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1.
Chem Sci ; 15(23): 8966-8973, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38873077

ABSTRACT

Transition metal sulfides (TMS) have gained significant attention as potential anode materials for sodium ion batteries (SIBs) due to their high theoretical capacity and abundance in nature. Nevertheless, their practical use has been impeded by challenges such as large volume changes, unstable solid electrolyte interphase (SEI), and low initial coulombic efficiency (ICE). To address these issues and achieve both long-term cycling stability and high ICE simultaneously, we present a novel approach involving surface engineering, termed as the "dual-polar confinement" strategy, combined with interface engineering to enhance the electrochemical performance of TMS. In this approach, CoS crystals are meticulously coated with polar TiO2 and embedded within a polar S-doped carbon matrix, forming a composite electrode denoted as CoS/TiO2-SC. Significantly, an ether-based electrolyte with chemical stability and optimized solvation properties synergistically interacts with the Co-S-C bonds to create a stable, ultra-thin SEI. This concerted effect results in a notably high ICE, reaching approximately 96%. Advanced characterization and theoretical simulations confirm that the uniform surface modification effectively facilitates sodium ion transport kinetics, restrains electrode pulverization, and concurrently enhances interaction with the ether-based electrolyte to establish a robust SEI. Consequently, the CoS/TiO2-SC electrode exhibits high reversible capacity, superior rate capability, and outstanding cycling stability.

2.
Int Ophthalmol ; 43(10): 3549-3558, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37318667

ABSTRACT

PURPOSE: To evaluate whether the six-month repeated irradiation of 650 nm low-level red light (LLRL) decreases the risk of myopia onset in children. METHODS: This was a single-masked, randomized controlled trial. A total of 112 children (aged 6-12 years) were enrolled and randomized to the treatment group or control group in a 1:1 ratio. The cycloplegic spherical equivalent error (SER) of children at baseline was -0.5 diopter (D) to 3D. Children in the treatment group were irradiated with the 650 nm LLRL for 6 min daily. No intervention was given to the control. The primary outcomes are myopia incidence, change in cycloplegic SER, and change in axial length (AL). RESULTS: For the treatment group and control group, the six-month myopia incidence rates were 1.8% (95% confidence interval, CI: 0.2-4.9%) and 12.5% (95% CI: 5.5-21.9%), respectively. The difference was significant (p = 0.028). The median changes in AL for the treatment group and control group were -0.02 (interquartile range, IQR: -0.12 to 0.06) mm, and 0.09 (IQR: 0-0.18) mm, respectively. The difference was significant (p < 0.001). The median changes in cycloplegic SER for the treatment group and control group were 0 (IQR: 0-0.25) D, and -0.125 (IQR: -0.375 to 0) D, respectively. The difference was significant (p < 0.001). There was no adverse event. CONCLUSION: The repeated irradiation of 650 nm LLRL may have a strong effect for myopia prevention in children, without risk of adverse events. TRIAL REGISTRATION: this trial is retrospectively registered in the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/ ), the registration number is ChiCTR2200058963.


Subject(s)
Mydriatics , Myopia , Humans , Child , Myopia/epidemiology , Refraction, Ocular , Light , Incidence , Disease Progression
3.
Ophthalmol Ther ; 11(6): 2259-2270, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36208391

ABSTRACT

INTRODUCTION: To evaluate the 6-month efficacy and safety of 650 nm low-level red light (LLRL) for myopia control in children. METHODS: This was a single-center, single-masked randomized controlled trial. A total of 224 children aged 6-12 years with spherical equivalent error (SER) of - 6 diopter (D) to - 0.5 D were enrolled, and were randomized to LLRL group or control group. Children in the LLRL group underwent treatment twice daily, each lasting for 3 min, there was an interval of at least 4 h between treatments. Children in both groups were allowed to wear single-vision spectacles; no additional intervention was given to the control. The primary outcomes included change in cycloplegic SER and change in axial length (AL) during 6 months. RESULTS: The median 6-month changes in AL of the LLRL and control groups were - 0.06 mm (interquartile range, IQR - 0.15, 0) and 0.14 mm (IQR 0.07, 0.22), respectively. The difference between groups was significant (Z = 10.021, p < 0.001). The median 6-month changes in SER were 0.125 D (IQR 0, 0.375) and - 0.25 D (IQR - 0.5, 0) for the LLRL and control groups, respectively. The difference between groups was significant (Z = 8.827, p < 0.001). Compared with the control, the proportion of children with hyperopic shift in the LLRL group was higher (51.65% vs. 3.41%, p < 0.001), and the proportion of children with shortened AL in the LLRL group was higher (63.74% vs. 2.27%, p < 0.001). No adverse event was observed. CONCLUSION: 650 nm LLRL significantly slowed down the myopia progression in children aged 6-12 years, and there was no observable side effect in the short term.

4.
Adv Sci (Weinh) ; 9(35): e2204837, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36310145

ABSTRACT

Interface engineering in electrode materials is an attractive strategy for enhancing charge storage, enabling fast kinetics, and improving cycling stability for energy storage systems. Nevertheless, the performance improvement is usually ambiguously ascribed to the "synergetic effect", the fundamental understanding toward the effect of the interface at molecular level in composite materials remains elusive. In this work, a well-defined nanoscale MoS2 /TiO2 interface is rationally designed by immobilizing TiO2 nanocrystals on MoS2 nanosheets. The role of heterostructure interface between TiO2 and MoS2 by operando synchrotron X-ray diffraction (sXRD), solid-state nuclear magnetic resonance, and density functional theory calculations is investigated. It is found that the existence of a hetero-interfacial electric field can promote charge transfer kinetics. Based on operando sXRD, it is revealed that the heterostructure follows a solid-solution reaction mechanism with small volume changes during cycling. As such, the electrode demonstrates ultrafast Na+ ions storage of 300 mAh g-1 at 10 A g-1 and excellent reversible capacity of 540 mAh g-1 at 0.2 A g-1 . This work provides significant insights into understanding of heterostructure interface at molecular level, which suggests new strategies for creating unconventional nanocomposite electrode materials for energy storage systems.

5.
J Dermatol ; 49(6): 629-636, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35437858

ABSTRACT

The exact efficacy of cyclosporine in the treatment of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) still needs evidence from more clinical data. This study was designed to compare the effectiveness and side-effects of combined use of cyclosporine in the treatment TEN with glucocorticoids (GC)/i.v. immunoglobulin G (IVIG). A total of 46 patients with SJS/TEN were enrolled and classified into two groups based on the therapeutic drugs used. Clinical characteristics, interventions, outcomes, and disease progressions were collected and compared between the two groups. In our cohort, seven patients eventually died and the overall fatality rate was 15.2%, but there was no difference between the two groups (p = 0.557). On discharge, the median SCORe of Toxic Epidermal Necrosis (SCORTEN) fell from 2.0 at admission to 1.0 and the median body surface area detached fell from 32.0% at admission to 9.5%. Patients in the cyclosporine group had a higher rate of re-epithelialized area than patients in the non-cyclosporine group (p < 0.05). Cyclosporine significantly reduced the length of stay (19.0 vs. 13.0 days, p = 0.019) and the rate of systemic infection (71.4% vs. 36.0%, p = 0.017) compared with the non-cyclosporine group. SCORTEN was the only significant risk factor for death and the risk ratio was 1.96 (1.17-3.31, p = 0.011). Conclusively, the combined use of cyclosporine could reduce the occurrence of systemic infection and accelerate the re-epithelialization.


Subject(s)
Stevens-Johnson Syndrome , Cohort Studies , Cyclosporine/adverse effects , Glucocorticoids/therapeutic use , Humans , Retrospective Studies , Stevens-Johnson Syndrome/drug therapy , Stevens-Johnson Syndrome/etiology
6.
ACS Appl Mater Interfaces ; 12(46): 51397-51408, 2020 Nov 18.
Article in English | MEDLINE | ID: mdl-33141552

ABSTRACT

Layered NaNixFeyMnzO2 cathode (NFM) is of great interest in sodium ion batteries because of its high theoretical capacity and utilization of abundant, low-cost, environmentally friendly raw materials. Nevertheless, there remains insufficient understanding on the concurrent local environment evolution in each transition metal (TM) that largely influences the reversibility of the cathode materials upon cycling. In this work, we investigate the reversibility of TM ions in layered NFMs with varying Fe contents and potential windows. Utilizing ex situ synchrotron X-ray absorption near-edge spectroscopy and extended X-ray absorption fine structure of precycled samples, the valence and bonding evolution of the TMs are elucidated. It is found that Mn is electrochemically inactive, as indicated by the insignificant change of Mn valence and the Mn-O bonding distance. Fe is electrochemically inactive after the first five cycles. The Ni redox couple contributes most of the charge compensation for NFMs. Ni redox is quite reversible in the cathodes with less Fe content. However, the Ni redox couple shows significant irreversibility with a high Fe content of 0.8. The electrochemical reversibility of the NFM cathode becomes increasingly enhanced with the decrease of either Fe content or with lower upper charge cutoff potential.

7.
Anal Chem ; 91(21): 14029-14035, 2019 11 05.
Article in English | MEDLINE | ID: mdl-31609110

ABSTRACT

The great pain and stress from finger-prick glucose measurements have resulted in great motivation to find noninvasive glucose monitoring technologies where salivary glucose measurement is desirable. However, the relative low concentration of glucose and coexisting chemicals in saliva challenges the sensitive and selective salivary glucose detection. In this article, we have rationally designed and constructed a salivary glucose sensor by modifying the inner wall of the Au-decorated glass nanopore with stimuli-responsive copolymer poly(3-(acryloylthioureido) phenylboronic acid-co-N-isopropylacrylamide) (denoted as PATPBA-co-PNIPAAm) via Au-S interaction. Notably, upon recognition of glucose, the copolymer could undergo a wettability switch and pKa shifts in the boronic acid functional groups, which significantly regulated the ion transport through nanopores, thus showing improved sensitivity with the detection limit of 1 nM. Moreover, benefiting from the multivalent boronic acid-glucose interaction and the cooperation of thiourea units, the copolymer exhibited good selectivity for glucose detection against the coexisting saccharides and other biological molecules in saliva. The nanopores with well-demonstrated analytical performance were finally applied for monitoring glucose in saliva. Together, this work unveiled a new platform for glucose detection in saliva, and promised to provide a new strategy for detecting other biomolecules in accessible biofluid involved in physiological and pathological events.


Subject(s)
Glucose/analysis , Nanopores , Polymers/chemistry , Saliva/chemistry , Boronic Acids/chemistry , Humans , Particle Size , Polymers/chemical synthesis , Surface Properties
9.
ACS Nano ; 13(1): 671-680, 2019 Jan 22.
Article in English | MEDLINE | ID: mdl-30592609

ABSTRACT

The sluggish kinetic in electrode materials is one of the critical challenges in achieving high-power sodium ion storage. We report a coaxial core-shell nanostructure composed of carbon nanotube (CNT) as the core and TiO2@MoO2@C as shells for a hierarchically nanoarchitectured anode for improved electrode kinetics. The 1D tubular nanostructure can effectively reduce ion diffusion path, increase electrical conductivity, accommodate the stress due to volume change upon cycling, and provide additional interfacial active sites for enhanced charge storage and transport properties. Significantly, a synergistic effect between TiO2 and MoO2 nanostructures is investigated through ex situ solid-state nuclear magnetic resonance. The electrode exhibits a good rate capability (150 mAh g-1 at 20 A g-1) and superior cycling stability with a reversibly capacity of 175 mAh g-1 at 10 A g-1 for over 8000 cycles.

10.
ACS Appl Mater Interfaces ; 10(43): 36969-36975, 2018 Oct 31.
Article in English | MEDLINE | ID: mdl-30273484

ABSTRACT

Slow kinetics and low specific capacity of graphite anode significantly limit its applications in the rapidly developing lithium-ion battery (LIB) markets. Herein, we report a carbon framework anode with ultrafast rate and cycling stability for LIBs by nitrogen and phosphorus doping. The electrode structure is constructed of a 3D framework built from 2D heteroatom-doped graphene layers via pyrolysis of self-assembled supramolecular aggregates. The synergistic effect from the nanostructured 3D framework and chemical doping (i.e., N- and P-doping) enables fast kinetics in charge storage and transport. A high reversible capacity of 946 mAh g-1 is delivered at a current rate of 0.5 A g-1, and excellent rate capability (e.g., a capacity of 595 mAh g-1 at 10 A g-1) of the electrode is shown. Moreover, a moderate surface area from the 3D porous structure contributes to a relatively high initial Coulombic efficiency of 74%, compared to other graphene-based anode materials. The electrode also demonstrates excellent cycling stability at a current rate of 2 A g-1 for 2000 cycles. The synthetic strategy proposed here is highly efficient and green, which can provide guidance for large-scale controllable fabrication of carbon-based anode materials.

11.
Chem Commun (Camb) ; 54(80): 11348-11351, 2018 Oct 04.
Article in English | MEDLINE | ID: mdl-30246200

ABSTRACT

A novel electrode design strategy of carbon-coated FeP particles anchored on a conducting carbon nanotube network (CNT@FeP-C) is designed to achieve superior sodium ion storage. Such a unique structure demonstrated excellent long-life cycling stability (a 95% capacity retention for more than 1200 cycles at 3 A g-1) and rate capability (delivered 272 mA h g-1 at 8 A g-1).

12.
Nanoscale ; 8(7): 4121-6, 2016 Feb 21.
Article in English | MEDLINE | ID: mdl-26866581

ABSTRACT

Hierarchically structured carbon coated SnO2 nanoparticles well-anchored on the surface of a CNT (C-SnO2/CNT) material were synthesized by a facile hydrothermal process and subsequent carbonization. The as-obtained C-SnO2/CNT hybrid, when applied as an anode material for lithium ion batteries (LIBs), showed a high reversible capacity up to 1572 mA h g(-1) at 200 mA g(-1) with a superior rate capability (685 mA h g(-1) at 4000 mA g(-1)). Even after 100 charge/discharge cycles at 1000 mA g(-1), a specific capacity of 1100 mA h g(-1) can still be maintained. Such impressive electrochemical performance can be mainly attributed to the hierarchical sandwiched structure and strong synergistic effects of the ultrafine SnO2 nanoparticles and the carbon coating, and thus presents this material a promising anode material for LIBs.

13.
Bioorg Med Chem ; 18(21): 7548-64, 2010 Nov 01.
Article in English | MEDLINE | ID: mdl-20888240

ABSTRACT

A series of 3,6-disubstituted ß-carbolines was synthesized and evaluated for their in vitro affinities at α(x)ß(3)γ(2) GABA(A)/benzodiazepine receptor subtypes by radioligand binding assays in search of α(1) subtype selective ligands to treat alcohol abuse. Analogues of ß-carboline-3-carboxylate-t-butyl ester (ßCCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted ß-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo-ßCCt (5). The bivalent ligands of ßCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands. Based on the pharmacophore/receptor model, a preliminary SAR study on 34 analogues illustrated that large substituents at position-6 of the ß-carbolines were well tolerated. As expected, these groups are proposed to project into the extracellular domain (L(Di) region) of GABA(A)/Bz receptors (see 32 and 33). Moreover, substituents located at position-3 of the ß-carboline nucleus exhibited a conserved stereo interaction in lipophilic pocket L(1), while N(2) presumably underwent a hydrogen bonding interaction with H(1). Three novel ß-carboline ligands (ßCCt, 3PBC and WYS8), which preferentially bound to α1 BzR subtypes permitted a comparison of the pharmacological efficacies with a range of classical BzR antagonists (flumazenil, ZK93426) from several different structural groups and indicated these ß-carbolines were 'near GABA neutral antagonists'. Based on the SAR, the most potent (in vitro) α(1) selective ligand was the 6-substituted acetylenyl ßCCt (WYS8, 7). Earlier both ßCCt and 3PBC had been shown to reduce alcohol self-administration in alcohol preferring (P) and high alcohol drinking (HAD) rats but had little or no effect on sucrose self-administration.(1-3) Moreover, these two ß-carbolines were orally active, and in addition, were anxiolytic in P rats but were only weakly anxiolytic in rodents. These data prompted the synthesis of the ß-carbolines presented here.


Subject(s)
Alcoholism/drug therapy , Benzodiazepines/chemistry , Carbolines/chemistry , GABA-A Receptor Antagonists/chemical synthesis , Receptors, GABA-A/chemistry , Animals , Binding Sites , Carbolines/chemical synthesis , Carbolines/therapeutic use , Cell Line , Computer Simulation , GABA-A Receptor Antagonists/chemistry , GABA-A Receptor Antagonists/therapeutic use , Humans , Protein Subunits/antagonists & inhibitors , Protein Subunits/metabolism , Rats , Receptors, GABA-A/metabolism , Stereoisomerism , Structure-Activity Relationship
14.
Neuropsychopharmacology ; 28(12): 2124-37, 2003 Dec.
Article in English | MEDLINE | ID: mdl-12968126

ABSTRACT

It has been hypothesized that alcohol addiction is mediated, at least in part, by specific gamma-aminobutyric acid(A) (GABA(A)) receptors within the ventral pallidum (VP). Among the potential GABA(A) receptor isoforms regulating alcohol-seeking behaviors within the VP, the GABA(A) alpha1 receptor subtype (GABA(A1)) appears pre-eminent. In the present study, we developed beta-carboline-3-carboxylate-t-butyl ester (betaCCt), a mixed agonist-antagonist benzodiazepine (BDZ) site ligand, with binding selectivity at the A1 receptor to explore the functional role of VP(A1) receptors in the euphoric properties of alcohol. The in vivo actions of betaCCt were then determined following microinfusion into the VP, a novel alcohol reward substrate that primarily expresses the A1 receptor. In two selectively bred rodent models of chronic alcohol drinking (HAD-1, P rats), bilateral microinfusion of betaCCt (0.5-40 microg) produced marked reductions in alcohol-reinforced behaviors. Further, VP infusions of betaCCt exhibited both neuroanatomical and reinforcer specificity. Thus, no effects on alcohol-reinforced behaviors were observed following infusion in the nucleus accumbens (NACC)/caudate putamen (CPu), or on response maintained by saccharin. Parenteral-administered betaCCt (1-40 mg/kg) was equally effective and selective in reducing alcohol-reinforced behaviors in P and HAD-1 rats. Additional tests of locomotor activity revealed that betaCCt reversed the locomotor sedation produced by both chlordiazepoxide (10 mg/kg) and EtOH (1.25 g/kg), but was devoid of intrinsic effects when given alone. Studies in recombinant receptors expressed in Xenopus oocytes revealed that betaCCt acted as a low-efficacy partial agonist at alpha3beta3gamma2 and alpha4beta3gamma2 receptors and as a low-efficacy inverse agonist at alpha1beta3gamma2, alpha2beta3gamma2, and alpha5beta3gamma2 receptors. The present study indicates that betaCCt is capable of antagonizing the reinforcing and the sedative properties of alcohol. These anti-alcohol properties of betaCCt are primarily mediated via the GABA(A1) receptor. betaCCt may represent a prototype of a pharmacotherapeutic agent to effectively reduce alcohol drinking behavior in human alcoholics.


Subject(s)
Alcohols/pharmacology , Globus Pallidus/drug effects , Receptors, GABA-A/metabolism , Reinforcement, Psychology , Alcoholism , Animals , Body Weight/drug effects , Carbolines/blood , Carbolines/chemistry , Carbolines/pharmacology , Conditioning, Operant/drug effects , Disease Models, Animal , Drug Administration Routes , Drug Interactions , Ethanol/pharmacology , Female , GABA-A Receptor Agonists , GABA-A Receptor Antagonists , Globus Pallidus/physiology , Membrane Potentials/drug effects , Microinjections , Motor Activity/drug effects , Neostriatum/drug effects , Oocytes , Patch-Clamp Techniques , Protein Subunits , Rats , Receptors, GABA-A/drug effects , Saccharin/pharmacology , Self Administration , Sucrose/pharmacology , Sweetening Agents/pharmacology , Time Factors , Xenopus , gamma-Aminobutyric Acid/pharmacology
15.
Psychopharmacology (Berl) ; 164(2): 151-9, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12404077

ABSTRACT

RATIONALE: Delineation of the receptor mechanisms underlying the behavioral effects of benzodiazepines should allow for the development of drugs with improved clinical utility and reduced side effects. OBJECTIVES. The purpose of the present study was to investigate the role of GABAA/alpha1 receptors in the sedative and motor-impairing effects of benzodiazepines. METHODS: Squirrel monkeys were tested with the GABAA/alpha1-preferring agonist zolpidem and the nonselective benzodiazepine agonist triazolam alone and in combination with the GABAA/alpha1-preferring antagonist beta-CCt and the nonselective benzodiazepine antagonist flumazenil. During 30-min experimental sessions, all occurrences of normal behaviors like locomotion, environment- and self-directed behaviors, as well as side effects such as ataxia, rest and procumbent postures were scored. RESULTS: Zolpidem and triazolam produced dose-dependent reductions in locomotion and environment-directed behavior and increased ataxia and procumbent posture. Triazolam, but not zolpidem, also engendered species-typical rest posture at some doses. Flumazenil antagonized all of the behavioral effects of zolpidem and triazolam, whereas beta-CCt antagonized only zolpidem- and triazolam-induced ataxia. CONCLUSIONS: GABAA/alpha1 receptor mechanisms appear to play a key role in the ataxic effects of benzodiazepine agonists in squirrel monkeys, similar to recent results with transgenic mice. In contrast to the findings of these recent studies, GABAA mechanisms other than or in addition to those mediated at the alpha1 subunit may play a more important role in the sedative/hypnotic effects of benzodiazepines in squirrel monkeys.


Subject(s)
Ataxia/chemically induced , Benzodiazepines/pharmacology , Carbolines/pharmacology , GABA Agonists/adverse effects , GABA Modulators/adverse effects , Motor Activity/drug effects , Pyridines/adverse effects , Receptors, GABA-A/drug effects , Triazolam/adverse effects , Animals , Ataxia/drug therapy , Benzodiazepines/antagonists & inhibitors , Dose-Response Relationship, Drug , Drug Interactions , Flumazenil/pharmacology , GABA Agonists/pharmacology , GABA Modulators/pharmacology , GABA-A Receptor Antagonists , Male , Motor Activity/physiology , Pyridines/pharmacology , Receptors, GABA-A/classification , Receptors, GABA-A/physiology , Saimiri , Social Behavior , Triazolam/pharmacology , Zolpidem
16.
Psychopharmacology (Berl) ; 161(2): 180-8, 2002 May.
Article in English | MEDLINE | ID: mdl-11981598

ABSTRACT

RATIONALE: Conventional benzodiazepines (BZs), clinically used for treatment of anxiety and insomnia, bind to GABA(A) receptors containing alpha(1), alpha(2), alpha(3), or alpha(5) subunits. The role of these different GABA(A) receptor subtypes in mediating the subjective effects of BZs remains largely unknown. OBJECTIVE: The purpose of the present study was to evaluate the role of GABA(A) receptors containing the alpha(1) or alpha(5) subunits in the discriminative stimulus (DS) effects of the conventional BZ agonist triazolam. METHODS: Squirrel monkeys were trained to discriminate triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 schedule of food reinforcement. RESULTS: The GABA(A)/alpha(1)-preferring agonists zolpidem and zaleplon engendered responses predominantly on the triazolam lever (73-80% drug-lever responding), and the GABA(A)/alpha(1) partial agonist CL 218,872 engendered an average maximum of less than 50% triazolam-lever responding. The GABA(A)/alpha(1)-preferring antagonists beta-carboline-3-carboxylate-t-butyl ester (betaCCT) and 3-(propyloxy)-beta-carboline (3-PBC) blocked the DS effects of triazolam and zolpidem in a surmountable manner. Schild analyses for betaCCT and 3-PBC in combination with triazolam and zolpidem suggest that the interactions between these compounds were competitive in nature and mediated by a common population of receptors, presumably GABA(A)/alpha(1) receptors. In contrast, the GABA(A)/alpha(5)-preferring agonist QH-ii-66 did not engender triazolam-lever responding regardless of dose and did not alter the DS effects of triazolam when administered in combination. CONCLUSIONS: The results are consistent with GABA(A)/alpha(1) receptor involvement in mediating the DS effects of triazolam. In contrast, binding to GABA(A)/alpha(5) receptors may not play a critical role in mediating triazolam's DS effects.


Subject(s)
Anti-Anxiety Agents/pharmacology , Discrimination, Psychological/drug effects , Receptors, GABA-A/physiology , Triazolam/pharmacology , Animals , Benzodiazepines/pharmacology , Carbolines/pharmacology , Discrimination, Psychological/physiology , Dose-Response Relationship, Drug , GABA Agonists/pharmacology , GABA Antagonists/pharmacology , GABA Modulators/pharmacology , GABA-A Receptor Agonists , Male , Models, Statistical , Reaction Time/drug effects , Reaction Time/physiology , Saimiri
17.
J Neurosci ; 22(9): 3765-75, 2002 May 01.
Article in English | MEDLINE | ID: mdl-11978852

ABSTRACT

We investigated the potential role of the alpha1-containing GABA(A) receptor in regulating the reinforcing properties of alcohol. To accomplish this, we developed 3-propoxy-beta-carboline hydrochloride (3-PBC), a mixed agonist-antagonist benzodiazepine site ligand with binding selectivity at the alpha1 receptor. We then tested the capacity of 3-PBC to block alcohol-maintained responding in the ventral pallidum (VP), a novel alcohol reward substrate, which primarily expresses the alpha1-receptor isoform. Our results demonstrated that bilateral microinfusion of 3-PBC (0.5-40 microg) in the anterior and medial VP produced marked reductions in alcohol-maintained responding in a genetically selected rodent model of alcohol drinking. The VP infusions showed both neuroanatomical and reinforcer specificity because no effects were seen in sites dorsal to the VP (e.g., nucleus accumbens, caudate putamen). The saccharin-maintained responding was reduced only with the highest dose (40 microg). Parenteral injections of 3-PBC (1-20 mg/kg) also showed a similar selectivity on alcohol-maintained responding. Complementary in vitro studies revealed that 3-PBC exhibited a low partial agonist efficacy profile at recombinant diazepam-sensitive receptors (e.g., alpha1beta3gamma2, alpha2beta3gamma, and alpha3beta3gamma2). The selective suppression of 3-PBC on alcohol-maintained responding after central and parenteral administrations, together with its low-efficacy agonist profile, suggest that the reduction in alcohol-maintained behaviors was not attributable to a general suppression on consummatory behaviors. These results demonstrate that the alpha1-containing GABA(A) receptors in both the anterior and medial VP are important in regulating the reinforcing properties of alcohol. These receptors represent novel targets in the design and development of pharmacotherapies for alcohol-dependent subjects.


Subject(s)
Alcoholism , Ethanol/pharmacology , Globus Pallidus/metabolism , Receptors, GABA-A/metabolism , Reinforcement, Psychology , Alcoholism/drug therapy , Alcoholism/metabolism , Animals , Appetitive Behavior/drug effects , Behavior, Animal/drug effects , Benzodiazepines/antagonists & inhibitors , Binding, Competitive/drug effects , Carbolines/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Routes , GABA Antagonists/administration & dosage , GABA Modulators/administration & dosage , Globus Pallidus/drug effects , Ligands , Male , Microinjections , Oocytes/metabolism , Patch-Clamp Techniques , Protein Isoforms/drug effects , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Subunits , RNA, Complementary/administration & dosage , Rats , Rats, Inbred Strains , Receptors, GABA-A/drug effects , Receptors, GABA-A/genetics , Recombinant Proteins/drug effects , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Synaptosomes/chemistry , Synaptosomes/drug effects , Synaptosomes/metabolism , Xenopus laevis
18.
J Pharmacol Exp Ther ; 300(2): 505-12, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11805210

ABSTRACT

Drug discrimination was used to examine the effects of benzodiazepine (BZ)(1) receptor-selective ligands in rhesus monkeys. In diazepam-treated (5.6 mg/kg, p.o.) monkeys discriminating the nonselective BZ antagonist flumazenil (0.32 mg/kg, s.c.), the BZ(1)-selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) substituted for flumazenil. The onset of action of beta-CCt was delayed with a dose of 5.6 mg/kg beta-CCt substituting for flumazenil 2 h after injection. In monkeys discriminating the nonselective BZ agonist midazolam (0.56 mg/kg, s.c.), the BZ(1)-selective agonists zaleplon (ED(50) = 0.78 mg/kg) and zolpidem (ED(50) = 1.73 mg/kg) substituted for midazolam. The discriminative stimulus effects of midazolam, zaleplon, and zolpidem were antagonized by beta-CCt (1.0-5.6 mg/kg, s.c.), and the effects of zaleplon and zolpidem were also antagonized by flumazenil (0.01-0.32 mg/kg, s.c.). Schild analyses supported the notion of a simple, competitive interaction between beta-CCt and midazolam (slope = -1.08; apparent pA(2) = 5.41) or zaleplon (slope = -1.57; apparent pA(2) = 5.49) and not between beta-CCt and zolpidem. Schild analyses also were consistent with a simple, competitive interaction between flumazenil and zaleplon (slope = -1.03; apparent pA(2) = 7.45) or zolpidem (slope = -1.11; apparent pA(2) = 7.63). These results suggest that the same BZ receptor subtype(s) mediate(s) the effects of midazolam, zolpidem, and zaleplon under these conditions and that selective binding of BZ ligands does not necessarily confer selective effects in vivo.


Subject(s)
Discrimination, Psychological/drug effects , Receptors, GABA-A/drug effects , Acetamides/pharmacology , Animals , Carbolines/pharmacology , Diazepam/pharmacology , Dose-Response Relationship, Drug , Female , Flumazenil/pharmacology , GABA Agonists/pharmacology , GABA Antagonists/pharmacology , GABA Modulators/pharmacology , GABA-A Receptor Agonists , GABA-A Receptor Antagonists , Hypnotics and Sedatives/pharmacology , Ligands , Macaca mulatta , Midazolam/pharmacology , Pyridines/pharmacology , Pyrimidines/pharmacology , Zolpidem
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