共查询到20条相似文献,搜索用时 31 毫秒
1.
Victoria Lutgen Jon Resch Krista Qualmann Nicholas J. Raddatz Cristina Panhans Ellen M. Olander Linghai Kong SuJean Choi John R. Mantsch David A. Baker 《Psychopharmacology》2014,231(24):4637-4647
Rationale
Gaps in our understanding of glutamatergic signaling may be key obstacles in accurately modeling complex CNS diseases. System xc - is an example of a poorly understood component of glutamate homeostasis that has the potential to contribute to CNS diseases.Objectives
This study aims to determine whether system xc - contributes to behaviors used to model features of CNS disease states.Methods
In situ hybridization was used to map mRNA expression of xCT throughout the brain. Microdialysis in the prefrontal cortex was used to sample extracellular glutamate levels; HPLC was used to measure extracellular glutamate and tissue glutathione concentrations. Acute administration of sulfasalazine (8–16 mg/kg, IP) was used to decrease system xc - activity. Behavior was measured using attentional set shifting, elevated plus maze, open-field maze, Porsolt swim test, and social interaction paradigm.Results
The expression of xCT mRNA was detected throughout the brain, with high expression in several structures including the basolateral amygdala and prefrontal cortex. Doses of sulfasalazine that produced a reduction in extracellular glutamate levels were identified and subsequently used in the behavioral experiments. Sulfasalazine impaired performance in attentional set shifting and reduced the amount of time spent in an open arm of an elevated plus maze and the center of an open-field maze without altering behavior in a Porsolt swim test, total distance moved in an open-field maze, or social interaction.Conclusions
The widespread distribution of system xc - and involvement in a growing list of behaviors suggests that this form of nonvesicular glutamate release is a key component of excitatory signaling. 相似文献2.
Jacob P. R. Jacobsen Per Plenge Benjamin D. Sachs Alan L. Pehrson Manuel Cajina Yunzhi Du Wendy Roberts Meghan L. Rudder Prachiti Dalvi Taylor J. Robinson Sharon P. O’Neill King S. Khoo Connie Sanchez Morillo Xiaodong Zhang Marc G. Caron 《Psychopharmacology》2014,231(23):4527-4540
Rationale
Escitalopram appears to be a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inhibition of the SERT, thereby curtailing the elevation of extracellular 5-hydroxytryptamine (5-HTExt), and hence antidepressant efficacy. Further, it has been suggested that a putative allosteric binding site is important for binding of escitalopram to the primary, orthosteric, site, and for R-citalopram’s inhibition hereof.Objectives
Primary: Investigate at the human (h)SERT, at clinical relevant doses, whether R-citalopram antagonizes escitalopram-induced 5-HTExt elevation. Secondary: Investigate whether abolishing the putative allosteric site affects escitalopram-induced 5-HTExt elevation and/or modulates the effect of R-citalopram.Methods
Recombinant generation of hSERT transgenic mice; in vivo microdialysis; SERT binding; pharmacokinetics; 5-HT sensitive behaviors (tail suspension, marble burying).Results
We generated mice expressing either the wild-type human SERT (hSERTWT) or hSERT carrying amino acid substitutions (A505V, L506F, I507L, S574T and I575T) collectively abolishing the putative allosteric site (hSERTALI/VFL+SI/TT). One mg/kg escitalopram yielded clinical relevant plasma levels and brain levels consistent with therapeutic SERT occupancy. The hSERT mice showed normal basal 5-HTExt levels. Escitalopram-induced 5-HTExt elevation was not decreased by R-citalopram co-treatment and was unaffected by loss of the allosteric site. The behavioral effects of the clinically relevant escitalopram dose were small and tended to be enhanced by R-citalopram co-administration.Conclusions
We find no evidence that R-citalopram directly antagonizes escitalopram or that the putative allosteric site is important for hSERT inhibition by escitalopram. 相似文献3.
Eric W. Fish Buddy J. Whitman Jeff F. DiBerto J. Elliott Robinson A. Leslie Morrow C. J. Malanga 《Psychopharmacology》2014,231(17):3415-3423
Rationale
The neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) has effects on reward-related behaviors in mice and rats that suggest that it may activate brain reward circuits. Intracranial self-stimulation (ICSS) is an operant behavioral technique that detects changes in the sensitivity of brain reward circuitry following drug administration.Objective
To examine the effects of the neuroactive steroid allopregnanolone on ICSS and to compare these effects to those of cocaine.Methods
Male C57BL/6J mice implanted with stimulating electrodes implanted into the medial forebrain bundle responded for reinforcement by electrical stimulation (brain stimulation reward (BSR)). Mice received cocaine (n?=?11, 3.0–30.0 mg/kg, intraperitoneal (i.p.)) or the neuroactive steroid allopregnanolone (n?=?11, 3.0–17.0 mg/kg, i.p.). BSR thresholds (θ 0) and maximum (MAX) operant response rates after drug treatments were compared to those after vehicle injections.Results
Cocaine and allopregnanolone dose dependently lowered BSR thresholds relative to vehicle injections. Cocaine was maximally effective (80 % reduction) in the second 15 min following the 30 mg/kg dose, while allopregnanolone was maximally effective (30 % reduction) 15–45 min after the 17 mg/kg dose. Neither drug had significant effects on MAX response rates.Conclusions
The effects of allopregnanolone on BSR thresholds are consistent with the previously reported effects of benzodiazepines and alcohol, suggesting that positive modulation of GABAA receptors can facilitate reward-related behaviors in C57BL/6J mice. 相似文献4.
In vivo visualization of donepezil binding in the brain of patients with Alzheimer's disease 总被引:1,自引:1,他引:0
Okamura N Funaki Y Tashiro M Kato M Ishikawa Y Maruyama M Ishikawa H Meguro K Iwata R Yanai K 《British journal of clinical pharmacology》2008,65(4):472-479
Aims
The aims of this study were to visualize in vivo binding of donepezil to acetylcholinesterase (AChE) in the brain and to establish a method for measuring the amount of binding of orally administered donepezil.Methods
[5-11C-methoxy]-donepezil ([11C]-donepezil) was radiolabelled as a positron emission tomography (PET) tracer. The biodistribution of [11C]-donepezil was measured by PET in 10 AD patients and six elderly normal subjects. Two AD patients underwent additional PET measurements after oral administration of donepezil for 6 months.Results
[11C]-donepezil-PET images demonstrated high densities of tracer distribution in AChE-rich brain regions such as the striatum, thalamus, and cerebellum. Compared with elderly normal subjects, patients with mild AD exhibited about 18–20% reduction of donepezil binding in the neocortex and hippocampus, while patients with moderate AD exhibited about 24–30% reduction of donepezil binding throughout the brain. Orally administered donepezil (5 mg day−1) induced 61.6–63.3% reduction of donepezil binding in AD brains. The distribution volume of [11C]-donepezil in the hippocampus was significantly correlated with MMSE scores in AD patients.Conclusions
[11C]-donepezil-PET enables quantitative measurement of donepezil binding in the brain. AD patients exhibited reduction of donepezil binding in the brain, even in the early stage of disease. Longitudinal evaluation by this technique enables determination of AChE binding occupancy of orally administered donepezil.What is already known about this subject
- Deficit in central cholinergic neurotransmission is a consistent change associated with Alzheimer''s disease (AD).
- Donepezil hydrochloride exhibits selective inhibition of acetylcholinesterase (AChE) and is widely used for the treatment of AD.
- The biodistribution of donepezil in the brain after administration is not precisely understood in vivo.
- There is no method to measure the amount of binding of orally administered donepezil to AChE.
What this study adds
- This study clearly visualizes the distribution of donepezil in human brain using [11C]-donepezil and positron emission tomography.
- This study demonstrates prominent reduction of the donepezil binding site in the AD brain.
- This study provides methodology to measure the AChE binding occupancy of orally administered donepezil and provides a new surrogate marker for evaluation and prediction of response to donepezil treatment.
5.
Rationale
The neurosteroid pregnenolone sulfate (PregS) acts as a cognitive enhancer and modulator of neurotransmission, yet aligning its pharmacological and physiological effects with reliable measurements of endogenous local concentrations and pharmacological and therapeutic targets has remained elusive for over 20 years.Objectives
New basic and clinical research concerning neurosteroid modulation of the central nervous system (CNS) function has emerged over the past 5 years, including important data involving pregnenolone and various neurosteroid precursors of PregS that point to a need for a critical status update.Results
Highly specific actions of PregS affecting excitatory N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission and the pharmacological effects of PregS on various receptors and ion channels are discussed. The discovery of a high potency (nanomolar) signal transduction pathway for PregS-induced NMDAR trafficking to the cell surface via a Ca2+- and G protein-coupled receptor (GPCR)-dependent mechanism and a potent (EC50?~?2 pM) direct enhancement of intracellular Ca2+ levels is discussed in terms of its agonist effects on long-term potentiation (LTP) and memory. Lastly, preclinical and clinical studies assessing the promnestic effects of PregS and pregnenolone toward cognitive dysfunction in schizophrenia, and altered serum levels in epilepsy and alcohol dependence, are reviewed.Conclusions
PregS is present in human and rodent brain at physiologically relevant concentrations and meets most of the criteria for an endogenous neurotransmitter/neuromodulator. PregS likely plays a significant role in modulation of glutamatergic excitatory synaptic transmission underlying learning and memory, yet the molecular target(s) for its action awaits identification. 相似文献6.
Ballard TM Knoflach F Prinssen E Borroni E Vivian JA Basile J Gasser R Moreau JL Wettstein JG Buettelmann B Knust H Thomas AW Trube G Hernandez MC 《Psychopharmacology》2009,202(1-3):207-223
Rationale
GABAA α5 subunit-containing receptors are primarily expressed in the hippocampus and their role in learning and memory has been demonstrated recently by both genetic and pharmacological approaches.Objectives
The objective of the study is to evaluate the cognitive effects of a novel GABAA α5 receptor inverse agonist, RO4938581 in rats and monkeys.Materials and methods
The in vitro profile was determined using radioligand binding and electrophysiological assays for the GABAA α1, α2, α3, and α5 receptors. Long-term potentiation (LTP) was performed in mouse hippocampal slices. Cognitive effects were assessed in rats in the delayed match to position (DMTP) task and the Morris water maze. In monkeys, the object retrieval task was used. Pro-convulsant and anxiogenic potentials were evaluated in mice and rats. In vivo receptor occupancy was determined using [3H]-RO0154513.Results
RO4938581 is a potent inverse agonist at the GABAA α5 receptor, with both binding and functional selectivity, enhancing hippocampal LTP. RO4938581 reversed scopolamine-induced working memory impairment in the DMTP task (0.3–1 mg/kg p.o.) and diazepam-induced spatial learning impairment (1–10 mg/kg p.o.). RO4938581 improved executive function in monkeys (3-10 mg/kg p.o.). Importantly, RO4938581 showed no anxiogenic and pro-convulsive potential. RO4938581 dose-dependently bound to GABAA α5 receptors and approximately 30% receptor occupancy was sufficient to produce enhanced cognition in the rat.Conclusions
The data further support the potential of GABAA α5 receptors as a target for cognition-enhancing drugs. The dual binding and functional selectivity offers an ideal profile for cognition-enhancing effects without the unwanted side effects associated with activity at other GABAA receptor subtypes. 相似文献7.
Giovanni Biggio Maria Giuseppina Pisu Francesca Biggio Mariangela Serra 《Psychopharmacology》2014,231(17):3437-3444
Rationale
GABAergic neuronal circuits regulate neuroendocrine stress response, and the most potent positive endogenous modulator of GABAA receptor function is allopregnanolone. This neurosteroid acts in a nongenomic manner to selectively increase the inhibitory signal meditated by GABAA receptors; in addition, it also induces long-lasting changes in the expression of specific GABAA receptor subunits in various brain regions, with consequent changes in receptor function.Objective
The objective of this review is to summarize our findings on emotional state and stress responsiveness in three animal models in which basal brain concentrations of allopregnanolone differ. It is postulated that individual differences in allopregnanolone levels can influence general resilience.Results
The results showed that there is an apparent correlation between endogenous levels of brain allopregnanolone and basal and stress-stimulated HPA axis activity.Conclusion
The relationship between endogenous brain levels of allopregnanolone and HPA axis activity and function sustains the therapeutic potential of this neurosteroid for the treatment of stress-associated disorders. 相似文献8.
Srinivas Ganta Amit Singh Niravkumar R. Patel Joseph Cacaccio Yashesh H. Rawal Barbara J. Davis Mansoor M. Amiji Timothy P. Coleman 《Pharmaceutical research》2014,31(9):2490-2502
Purpose
Platinum-based chemotherapy is the treatment of choice for malignant epithelial ovarian cancers, but generalized toxicity and platinum resistance limits its use. Theranostic nanoemulsion with a novel platinum prodrug, myrisplatin, and the pro-apoptotic agent, C6-ceramide, were designed to overcome these limitations.Methods
The nanoemulsions, including ones with an EGFR binding peptide and gadolinium, were made using generally regarded as safe grade excipients and a high shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3, A2780 and A2780CP.Results
The nanoemulsion with particle size <150 nm were stable in plasma and parenteral fluids for 24 h. Ovarian cancer cells in vitro efficiently took up the non-targeted and EGFR-targeted nanoemulsions; improved cytotoxicity was observed for the these nanoemulsions with the latter showing a 50-fold drop in the IC50 in SKOV3 cells as compared to cisplatin alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist®.Conclusion
The myrisplatin/C6-ceramide nanoemulsion synergistically enhanced in vitro cytotoxicity. An EGFR binding peptide addition further increased in vitro cytotoxicity in EGFR positive cancer cells. The diagnostic version showed MR imaging similar to the clinically relevant Magnevist® and may be suitable as a theranostic for ovarian cancer. 相似文献9.
Qihong Zhang Peter Saad Guangru Mao Russel M. Walters Mary Catherine Mack Correa Richard Mendelsohn Carol R. Flach 《Pharmaceutical research》2014,31(10):2762-2773
Purpose
To demonstrate the efficacy of infrared (IR) spectroscopic imaging for evaluation of lateral diffusion in stratum corneum (SC) and for elucidation of intermolecular interactions between exogenous agents and SC constituents.Methods
In separate experiments, acyl chain perdeuterated oleic acid (OA-d) and deuterated dimethyl sulfoxide (DMSO-d) were applied to the surface of isolated human SC. The lateral distribution of permeant concentrations was monitored using the time-dependence of IR images. Diffusion coefficients (D) were estimated from Fick’s second law. Interactions between the exogenous agents and the SC were tracked from changes in CD2 and Amide I stretching frequencies.Results
Networked glyphs served as the major pathway for lateral distribution of OA-d. In glyph-poor regions, D values from 0.3–1?×?10?8 cm2/s bracketed the OA-d data and apparently decreased with time. Although diffusion of DMSO-d is relatively fast compared to our experimental measurement time, the results suggest values of ~10?7 cm2/s. OA-d spectral changes suggest penetration into the ordered lipids of the SC; DMSO-d penetration results in perturbation of SC keratin structure.Conclusions
IR imaging provides concentration profiles, diffusion coefficients, and unique molecular level information about structural changes in the endogenous SC constituents and exogenous agents upon their mutual interaction. Transport along glyphs is the dominant mode of distribution for OA-d. 相似文献10.
Joseph P. Schacht Raymond F. Anton Patrick K. Randall Xingbao Li Scott Henderson Hugh Myrick 《Psychopharmacology》2014,231(18):3799-3807
Rationale
The α4β2 nicotinic acetylcholine receptor partial agonist varenicline has been reported to reduce drinking among both heavy-drinking smokers and primary alcoholics, and this effect may be related to varenicline-mediated reduction of alcohol craving. Among smokers, varenicline has been reported to modulate cigarette cue-elicited brain activation in several reward-related areas.Objectives
This pilot study tested varenicline’s effects on drinking, alcohol craving, and alcohol cue-elicited activation of reward-related brain areas among non-treatment-seeking alcohol-dependent individuals.Methods
Thirty-five such individuals (mean age?=?30, 57 % male, 76 % heavy drinking days in the past month, 15 smokers) were randomized to either varenicline (titrated to 2 mg) or placebo for 14 days, and were administered an alcohol cue reactivity fMRI task on day 14. A priori regions of interest (ROIs) were bilateral and medial orbitofrontal cortex (OFC), right ventral striatum (VS), and medial prefrontal cortex (mPFC).Results
Despite good medication adherence, varenicline did not reduce heavy drinking days or other drinking parameters. It did, however, increase self-reported control over alcohol-related thoughts and reduced cue-elicited activation bilaterally in the OFC, but not in other brain areas.Conclusions
These data indicate that varenicline reduces alcohol craving and some of the neural substrates of alcohol cue reactivity. However, varenicline effects on drinking mediated by cue-elicited brain activation and craving might be best observed among treatment-seekers motivated to reduce their alcohol consumption. 相似文献11.
Shahin Akhondzadeh Mehdi Shafiee Sabet Mohammad Hossein Harirchian Mansoreh Togha Hamed Cheraghmakani Soodeh Razeghi Seyyed Shamssedin Hejazi Mohammad Hossein Yousefi Roozbeh Alimardani Amirhossein Jamshidi Shams-Ali Rezazadeh Aboulghasem Yousefi Farhad Zare Atbin Moradi Ardalan Vossoughi 《Psychopharmacology》2010,207(4):637-643
Rationale
There is increasing evidence to suggest the possible efficacy of Crocus sativus (saffron) in the management of Alzheimer’s disease (AD).Objective
The purpose of the present investigation was to assess the efficacy of C. sativus in the treatment of patients with mild-to-moderate AD.Methods
Fifty-four Persian-speaking adults 55 years of age or older who were living in the community were eligible to participate in a 22-week, double-blind study of parallel groups of patients with AD. The main efficacy measures were the change in the Alzheimer’s Disease Assessment Scale—cognitive subscale and Clinical Dementia Rating Scale—Sums of Boxes scores compared with baseline. Adverse events (AEs) were systematically recorded. Participants were randomly assigned to receive a capsule saffron 30 mg/day (15 mg twice per day) or donepezil 10 mg/day (5 mg twice per day).Results
Saffron at this dose was found to be effective similar to donepezil in the treatment of mild-to-moderate AD after 22 weeks. The frequency of AEs was similar between saffron extract and donepezil groups with the exception of vomiting, which occurred significantly more frequently in the donepezil group.Conclusion
This phase II study provides preliminary evidence of a possible therapeutic effect of saffron extract in the treatment of patients with mild-to-moderate Alzheimer’s disease. This trial is registered with the Iranian Clinical Trials Registry (IRCT138711051556N1). 相似文献12.
Zi-Wei Chen Cunde Wang Kathiresan Krishnan Brad D. Manion Randy Hastings John Bracamontes Amanda Taylor Megan M. Eaton Charles F. Zorumski Joseph H. Steinbach Gustav Akk Steven Mennerick Douglas F. Covey Alex S. Evers 《Psychopharmacology》2014,231(17):3479-3491
Rationale
While neurosteroids are well-described positive allosteric modulators of gamma-aminobutyric acid type A (GABAA) receptors, the binding sites that mediate these actions have not been definitively identified.Objectives
This study was conducted to synthesize neurosteroid analogue photolabeling reagents that closely mimic the biological effects of endogenous neurosteroids and have photochemical properties that will facilitate their use as tools for identifying the binding sites for neurosteroids on GABAA receptors.Results
Two neurosteroid analogues containing a trifluromethyl-phenyldiazirine group linked to the steroid C11 position were synthesized. These reagents, CW12 and CW14, are analogues of allopregnanolone (5α-reduced steroid) and pregnanolone (5β-reduced steroid), respectively. Both reagents were shown to have favorable photochemical properties with efficient insertion into the C–H bonds of cyclohexane. They also effectively replicated the actions of allopregnanolone and pregnanolone on GABAA receptor functions: they potentiated GABA-induced currents in Xenopus laevis oocytes transfected with α1β2γ2L subunits, modulated [35S]t-butylbicyclophosphorothionate binding in rat brain membranes, and were effective anesthetics in Xenopus tadpoles. Studies using [3H]CW12 and [3H]CW14 showed that these reagents covalently label GABAA receptors in both rat brain membranes and in a transformed human embryonal kidney (TSA) cells expressing either α1 and β2 subunits or β3 subunits of the GABAA receptor. Photolabeling of rat brain GABAA receptors was shown to be both concentration-dependent and stereospecific.Conclusions
CW12 and CW14 have the appropriate photochemical and pharmacological properties for use as photolabeling reagents to identify specific neurosteroid-binding sites on GABAA receptors. 相似文献13.
Rationale
The cAMP-dependent protein kinase A (PKA) signaling transduction pathway has been shown to play an important role in the modulation of several ethanol-induced behaviors. Different studies have demonstrated intracellular calcium (Ca2+)-dependent activation of the PKA cascade after ethanol administration. Thus, the cAMP cascade mediator Ca2+-dependent calmodulin (CaM) has been strongly implicated in the central effects of ethanol.Objectives
In this study, we assessed the role of the CaM inhibitor W7 on ethanol-induced stimulation, ethanol intake, and ethanol-induced activation of PKA.Methods
Swiss mice were pretreated with W7 (0–10 mg/kg) 30 min before ethanol (0–3.75 g/kg) administration. Immediately, animals were placed during 20 min in an open-field chamber. Ethanol (10 %, v/v) intake in 2 h was assessed using a limited access paradigm. Experiments with caffeine (0–15 mg/kg), cocaine (0–4 mg/kg), and saccharine (0.1 %, w/v) were designed to compare their results to those obtained with ethanol. Western blot was assayed 45 min after ethanol administration.Results
Results showed that pretreatment with W7, reduced selectively in a dose-dependent fashion ethanol-induced locomotor stimulation and ethanol intake. The ethanol-induced activation of PKA was also prevented by W7 administration.Conclusions
These results demonstrate that CaM inhibition resulted in a selective reduction of ethanol-stimulating effects and ethanol intake. The PKA activation induced by ethanol was blocked after the CaM blockade with W7. These results provide further evidence of the key role of cellular Ca2+-dependent pathways on the central effects of ethanol. 相似文献14.
Renu Chadha Swati Bhandari Sadhika Khullar Sanjay K. Mandal D. V. S. Jain 《Pharmaceutical research》2014,31(9):2479-2489
Purpose
The present work aims at improving the physicochemical properties of hydrochlorothiazide, a poorly water soluble antihypertensive drug by preparing its multi-component crystals with nicotinic acid (HCT-NA) and 2-picolinic acid (HCT-PIC).Methods
The crystals prepared by solution crystallization were investigated by thermoanalytical techniques. The crystal structures of HCT-NA (1) and HCT-PIC (2) were determined by the single crystal X-ray diffraction and were assessed for their aqueous solubility, antihypertensive activity and acute toxicity in rats.Results
Both 1 and 2 crystallized in the orthorhombic space group P212121 and formation of salts were confirmed. The solubility profiles of 1 and 2 in basic media showed a maximum release of 2.5 mg/ml and 1.9 mg/ml, respectively, in comparison to the drug (0.82 mg/ml). The in-vivo antihypertensive activity of 1 in deoxycorticosterone acetate salt induced hypertensive rats showed 1.5 fold improvement. No increase in the signs of toxicity were revealed in rats during the acute toxicity studies even at doses of 2,000 mg/kg by body weight in comparison to the free drug. Histopathological findings supported the safety of these multi-component crystals.Conclusions
The new solid phases exhibit potential to be explored for the oral drug delivery of HCT with improved solubility and therapeutic outcome. 相似文献15.
Jayme R. McReynolds Oliver Vranjkovic Malia Thao David A. Baker Khadijah Makky Yiwei Lim John R. Mantsch 《Psychopharmacology》2014,231(20):3953-3963
Rationale
Understanding the mechanisms responsible for stress-induced relapse is important for guiding treatment strategies aimed at minimizing the contribution of stress to addiction. Evidence suggests that these mechanisms involve interactions between noradrenergic systems and the neuropeptide corticotropin-releasing factor (CRF).Objectives
The interaction between β-adrenergic receptors (ARs) and CRF as it relates to the reinstatement of cocaine-conditioned reward in response to a stressor was examined in mice. We hypothesized that β2-ARs are required for stress-induced activation of CRF pathways responsible for reinstatement.Methods
Stress-induced relapse was examined based on the re-establishment of cocaine-induced conditioned place preference (CPP; 4?×?15 mg/kg cocaine, i.p.) after extinction using forced swim (6 min at 22 °C) or an injection of the β2-AR agonist, clenbuterol (4 mg/kg, i.p.). The CRF-R1 antagonist antalarmin (10 mg/kg, i.p.) or the β2-AR antagonist ICI-118,551 (1 mg/kg, i.p.) were given 30 min prior to reinstating stimuli. Quantitative PCR was conducted in dissected bed nucleus of the stria terminalis (BNST) and amygdala, putative sources of CRF that contribute to reinstatement, to examine the effects of ICI-118,551 on swim-induced increases in CRF messenger RNA (mRNA) in mice with a cocaine history.Results
Pretreatment with ICI-118,551 or antalarmin blocked swim-induced reinstatement of CPP. Reinstatement by clenbuterol was also blocked by antalarmin. ICI-118,551 pretreatment prevented swim-induced increases in CRF mRNA in the BNST. Effects in the amygdala were not observed.Conclusions
These findings indicate that, during stress, norepinephrine, via β2-ARs, either directly or indirectly activates CRF-releasing neurons in the BNST that interface with motivational neurocircuitry to induce reinstatement of cocaine-conditioned reward. 相似文献16.
Antoniette M. Maldonado-Devincci Matthew C. Beattie Danielle H. Morrow Raechel E. McKinley Jason B. Cook Todd K. O’Buckley A. Leslie Morrow 《Psychopharmacology》2014,231(17):3281-3292
Rationale
Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, and GABAergic neuroactive steroids contribute to homeostatic regulation of this circuitry. Acute forced swim stress (FSS) increases plasma, cortical, and hypothalamic (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP) levels in rats. However, there have not been systemic investigations of acute stress on changes in plasma and brain levels of 3α,5α-THP in mouse models.Objectives
The present experiments aimed to assess circulating and local brain levels of 3α,5α-THP following acute FSS in C57BL/6J mice.Methods
Mice were exposed to FSS (10 min), and 50 min later, blood and brains were collected. Circulating pregnenolone and 3α,5α-THP levels were assessed in serum. Free-floating brain sections (40 μm, four to five sections/region) were immunostained and analyzed in cortical and limbic brain structures.Results
FSS decreased circulating 3α,5α-THP (?41.6?±?10.4 %) and reduced 3α,5α-THP immunolabeling in the paraventricular nucleus of the hypothalamus (?15.2?±?5.7 %), lateral amygdala (LA, ?31.1?±?13.4 %), and nucleus accumbens (NAcc) shell (?31.9?±?14.6). Within the LA, vesicular glutamate transporter 1 (VGLUT1) and vesicular GABA transporter were localized in 3α,5α-THP-positively stained cells, while in the NAcc shell, only VGLUT1 was localized in 3α,5α-THP-positively stained cells, suggesting that both glutamatergic and GABAergic cells within the LA are 3α,5α-THP-positive, while in the NAcc shell, 3α,5α-THP only localizes to glutamatergic cells.Conclusions
The decrease in circulating and brain levels of 3α,5α-THP may be due to alterations in the biosynthesis/metabolism or changes in the regulation of the HPA axis following FSS. Changes in GABAergic neuroactive steroids in response to stress likely mediate functional adaptations in neuronal activity. This may provide a potential targeted therapeutic avenue to address maladaptive stress responsivity. 相似文献17.
Judy L. Thompson Daniel R. Rosell Mark Slifstein Ragy R. Girgis Xiaoyan Xu Yosefa Ehrlich Lawrence S. Kegeles Erin A. Hazlett Anissa Abi-Dargham Larry J. Siever 《Psychopharmacology》2014,231(21):4231-4240
Rationale
Schizotypal personality disorder (SPD) is associated with working memory (WM) impairments that are similar to those observed in schizophrenia. Imaging studies have suggested that schizophrenia is associated with alterations in dopamine D1 receptor availability in the prefrontal cortex (PFC) that may be related to the WM impairments that characterize this disorder.Objectives
The aim of this study was to characterize prefrontal D1 receptor availability and its relation to WM performance in SPD.Methods
We used positron emission tomography (PET) and the radiotracer [11C]NNC112 with 18 unmedicated SPD and 21 healthy control participants; as an index of D1 receptor availability, binding potential (BP) measures (BPF, BPND, and BPP) were calculated for prefrontal and striatal subregions. To assess WM, SPD participants completed the 2-back and Paced Auditory Serial Addition Test (PASAT).Results
There were no significant group differences in PFC BP. BPF and BPP in the medial PFC were significantly negatively related to PASAT performance (r s ?=??0.551, p?=?.022 and r s ?=??0.488, p?=?.047, respectively), but BP was not related to 2-back performance.Conclusions
In contrast to what has been found in schizophrenia, SPD was not associated with significant alterations in prefrontal D1 receptor availability. Similar to previous schizophrenia findings, however, higher prefrontal D1 receptor availability was associated with poorer WM performance (as measured by the PASAT) in SPD. These findings suggest that schizophrenia and SPD may share a common pathophysiological feature related to prefrontal dopamine functioning that contributes to WM dysfunction, but that in SPD, alterations in D1 may occur only in a subset of individuals and/or to an extent that is minor relative to what occurs in schizophrenia. 相似文献18.
Xu-Ping Yang Dan Lai Xiao-Yan Zhong Hong-Ping Shen Yi-Lan Huang 《European journal of clinical pharmacology》2014,70(10):1149-1158
Purpose
To assess the efficacy and safety of the novel sodium glucose co-transporter 2 (SGLT2) inhibitor—canagliflozin for type 2 diabetes (T2DM).Methods
A search of Medline (1946–January 2014), Embase (1950–January 2014), and The Cochrane Library for randomized controlled trials of canagliflozin compared to placebo or active comparator in T2DM was performed. Clinical Trials website and unpublished U.S. Food and Drug Administration data were also searched.Results
Ten trials including 6,701 patients were analyzed. Compared with placebo, canagliflozin produced absolute reductions in glycated hemoglobin A1c levels when used as monotherapy (weighted mean difference (WMD) ?1.08 %, 95 % confidence interval (CI) [?1.25 to ?0.90], p?0.00001) or add-on treatment (WMD ?0.73 %, 95 %CI [?0.84 to ?0.61], p?0.00001). When compared with other active comparators, canagliflozin significantly reduced HbA1c by ?0.21 % (WMD, 95 %CI [?0.33 to ?0.08], p?=?0.001). Canagliflozin led to greater body weight loss (vs. placebo, WMD ?2.81 kg, 95 %CI [?3.26 to ?2.37]; vs. active comparators, WMD ?3.49 kg, 95 %CI [?4.86 to ?2.12]). Hypoglycemia with canagliflozin was similar to placebo or sitagliptin, and was lower than glimepiride (risk ratio (RR) 0.15, 95 %CI [0.10 to 0.22]). Genital tract infections were more common with canagliflozin (vs. placebo, RR 3.76, 95 %CI [2.23 to 6.35]; vs. active comparators, RR 4.95, 95 %CI [3.25 to 7.52]). Similar incidences of urinary tract infections were noted with canagliflozin compared with control groups.Conclusion
Canagliflozin led to improvements in reducing glycated hemoglobin A1c levels and body weight with low risk of hypoglycemia in patients with T2DM. Common adverse effects including genital tract infections and osmotic diuresis-related AEs were identified and reviewed. Risks of cardiovascular events are even less certain, and more data on long-term effects are needed. 相似文献19.
Hyunjeong Kim Minsun Park Su-Kyoung Lee Jihyeon Jeong Kee Namkoong Hyun-Sang Cho Jin Young Park Byung-In Lee Eosu Kim 《Psychopharmacology》2014,231(20):4059-4069
Rationale
Alpha-lipoic acid (ALA) was shown to suppress atypical antipsychotic drug (AAPD)-induced weight gain. However, its mode of action has remained unidentified.Objective
We aimed to identify mechanisms underlying anti-obesity effects of ALA in mice treated with olanzapine.Methods
We compared body weight and food intake among vehicle-, olanzapine-, and olanzapine plus ALA-treated mice, and measured hypothalamic AMP-activated protein kinase (AMPK) activity by detecting levels of Thr172 and Ser485/491 phosphorylation, which indicate activation and inhibition of AMPK, respectively.Results
Body weights were increased by olanzapine in parallel with increased levels of Thr172 phosphorylation of hypothalamic AMPK. Initially increased rate of weight gain was diminished as Thr172 phosphorylation levels were decreased to control levels after 10 days of olanzapine treatment. ALA successfully not only prevented olanzapine-induced weight gain but also induced additional weight loss even relative to control levels throughout the treatment period. During the initial stage, ALA’s action was indicated by both suppression of olanzapine-induced Thr172 phosphorylation and an increase in Ser485/491 phosphorylation levels. However, in the later stage when no more increases in Thr172 phosphorylation and weight gain by olanzapine were observed, ALA’s action was only indicated by increased levels of Ser485/491 phosphorylation.Conclusions
Our data suggest that anti-obesity effects of ALA may be related to modulation of both Ser485/491 phosphorylation and Thr172 phosphorylation of hypothalamic AMPK, while olanzapine-induced weight gain may be only associated with increase in Thr172 phosphorylation. This might be an important mechanistic clue for the future development of anti-obesity drugs beyond control of AAPD-induced weight gain. 相似文献20.
Nabil E. Kassan Haythem A. Saadeh Wamid H. Talib Adel M. Mahasneh Hargobinder Kaur Kapil Goyal Rakesh Sehgal Mohammad S. Mubarak 《Medicinal chemistry research》2014,23(11):4872-4882
A number of novel Schiff bases (5a–i) and (7a–d) derived from metronidazole were synthesized. Reaction of 2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl ester toluene-4-sulfonate with 4-hydroxybenzaldehyde and with 3-hydroxybenzaldehyde in the presence of a base afforded 4-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)benzaldehyde (5) and 3-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy)benzaldehyde (7), respectively. The reaction of aldehydes 5 and 7 with a number of primary aromatic amines produced Schiff bases 5a–i and 7a–d, respectively. Structures of these compounds were confirmed through different spectroscopic methods such as 1H-NMR, 13C-NMR, mass spectrometry, and also by elemental analyses. The prepared compounds were evaluated in vitro for their antigiardial, anti-trichomonal, antibacterial, and antifungal activities. Compounds 5e, 5g, 5i, 7a, 7b, 7c, and 7d exhibited remarkable antigiardial activity and were found to be more active than metronidazole with IC50 of 7.2, 3.3, 1.5, 5.8, 4.5, 2.9, and 3.8 µg/mL, respectively. Compounds 5a and 5c also exhibited antigiradial activity with similar IC50 values compared to the reference drug metronidazole with IC50 of 7.2 µg/mL. The other compounds 5b, 5d, 5f, and 5 h also showed antigiardial activity but with higher IC50 compared to the reference drug. Compounds were also tested for their anti-trichomonal activity, they, however, exhibited higher IC50 compared to the reference drug metronidazole (7.4 µg/mL), except for compound 5a which exhibited anti-trichomonal activity with an IC50 of 6.3 µg/mL. On the bases of preliminary screening, the newly synthesized compounds exhibited moderate to potent antimicrobial activities. Compound 5e inhibited the growth of Methicillin resistant Staphylococcus aureus (MRSA) and Bacillus cereus and compound 5c inhibited Candida Pathogenic fungus at 50 μg/mL compared with the positive control (Nystatin) which inhibits Candida at 25 μg/mL. 相似文献