To use or not to use? Compulsive behavior and its role in smartphone addiction.

Global smartphone penetration has led to unprecedented addictive behaviors. To develop a smartphone use/non-use pattern by mobile application (App) in order to identify problematic smartphone use, a total of 79 college students were monitored by the App for 1 month. The App-generated parameters included the daily use/non-use frequency, the total duration and the daily median of the duration per epoch. We introduced two other parameters, the root mean square of the successive differences (RMSSD) and the Similarity Index, in order to explore the similarity in use and non-use between participants. The non-use frequency, non-use duration and non-use-median parameters were able to significantly predict problematic smartphone use. A lower value for the RMSSD and Similarity Index, which represent a higher use/non-use similarity, were also associated with the problematic smartphone use. The use/non-use similarity is able to predict problematic smartphone use and reach beyond just determining whether a person shows excessive use.

The Effects of Antidepressants and Quetiapine on Heart Rate Variability.

Introduction: The autonomic effects of antidepressants and quetiapine on heart rate variability (HRV) are inconsistent based on past studies. The aim of this study was to explore their influence on the HRV of psychiatric patients without psychotic symptoms. Methods: A total of 94 patients with depression, anxiety, or somatic symptoms, were recruited into this study. Based on their medication, 4 groups were identified: the no antidepressant group (n=19), the SSRI group (using sertraline or escitalopram, n=53), the other antidepressants group (using venlafaxine or mirtazapine, n=9), and the augmentation group (AG, using an antidepressant+quetiapine, n=13). The HRV of the 4 groups were compared. The correlations between HRV and the medication(s) used were clarified. Results: Among the 4 groups, the AG had the lowest HRV with its total power (TP), very low frequency power (VLF) and low frequency power (LF) of HRV being significantly different from those of the other groups. Age and using quetiapine were found to be negatively correlated with TP, VLF and LF. With this study group, the autonomic effects of antidepressants were found not to be significant. Discussion: Among psychiatric patients without psychotic symptoms, quetiapine causes an overt decrease in HRV.

Alteration of the interaction of mu-opioid receptor and G protein after chronic PL017 treatment in rats.

Alteration in ligand-receptor interaction during chronic drug treatment has been suggested as a possible mechanism underlying opioid tolerance. However, our previous studies found that chronic PL017 (a selective mu-opioid agonist) treatment of adult animals resulted in down regulation of mu opioid receptor levels only after 5 days of PL017 treatment although tolerance had significantly developed after 3 days of PL017 treatment. Since G protein seems to be involved in regulation of opioid receptors, we suspect that opioid receptor-G protein interaction may be altered after chronic PL017 treatment before down-regulation of opioid receptors occurrs. Our investigation proceeded first, by measuring the ability of Gpp(NH)p to alter mu-opioid agonist: [3H]DAMGO binding; and second, by measuring the opioid agonist-stimulated GTPase activity before and after chronic PL017 treatment for 1 or 3 days when tolerance has developed but without down-regulation. We found that after 1 day and 3 days of PL017 treatment, rats produced 1.9 and 7.4 fold degree of tolerance. In receptor binding assay, we found the Bmax values did not show significant difference before and after chronic PL017 treatment. On the other hand, 10 microM Gpp(NH)p (a stable GTP analogue) significantly increased the Kd of the control midbrain by 2.59 +/- 0.21 fold but only increased the Kd by 1.92 +/- 0.11 fold after 3 days of PL017 treatment. Furthermore, the EC50 and maximal effect of DAMGO on stimulating low Km GTPase activity for control midbrain are 1.2 +/- 0.3 10(-8) M and 21.7 +/- 0.6%, respectively; in the experimental group, after 3 days PL017 treatment, the EC50 has increased to 7.3 +/- 2.7 x 10(-8) M and maximal stimulation decreased to 16.6 +/- 1.1%. The present findings indicate that after 3 days chronic PL017 treatment: (1) The effect of Gpp(NH)p on the affinity of mu-opioid receptor and DAMGO has been diminished. (2) The effect of DAMGO on stimulating low Km GTPase activity of G protein has been decreased. Therefore, it seems that the interaction between opioid receptor and G protein has been altered after chronic PL017 treatment. This phenomenum happens before down-regulation, and it may be one of the mechanisms for opioid tolerance.

Three-dimensional structure in solution of griseoviridin, a group A antibiotic.

The solution conformation of griseoviridin, a broad spectrum antibiotic, has been determined by 1H-NMR in deuterated dimethylsulfoxide. The structural determination is based on experimental data of NOE constraints Five structures were obtained from restrained molecular dynamics calculations, by imposing (the condition for) a minimum violation of distance constraints. These structures satisfy well the experimental restraints, with small values of NOE violation and total energies. On comparison with its crystal structure, a good agreement is noted with a backbone root-mean-square deviation value of 0.084 nm. However, a small variation between the structures is observed at the aminodecanoic acid part of the molecule.

Solution conformation of enopeptin A, a depsipeptide antibiotic, using 2D NMR and restrained molecular dynamics studies.

Studies on the solution conformation of the cyclic depsipeptide antibiotic enopeptin A have been carried out using 2D NMR and molecular modelling techniques. The proton resonances of the antibiotic in DMSO-d6 have been assigned by the use of TOCSY and ROESY experiments. The interproton distance information obtained from the ROESY experiments have been used as the basis for elucidating the probable structures in solution. The restrained molecular dynamics technique was applied to calculate the structures in solution, and six resultant structures with fewer distance constraint violations were obtained that satisfy the experimental restraints very well. The conformation of the cyclic moiety of the molecules is well defined whereas the aliphatic chain segment is disordered.

FL-120A-D', new products related to kinamycin from Streptomyces chattanoogensis subsp. taitungensis subsp. nov. I. Taxonomy, fermentation and biological properties.

Six new kinamycin antibiotics, designated as FL-120A-D' (1-6) were isolated from the culture filtrate of Streptomyces sp. strain IY2-13. Based on its cultural, physiological, morphological and chemical characteristics, this strain was identified as a new subspecies of Streptomyces chattanoogensis and named S. chattanoogensis subsp. taitungensis. These kinamycins have demonstrated a potent activity against Gram-positive aerobic and anaerobic bacteria.

FL-120A-D', new products related to kinamycin from Streptomyces chattanoogensis subsp. taitungensis subsp. nov. II. Isolation and structure determination.

Six new kinamycin antibiotics have been isolated from the culture filtrate of Streptomyces chattanoogensis. The structures of six related components were determined employing 1D and 2D NMR spectroscopy and mass spectrometry. These structures represent the first reported epoxide kinamycin (2, 3) and propionyl derivative of kinamycin (5), and new isobutyryl derivatives of kinamycin (1, 4, 6).

Chronic opioid treatment may uncouple opioid receptors and G-proteins: evidence from radiation inactivation analysis.

Radiation inactivation (target size analysis) was used in this study to determine whether uncoupling of opioid receptor and G-protein is a contributing mechanism to opioid tolerance. Male Sprague-Dawley rats (160-260 g) were rendered tolerant to morphine or [D-Ala2,D-Leu5]enkephalin (DADLE) by multiple i.p. or i.c.v. injections twice a day for 6 or 5 days. Control rats were injected with saline instead of opioids. The animals were killed, the midbrains excised and pooled together for each group. The washed P2 membranes were suspended in buffer and irradiated with 1-10 Mrad doses of 60Co irradiation, following which mu- or delta-opioid receptor binding activity of each sample was assayed. The molecular weight of the receptor was calculated from a standard irradiation curve constructed using several enzyme markers of known molecular weight. We found that the functional molecular size of mu-opioid receptor significantly decreased from 349 kDa to 228 kDa after 6 days of chronic morphine treatment, while, the molecular size of delta-opioid receptor decreased from 303 kDa to 223 kDa after 5 days of chronic DADLE treatment. These results are consistent with the uncoupling of opioid receptor from G-protein during chronic opioid treatment.

Chronic effect of [D-Pen2,D-Pen5]enkephalin on rat brain opioid receptors.

In previous studies, we have demonstrated that chronic etorphine or [D-Ala2,D-Leu5]enkephalin (DADLE) treatment of rats results in the reduction of mu- and delta-opioid receptor binding activities as tolerance develops. As both etorphine and DADLE are relatively non-specific opioid ligands, interacting with both mu- and delta-receptors, these studies could not determine whether down-regulation of a specific receptor type occurs. Therefore, in the present studies, animals were rendered tolerant to the delta-opioid receptor-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE), and receptor binding activities were measured. Treating Sprague-Dawley rats with increasing doses of DPDPE (80-160-240-320 micrograms/kg) i.c.v. for 1 to 4 days resulted in a time-dependent increase in the AD50 of DPDPE to elicit an antinociceptive response. When delta-receptor binding was determined by using [3H]DPDPE, a 40-50% decrease in binding in the midbrain and cortex, and 25-35% decrease in binding in the striatum were observed after 3 or 4 days of DPDPE treatment. Scatchard analysis of the [3H]DPDPE saturation binding data revealed a decrease in Bmax values and no significant change in Kd values. To our surprise, when mu-receptor binding was determined by using [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO), a 10-15% decrease in binding was also observed in the midbrain and cortex after 4 days of DPDPE treatment. Our conclusion is that chronic DPDPE treatment preferentially reduces delta-opioid receptor binding activity. Its minor effect on the mu-opioid receptor maybe due to an interaction between delta cx and mu cx binding sites.

Decrease in mu-opioid receptor binding capacity in rat brain after chronic PL017 treatment.

In previous studies, we have demonstrated that chronic treatment of rats with either etorphine or D-Ala2, D-Leu5-enkephalin (DADLE) resulted in the reduction of opioid receptor binding activities during the course of tolerance development. In both cases, mu-opioid receptor binding capacity was attenuated together with the delta-opioid receptor binding capacity. Because both etorphine and DADLE are relatively non-specific opioid ligands, interacting with both mu and delta receptors, these studies could not determine whether down-regulation of a specific receptor type is possible. Therefore, in the current studies, animals were rendered tolerant to the mu-opioid receptor-selective ligand PL017 and the receptor binding capacity was measured afterwards. Treating Sprague-Dawley rats with increasing doses of PL017 (2.5-20 micrograms/kg) i.c.v. for 5 days resulted in a 30- to 40-fold increase in the AD50 of the peptide to elicit the antinociceptive response and about 14-fold increase in the ED50 of the peptide to elicit the catatonic effect. When mu- and delta-binding was determined using [3H]diprenorphine in the presence of morphiceptin or DPDPE respectively, a significant decrease (20-30%) in the mu-opioid receptor binding but not in delta-opioid receptor binding was observed in all the brain areas tested after 5 days of PL017 treatment. Scatchard analysis of the [3H]DAMGO saturation binding data revealed a decrease in Bmax values and no change in the Kd values. Hence, mu-opioid receptors can be specifically regulated by ligand in the brain as delta-receptors are in neuroblastoma x glioma NG 108-15 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Decrease in delta-opioid receptor density in rat brain after chronic [D-Ala2,D-Leu5]enkephalin treatment.

Chronic treatment of Sprague-Dawley rats with [D-Ala2,D-Leu5]enkephalin (DADLE) resulted in the development of tolerance to the antinociceptive effect of this opioid peptide. When opioid receptor binding was measured, time-dependent decreases in [3H]diprenorphine binding to the P2 membranes prepared from the cortex, midbrain and striatum were observed. Scatchard analysis of the saturation binding data revealed a decrease in Bmax values and no change in the Kd values of [3H]diprenorphine binding to these brain regions, indicative of down-regulation of the receptor. This reduction in the opioid receptor binding activities could be demonstrated to be due to the DADLE effect on the delta-opioid receptors in these brain regions. When [3H]DADLE binding was carried out in the presence of morphiceptin, a significant reduction in the delta-opioid receptor binding was observed in all brain areas tested. mu-Opioid receptor binding decrease was observed only in the striatum after 5 days of DADLE treatment. Additionally, the onset of delta-opioid receptor decrease in the midbrain area was rapid, within 6 h of the initiation of the chronic DADLE treatment. Thus, analogous to previous observations in which chronic etorphine treatment preferentially reduced mu-opioid receptor binding, chronic DADLE treatment preferentially reduced delta-opioid receptor binding activity.

Determination of the sizes of the opioid receptors in their membrane environment by radiation inactivation.

Opioids, like other drugs, are thought to initiate their effects by association with their specific receptors. However, very little is known about the opioid receptor as a molecular entity. The binding components have been solubilized in detergent and purified by different approaches, but the molecular size of soluble opioid receptor complexes reported by different groups varied from 23,000 to 750,000. In this study, the technique of radiation inactivation by gamma rays was used to investigate the apparent size of the opioid receptor in rat brain membranes under different conditions. The molecular sizes of opioid receptor complexes were estimated as 313,000 +/- 13,500 in the presence of [D-Ala2, D-Leu5] enkephalin, NaCl and Gpp (NH)p; as 165,000 +/- 8,500 in the presence of NaCl only, or of both NaCl and Gpp (NH)p; as 217,000 +/- 6,600 in the presence of Gpp (NH)p only; and as 286,000 +/- 60,900 in the presence of MgCl2 only. A simple model has been proposed to explain these different apparent target sizes of opioid receptors obtained under different conditions.

Heterogeneity of [3H]ethyl beta-carboline-3-carboxylate binding sites and [3H]gamma-aminobutyric acid binding sites.

Binding properties of [3H]flunitrazepam ([3H]FNZ), [3H]ethyl beta-carboline-3-carboxylate ([3H]beta CCE), [3H]muscimol ([3H]MUSC) and [3H]gamma-aminobutyric acid ([3H]GABA) to bovine cortical membranes and to their Triton extracts were studied. GABA, 1 X 10(-5) M, stimulated [3H]FNZ binding of frozen, thawed and washed membranes by an increase in affinity without alteration of the maximal number of binding sites, and this GABA stimulated [3H]FNZ binding can be inhibited by bicuculline methobromide. Freeze, thaw and wash with Triton X-100 removed the low affinity [3H]MUSC binding sites. The ratios of [3H]FNZ binding sites to [3H]beta CCE binding sites and [3H]MUSC binding sites to [3H]GABA binding sites were always found to be about 1:2 in both membranes and soluble extracts. The fact that [3H]beta CCE, after displaced by clonazepam, can be further displaced by unlabelled beta CCE from its binding sites and that a portion of [3H]beta CCE binding sites can be survived from FNZ-photolysis implied that there are at least two subclasses of beta CCE binding sites, one is sensitive to beta CCE only and the other is sensitive to both beta CCE and benzodiazepines (BZs). [3H]GABA, after displaced by MUSC, can be further displaced by unlabelled GABA from its binding sites. The results also support that there are two subclasses of BZ-related GABA binding sites, one is sensitive to GABA only and the other is sensitive to both GABA and MUSC. Furthermore, the decay rates of [3H]beta CCE and [3H]GABA binding activities exposed to various degree of electron bombardment are identical, which is evident that these two binding sites are believed to be functional associated in a macromolecular complex with molecular mass about 220,000 Mr.

The benzodiazepine/GABA receptor complex: molecular size in brain synaptic membranes and in solution.

The molecular size of the benzodiazepine (BZ) receptor in the synaptic membrane of brain cortex (bovine or rat) was determined by an improved version of the radiation inactivation method to be 220,000. An identical size was found simultaneously for the associated gamma-aminobutyric acid (GABA) receptor and for the component binding beta-carboline esters. It is proposed that all three activities reside in a single protein or protein complex in the membrane. The size in solution, after extraction into Triton X-100 medium from exhaustively washed membranes, was estimated by sedimentation constant (9.4S) and by gel filtration ( approximately 230,000 apparent MW), again with the BZ and GABA binding activities behaving identically. This size applies to the component that undergoes photoaffinity labelling by [3H]flunitrazepam in the membrane, and contains a 51,000 Mr polypeptide as the BZ-binding subunit. It is concluded that a protein complex or oligomer of 200,000-220,000 MW carries a class of BZ-binding sites and an associated class of GABAA sites.

Effect of GABA on the electrical potentials across the mouse small intestine.

The effects of gamma-aminobutyric acid (GABA) on transmural potential difference (PD) and radioactive chloride fluxes (J) across the mouse small intestine were studied. It was found that GABA decreased the PD and increased the J in both mucosal-to-serosal and serosal-to-mucosal directions (JMS and JSM) only at a concentration of or higher than 50 mM. The PD was increased by the presence of 10 mM glucose or glycine in bathing solutions. The PD was also decreased by increasing the osmolarity of the bathing solutions with increasing concentration of GABA, mannitol, sucrose, or glucose. Our results suggested that the hyperosmotic effect causes the decrease of PD and the increase of J across the mouse small intestine by GABA.

The effect of diuretics on sodium transport across the mouse intestine.

The effects of three natriuretic agents on Na transport across the mouse intestine were determined. It was found that ethacrynic acid at a concentration of 1mM, markedly reduced the net transmural transport of Na ion by decreasing themucosa-to-serosa flux with little or no effect on serosa-to-mucosa flux. Furosemide or amiloride at a concentration of 1 mM produced similar but less profound effects. A reduction of net Na22 flux was observed in the presence of either diuretic, but with furosemide and amiloride this inhibitory effect observed only if glucose was present in the bathing solution. It is, therefore, concluded that the intestinal transport of Na ion involves two processes, one is glucose or substrate-dependent, and the other glucose or substrate-independent. Ethacrynic acid inhibits the substrate-independent process while furosemide and amiloride affect only the substrate-dependent process of Na transport.