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- Long-lasting distortion of GABA signaling in MS/DB neurons after binge-like ethanol exposure during initial synaptogenesis. [JOURNAL ARTICLE]
- Brain Res 2013 May 15.
Using a well-established model of binge-like ethanol treatment of rat pups on postnatal days (PD) 4-9, we found that maturation of GABAA receptor (GABAAR) miniature postsynaptic currents (mPSCs) was substantially blunted for medial septum/diagonal band (MS/DB) neurons in brain slices on PD 11-16. Ethanol reduced mPSC amplitude, frequency, and decay kinetics, while attenuating or exaggerating allosteric actions of zolpidem and allopregnanolone, respectively. The impact of ethanol in vivo was long lasting as most changes in MS/DB GABAAR mPSCs were still observed as late as PD 60-85. Maturing MS/DB neurons in naïve brain slices PD 4-16 showed increasing mPSC frequency, decay kinetics, and zolpidem sensitivity that were nearly identical to our earlier findings in cultured septal neurons (DuBois et al., 2004, 2006). These rapidly developing mPSC parameters continued to mature through the first month of life then stabilized throughout the remainder of the lifespan. Finally, equivalent ethanol-induced alterations in GABAAR mPSC signaling were present in MS/DB neurons from both male and female animals. Previously, we showed ethanol treatment of cultured embryonic day 20 septal neurons distorts the maturation of GABAAR mPSCs predicting that early stages of GABAergic transmission in MS/DB neurons are vulnerable to intoxication injury (DuBois et al., 2004, 2006). Since the overall character, timing, and magnitude of GABAergic mPSC developmental- and ethanol-induced changes in the in vivo model so closely mirror chronologically equivalent adaptations in cultured septal neurons, this suggests that such parallel models of ethanol impairment of GABAergic synaptic development in vivo and in vitro should be useful for translational studies exploring the efficacy and mechanism of action of potential therapeutic interventions from the cellular to whole animal level.
- Segmental Hair Analysis after a Single Dose of Zolpidem: Comparison with a Previous Study. [JOURNAL ARTICLE]
- J Anal Toxicol 2013 May 8.
Hair is a useful aid and sometimes even the only matrix in the analytical strategy in drug-facilitated crime (DFC) investigations. In this novel study, segmental hair analysis was performed after a single 10 mg dose of zolpidem was given to 20 Chinese volunteers. Hair was collected 1 month after administration and was analyzed using ultra-high-pressure liquid chromatography/electrospray ionization tandem mass spectrometry. Zolpidem concentrations were found to be in the range of 135.0-554.6 pg/mg in the proximal 0-2 cm segments. These results were markedly different from those reported by Villain et al., who used volunteers administered equal doses of zolpidem. The analytical method used, as well as the volunteers' hair color, inter-individual variations such as metabolic capacity, hair growth rate, drug incorporation rates, physical state of the hair, age, gender, body weight, etc. and diffusion from sweat or other secretions are all factors that should be considered when interpreting the DFC results.
- Partial Agonism of Taurine at Gamma-Containing Native and Recombinant GABAA Receptors. [Journal Article]
- PLoS One 2013; 8(4):e61733.
Taurine is a semi-essential sulfonic acid found at high concentrations in plasma and mammalian tissues which regulates osmolarity, ion channel activity and glucose homeostasis. The structural requirements of GABAA-receptors (GABAAR) gated by taurine are not yet known. We determined taurine potency and efficacy relative to GABA at different types of recombinant GABAAR occurring in central histaminergic neurons of the mouse hypothalamic tuberomamillary nucleus (TMN) which controls arousal. At binary α1/2β1/3 receptors taurine was as efficient as GABA, whereas incorporation of the γ1/2 subunit reduced taurine efficacy to 60-90% of GABA. The mutation γ2F77I, which abolishes zolpidem potentiation, significantly reduced taurine efficacy at recombinant and native receptors compared to the wild type controls. As taurine was a full- or super- agonist at recombinant αxβ1δ-GABAAR, we generated a chimeric γ2 subunit carrying the δ subunit motif around F77 (MTVFLH). At α1/2β1γ2(MTVFLH) receptors taurine became a super-agonist, similar to δ-containing ternary receptors, but remained a partial agonist at β3-containing receptors. In conclusion, using site-directed mutagenesis we found structural determinants of taurine's partial agonism at γ-containing GABAA receptors. Our study sheds new light on the β1 subunit conferring the widest range of taurine-efficacies modifying GABAAR function under (patho)physiological conditions.
- Zolpidem improves tardive dyskinesia and akathisia. [LETTER]
- Mov Disord 2013 May 1.
- Determination of zolpidem in human hair by micropulverized extraction based on the evaluation of relative extraction efficiency of seven psychoactive drugs from an incurred human hair specimen. [Journal Article]
- J Chromatogr A 2013 Jun 7.:28-35.
A micropulverization method for rapid extraction of psychoactive drugs from hair was developed. A hair sample (10mg) was micropulverized for 10min at 42Hz with 0.2mL of 45% (w/v) aqueous ammonium phosphate (pH 8.4). Liquid-liquid extraction was carried out in the same tube using acetonitrile, and the organic layer was removed and filtered. Conventional methods, including solid-liquid extraction with an ammonium phosphate solution or methanol, were also employed, and the relative extraction efficiencies of amitriptyline, nortriptyline, norfludiazepam, flunitrazepam, 7-aminoflunitrazepam, mianserin and zolpidem with these methods from an incurred human hair specimen were compared using liquid chromatography/tandem mass spectrometry. The highest extraction efficiencies for all the analytes were achieved using the method developed here, even though the extraction time (10min) was short. Overnight methanol extraction has frequently been used for hair analysis; however, the extraction efficiency was not sufficient for amines. The method was successfully applied to the quantification of zolpidem in human hair. The range of quantification was 1-25,000pg/mg, and interday accuracy and precision (n=5) at three concentrations were 1.8-8.8% and 3.3-8.1%, respectively. The developed method was applied to three actual (incurred) samples, for which the concentrations of zolpidem were determined to be 78.9-18,300 (pg/mg).
- Tolerability, pharmacokinetics, and pharmacodynamics of single-dose almorexant, an orexin receptor antagonist, in healthy elderly subjects. [Journal Article]
- J Clin Psychopharmacol 2013 Jun; 33(3):363-70.
Sleep disorders are common in the elderly population. Orexin receptor antagonism has been proposed as a new sleep-enabling approach to treat insomnia. The tolerability, pharmacokinetics, and pharmacodynamics of ascending single doses of almorexant, a dual orexin receptor antagonist, were investigated in healthy elderly male and female subjects. In this double-blind, placebo- and active-controlled study, each dose (100, 200, and 400 mg) was investigated in a separate group of 12 subjects (almorexant, placebo, and zolpidem 10 mg in an 8:2:2 ratio). Morning doses of almorexant were well tolerated. As expected for sleep-enabling compounds, somnolence and fatigue were frequently reported. Other adverse events included headache and nausea. Muscular weakness was reported at a higher incidence only with the highest almorexant dose. The pharmacokinetic profile of almorexant was characterized by a median time to the maximum concentration of 1.5 hours, quick disposition with a distribution half-life of 1.6 hours, and rapidly decreasing concentrations to approximately 20% of the maximum concentration over 8 hours, with a terminal half-life of 32 hours. Objective pharmacodynamic measures showed decreases in saccadic peak velocity and adaptive tracking performance and increases in body sway with the 400-mg dose of almorexant. Subjective assessments revealed a dose-dependent decrease in alertness. Almorexant had no effects on mood, calmness, subjective internal and external perception, and feeling high. These findings provide a solid basis to study the effects of almorexant in elderly patients with insomnia.
- A multimodal perspective on the composition of cortical oscillations. [Journal Article]
- Front Hum Neurosci 2013.:132.
An expanding corpus of research details the relationship between functional magnetic resonance imaging (fMRI) measures and neuronal network oscillations. Typically, integrated electroencephalography and fMRI, or parallel magnetoencephalography (MEG) and fMRI are used to draw inference about the consanguinity of BOLD and electrical measurements. However, there is a relative dearth of information about the relationship between E/MEG and the focal networks from which these signals emanate. Consequently, the genesis and composition of E/MEG oscillations requires further clarification. Here we aim to contribute to understanding through a series of parallel measurements of primary motor cortex (M1) oscillations, using human MEG and in vitro rodent local field potentials. We compare spontaneous activity in the ∼10 Hz mu and 15-30 Hz beta frequency ranges and compare MEG signals with independent and integrated layers III and V (LIII/LV) from in vitro recordings. We explore the mechanisms of oscillatory generation, using specific pharmacological modulation with the GABA-A alpha-1 subunit modulator zolpidem. Finally, to determine the contribution of cortico-cortical connectivity, we recorded in vitro M1, during an incision to sever lateral connections between M1 and S1 cortices. We demonstrate that frequency distribution of MEG signals appear have closer statistically similarity with signals from integrated rather than independent LIII/LV laminae. GABAergic modulation in both modalities elicited comparable changes in the power of the beta band. Finally, cortico-cortical connectivity in sensorimotor cortex (SMC) appears to directly influence the power of the mu rhythm in LIII. These findings suggest that the MEG signal is an amalgam of outputs from LIII and LV, that multiple frequencies can arise from the same cortical area and that in vitro and MEG M1 oscillations are driven by comparable mechanisms. Finally, cortico-cortical connectivity is reflected in the power of the SMC mu rhythm.
- Involvement of the K(+) -Cl(-) co-transporter KCC2 in the sensitization to morphine-induced hyperlocomotion under chronic treatment with zolpidem in the mesolimbic system. [Journal Article]
- J Neurochem 2013 Jun; 125(5):747-55.
Benzodiazepines are commonly used as sedatives, sleeping aids, and anti-anxiety drugs. However, chronic treatment with benzodiazepines is known to induce dependence, which is considered related to neuroplastic changes in the mesolimbic system. This study investigated the involvement of K(+) -Cl(-) co-transporter 2 (KCC2) in the sensitization to morphine-induced hyperlocomotion after chronic treatment with zolpidem [a selective agonist of γ-aminobutyric acid A-type receptor (GABAA R) α1 subunit]. In this study, chronic treatment with zolpidem enhanced morphine-induced hyperlocomotion, which is accompanied by the up-regulation of KCC2 in the limbic forebrain. We also found that chronic treatment with zolpidem induced the down-regulation of protein phosphatase-1 (PP-1) as well as the up-regulation of phosphorylated protein kinase C γ (pPKCγ). Furthermore, PP-1 directly associated with KCC2 and pPKCγ, whereas pPKCγ did not associate with KCC2. On the other hand, pre-treatment with furosemide (a KCC2 inhibitor) suppressed the enhancing effects of zolpidem on morphine-induced hyperlocomotion. These results suggest that the mesolimbic dopaminergic system could be amenable to neuroplastic change through a pPKCγ-PP-1-KCC2 pathway by chronic treatment with zolpidem.
- Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition. [Journal Article]
- Sci Transl Med 2013 Apr 3; 5(179):179ra44.
Current treatments for insomnia, such as zolpidem (Ambien) and eszopiclone (Lunesta), are γ-aminobutyric acid type A (GABAA)-positive allosteric modulators that carry a number of side effects including the potential to disrupt cognition. In an effort to develop better tolerated medicines, we have identified dual orexin 1 and 2 receptor antagonists (DORAs), which promote sleep in preclinical animal models and humans. We compare the effects of orally administered eszopiclone, zolpidem, and diazepam to the dual orexin receptor antagonist DORA-22 on sleep and the novel object recognition test in rat, and on sleep and two cognition tests (delayed match to sample and serial choice reaction time) in the rhesus monkey. Each compound's minimal dose that promoted sleep versus the minimal dose that exerted deficits in these cognitive tests was determined, and a therapeutic margin was established. We found that DORA-22 has a wider therapeutic margin for sleep versus cognitive impairment in rat and rhesus monkey compared to the other compounds tested. These data were further supported with the demonstration of a wider therapeutic margin for DORA-22 compared to the other compounds on sleep versus the expression of hippocampal activity-regulated cytoskeletal-associated protein (Arc), an immediate-early gene product involved in synaptic plasticity. These findings suggest that DORAs might provide an effective treatment for insomnia with a greater therapeutic margin for sleep versus cognitive disturbances compared to the GABAA-positive allosteric modulators currently in use.
- Efficacy and safety of a polyherbal sedative-hypnotic formulation NSF-3 in primary insomnia in comparison to zolpidem: a randomized controlled trial. [Journal Article]
- Indian J Pharmacol 2013 Jan-Feb; 45(1):34-9.
To assess the efficacy and safety of NSF-3, a polyherbal sedative-hypnotic (containing standardized extracts of Valeriana officinalis, Passiflora incarnate and Humulus lupulus), in comparison to zolpidem in primary insomnia.The present study was designed as a parallel group, double- blind, randomized, controlled trial and registered with Clinical Trials Registry-India (CTRI/2011/12/002197). Patients diagnosed with primary insomnia with a perceived total sleep time of <6 hours per night and insomnia severity index >7 were included. They were treated with either NSF-3 (one tablet) or zolpidem (one 10 mg tablet) at bedtime for two weeks. Total sleep time, sleep latency and number of awakenings per night were assessed using a sleep diary. Quality of life and daytime sleepiness were evaluated by insomnia severity index and Epworth sleepiness score respectively. Vital signs, routine blood counts, liver and renal function tests, and treatment emergent adverse events were recorded for safety assessment.A total of 91 subjects were recruited, of which 39 in each group completed the study. There was significant improvement in total sleep time, sleep latency, number of nightly awakenings and insomnia severity index scores in both groups. However, no statistically significant difference was observed between the groups. Epworth sleepiness scores did not change significantly over the study period. Although 12 treatment emergent adverse events were reported with NSF-3 and 16 with zolpidem (commonest was drowsiness in both), most were mild and no serious adverse events were encountered.NSF-3 is a safe and effective short-term alternative to zolpidem for primary insomnia. It remains to be explored whether the benefits are sustained and whether there is dependence liability with this formulation upon long term use.