firing rate was significantly increased by (–)tertatolol (up to +47% in vitro, and +30% in vivo). These data indicate that (-)tertatolol is a potent competitive antagonist at both pre (in the dorsal raphe nucleus) - and post (in the hippocampus) - synaptic 5-HT1A receptors in the rat brain