Dual inhibitory action of trazodone on dorsal raphe serotonergic neurons through 5-HT1A receptor partial agonism and α1-adrenoceptor antagonism

Trazodone is an antidepressant drug with considerable affinity for 5-HT1A receptors and α1-adrenoceptors for which the drug is competitive agonist and antagonist, respectively. In this study, we used cell-attached or whole-cell patch-clamp recordings to characterize the effects of trazodone at somatodendritic 5-HT1A receptors (5-HT1AARs) and α1-adrenoceptors of serotonergic neurons in rodent dorsal raphe slices. To reveal the effects of trazodone at α1-adrenoceptors, the baseline firing of 5-HT neurons was facilitated by applying the selective α1-adrenoceptor agonist phenylephrine at various concentrations. In the absence of phenylephrine, trazodone (1-10 μM) concentration-dependently silenced neurons through activation of 5-HT1AARs. The effect was fully antagonized by the selective 5-HT1A receptor antagonist Way-100635. With 5-HT1A receptors blocked by Way-100635, trazodone (1-10 μM) concentration-dependently inhibited neuron firing facilitated by 1 μM phenylephrine. Parallel rightward shift of dose-response curves for trazodone recorded in higher phenylephrine concentrations (10-100 μM) indicated competitive antagonism at α1-adrenoceptors. Both effects of trazodone were also observed in slices from Tph2-/- mice that lack synthesis of brain serotonin, showing that the activation of 5-HT1AARs was not mediated by endogenous serotonin. In whole-cell recordings, trazodone activated 5-HT1AAR-coupled G protein-activated inwardly-rectifying (GIRK) channel conductance with weak partial agonist efficacy (~35%) compared to that of the full agonist 5-CT. Collectively our data show that trazodone, at concentrations relevant to its clinical effects, exerts weak partial agonism at 5-HT1AARs and disfacilitation of firing through α1-adrenoceptor antagonism. These two actions converge in inhibiting dorsal raphe serotonergic neuron activity, albeit with varying contribution depending on the intensity of α1-adrenoceptor stimulation

Hypercapnia augments resistive exercise‐induced elevations in intraocular pressure in older individuals

The present study assessed the effect of 6° head down (establishing the cephalad displacement noted in astronauts in microgravity) prone (simulating the effect on the eye) tilt during rest and exercise (simulating exercise performed by astronauts to mitigate the sarcopenia induced by unloading of weight‐bearing limbs), in normocapnic and hypercapnic conditions (the latter simulating conditions on the International Space Station) on IOP.Volunteers (average age = 57.8 ± 6 yrs.; N = 10) participated in two experimental sessions, each comprising: i) 10‐min rest, ii) 3‐min handgrip dynamometry (30% max), and iii) 2‐min recovery, inspiring either room air (NCAP), or a hypercapnic mixture (1% CO2, HCAP). We measured IOP in the right eye, cardiac output (CO), stroke volume (SV), heart rate (HR) and mean arterial pressure (MAP) at regular intervals. Baseline IOP in the upright seated position while breathing room air was 14.1 ± 2.9 mmHg. Prone 6° HDT significantly (p < 0.01) elevated IOP in all three phases of the NCAP (rest: 27.9 ± 3.7 mmHg; exercise: 32.3 ± 4.9 mmHg; recovery: 29.1 ± 5.8 mmHg) and HCAP (rest: 27.3 ± 4.3 mmHg; exercise: 34.2 ± 6.0 mmHg; recovery: 29.1) trials, with hypercapnia augmenting the exercise‐induced elevation in IOP (p < 0.01). CO, SV, HR and MAP were significantly increased during handgrip dynamometry, but there was no effect of hypercapnia. The observed IOP measured during prone 6°HDT in all phases of the NCAP and HCAP trials exceeded the threshold pressure defining ocular hypertension. The exercise‐induced increase in IOP is exacerbated by hypercapnia

Electro-elastic tuning of single particles in individual self-assembled quantum dots

We investigate the effect of uniaxial stress on InGaAs quantum dots in a charge tunable device. Using Coulomb blockade and photoluminescence, we observe that significant tuning of single particle energies (~ -0.5 meV/MPa) leads to variable tuning of exciton energies (+18 to -0.9 micro-eV/MPa) under tensile stress. Modest tuning of the permanent dipole, Coulomb interaction and fine-structure splitting energies is also measured. We exploit the variable exciton response to tune multiple quantum dots on the same chip into resonance.Comment: 16 pages, 4 figures, 1 table. Final versio

Molecular Background of Leak K+ Currents: Two-Pore Domain Potassium Channels

Enyedi P, Czirjak G. Molecular Background of Leak K+ Currents: Two-Pore Domain Potassium Channels. Physiol Rev 90: 559-605, 2010; doi:10.1152/physrev.00029.2009.-Two-pore domain K+ (K-2P) channels give rise to leak (also called background) K+ currents. The well-known role of background K+ currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K-2P channel types) that this primary hyperpolarizing action is not performed passively. The K-2P channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e. g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K-2P channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K-2P channel family into the spotlight. In this review, we focus on the physiological roles of K-2P channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation

Anisotropic Confinement, Electronic Coupling and Strain Induced Effects Detected by Valence-Band Anisotropy in Self-Assembled Quantum Dots

A method to determine the effects of the geometry and lateral ordering on the electronic properties of an array of one-dimensional self-assembled quantum dots is discussed. A model that takes into account the valence-band anisotropic effective masses and strain effects must be used to describe the behavior of the photoluminescence emission, proposed as a clean tool for the characterization of dot anisotropy and/or inter-dot coupling. Under special growth conditions, such as substrate temperature and Arsenic background, 1D chains of In0.4Ga0.6 As quantum dots were grown by molecular beam epitaxy. Grazing-incidence X-ray diffraction measurements directly evidence the strong strain anisotropy due to the formation of quantum dot chains, probed by polarization-resolved low-temperature photoluminescence. The results are in fair good agreement with the proposed model

High resolution nuclear magnetic resonance spectroscopy of highly-strained quantum dot nanostructures

Much new solid state technology for single-photon sources, detectors, photovoltaics and quantum computation relies on the fabrication of strained semiconductor nanostructures. Successful development of these devices depends strongly on techniques allowing structural analysis on the nanometer scale. However, commonly used microscopy methods are destructive, leading to the loss of the important link between the obtained structural information and the electronic and optical properties of the device. Alternative non-invasive techniques such as optically detected nuclear magnetic resonance (ODNMR) so far proved difficult in semiconductor nano-structures due to significant strain-induced quadrupole broadening of the NMR spectra. Here, we develop new high sensitivity techniques that move ODNMR to a new regime, allowing high resolution spectroscopy of as few as 100000 quadrupole nuclear spins. By applying these techniques to individual strained self-assembled quantum dots, we measure strain distribution and chemical composition in the volume occupied by the confined electron. Furthermore, strain-induced spectral broadening is found to lead to suppression of nuclear spin magnetization fluctuations thus extending spin coherence times. The new ODNMR methods have potential to be applied for non-invasive investigations of a wide range of materials beyond single nano-structures, as well as address the task of understanding and control of nuclear spins on the nanoscale, one of the central problems in quantum information processing

Acute effects of MDMA (3,4-methylenedioxymethamphetamine) on EEG oscillations: alone and in combination with ethanol or THC (delta-9-tetrahydrocannabinol)

Item does not contain fulltextRATIONALE: Typical users of 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") are polydrug users, combining MDMA with alcohol or cannabis [most active compound: delta-9-tetrahydrocannabinol (THC)]. OBJECTIVES: The aim of the present study was to investigate whether co-administration of alcohol or THC with MDMA differentially affects ongoing electroencephalogram (EEG) oscillations compared to the administration of each drug alone. METHODS: In two separate experiments, 16 volunteers received four different drug conditions: (1) MDMA (100 mg); (2) alcohol clamp (blood alcohol concentration = 0.6 per thousand) or THC (inhalation of 4, 6 and 6 mg, interval of 1.5 h); (3) MDMA in combination with alcohol or THC; and (4) placebo. Before and after drug administration, electroencephalography was recorded during an eyes closed resting state. RESULTS: Theta and alpha power increased after alcohol intake compared to placebo and reduced after MDMA intake. No interaction between alcohol and MDMA was found. Significant MDMA x THC effects for theta and lower-1-alpha power indicated that the power attenuation after the combined intake of MDMA and THC was less than the sum of each drug alone. For the lower-2-alpha band, the intake of MDMA or THC alone did not significantly affect power, but the intake of combined MDMA and THC significantly decreased lower-2-alpha power. CONCLUSIONS: The present findings indicate that the combined intake of MDMA and THC, but not of MDMA and alcohol, affects ongoing EEG oscillations differently than the sum of either one drug alone. Changes in ongoing EEG oscillations may be related to the impaired task performance that has often been reported after drug intake

Acute neuropsychological effects of MDMA and ethanol (co-)administration in healthy volunteers

Contains fulltext : 73592.pdf (publisher's version ) (Open Access)RATIONALE: In Western societies, a considerable percentage of young people expose themselves to 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"). Commonly, ecstasy is used in combination with other substances, in particular alcohol (ethanol). MDMA induces both arousing as well as hallucinogenic effects, whereas ethanol is a general central nervous system depressant. OBJECTIVE: The aim of the present study is to assess the acute effects of single and co-administration of MDMA and ethanol on executive, memory, psychomotor, visuomotor, visuospatial and attention function, as well as on subjective experience. MATERIALS AND METHODS: We performed a four-way, double-blind, randomised, crossover, placebo-controlled study in 16 healthy volunteers (nine male, seven female) between the ages of 18-29. MDMA was given orally (100 mg) and blood alcohol concentration was maintained at 0.6 per thousand by an ethanol infusion regime. RESULTS: Co-administration of MDMA and ethanol was well tolerated and did not show greater impairment of performance compared to the single-drug conditions. Impaired memory function was consistently observed after all drug conditions, whereas impairment of psychomotor function and attention was less consistent across drug conditions. CONCLUSIONS: Co-administration of MDMA and ethanol did not exacerbate the effects of either drug alone. Although the impairment of performance by all drug conditions was relatively moderate, all induced significant impairment of cognitive function