Administration of ceftriaxone, an astrocyte glutamate


Administration of ceftriaxone, an astrocyte glutamate

transporter enhancer, to axotomized mice significantly decreased the immunoreactivity for S100A6. In the third experiment, we tested an animal model of epilepsy using kainic acid (KA), a glutamate analog. In the mouse hippocampus after KA injection, S100A6 immunoreactivity was significantly increased in astrocytes, and pyknotic changes were observed in CA3 pyramidal neurons. Treatment of MK-801, an N-methyl-D-aspartate receptor antagonist, counteracted the KA-induced increase in S100A6 immunoreactivity, and reduced the numbers of pyknotic neurons. Our results indicate that upregulation of astrocytic S100A6 in response to extracellular Selleck Sotrastaurin glutamate may be involved in neuronal damage under pathophysiological conditions. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Prion diseases, or transmissible spongiform encephalopathies, are a group of infectious neurological diseases associated with the structural conversion

of an endogenous protein (PrP) in the central nervous system. There are two major forms of this protein: the native and noninfectious cellular form, PrP(C); and the misfolded, infectious, and proteinase K-resistant form, PrP(Sc). The C-terminal domain of PrP(C) is mainly alpha-helical in structure, whereas learn more PrP(Sc) in known to aggregate into an assembly of beta-sheets, forming amyloid fibrils. To identify the regions of PrP(C) potentially involved in the initial steps of the conversion to the infectious conformation, we have used high-resolution NMR spectroscopy to characterize the stability and structure of bovine recombinant PrP(C) (residues 121 to 230) during unfolding with the denaturant urea. Analysis

of the 800 MHz (1)H NMR spectra reveals region-specific information about the structural changes occurring upon unfolding. Our data suggest that the dissociation of the native beta-sheet of PrP(C) is a primary step in the urea-induced unfolding process, O-methylated flavonoid while strong hydrophobic interactions between helices alpha 1 and alpha 3, and between alpha 2 and alpha 3, stabilize these regions even at very high concentrations of urea.”
“Attempts were made to evaluate methods measuring the capsid integrity and/or functions of noroviruses (NoVs) following heat treatment. Intact viruses (Murine Norovirus-1 [MNV-1] and human NoV GII.4), virus like particles (VLPs) and P particles (expressed in vitro from the protruding domain of the viral capsid) of NoVs were used in this study. Following heat treatment, no significant difference of viral titer of MNV-1 versus NoV GII.4 was observed by RNase One RT-PCR or cell-binding RT-PCR, although cell-binding RT-PCR (to measure the capsid functions) revealed higher reductions than RNase One RT-PCR (to measure the capsid integrity).

We performed rescue experiments in which ApoE isoforms were ectop

We performed rescue experiments in which ApoE isoforms were ectopically expressed in cells depleted of endogenous ApoE. The ectopic expression of

the ApoE2 isoform, which has low affinity for the LDL receptor (LDLR), resulted in poor recovery of infectious HCV, whereas the expression of other isoforms, ApoE3 and ApoE4, rescued the production of infectious virus, raising it to an almost normal level. Furthermore, we found that the infectivity of HCV check details required both the LDLR and scavenger receptor class B, member I (SR-BI), ligands for ApoE. These findings indicate that ApoE is an essential apolipoprotein for HCV infectivity.”
“The host proteome response and molecular mechanisms that drive disease in vivo during infection by a human isolate of the highly pathogenic avian influenza virus (HPAI) and 1918 pandemic influenza virus remain poorly understood. This study presents a comprehensive characterization of the proteome response in cynomolgus macaque (Macaca fascicularis) lung tissue over 7 days of infection with HPAI (the most virulent), a reassortant

virus containing 1918 hemagglutinin and neuraminidase surface proteins (intermediate virulence), Selleck APR-246 or a human seasonal strain (least virulent). A high-sensitivity two-dimensional liquid chromatography-tandem mass spectroscopy strategy and functional network analysis were implemented to gain insight into response pathways activated in macaques during influenza virus infection. A macaque protein database was assembled and used in the identification of 35,239 unique peptide sequences corresponding to approximately 4,259 proteins. Quantitative analysis identified an increase in expression of 400 proteins during viral infection. The abundance levels

of a subset of these 400 proteins produced strong correlations with disease progression observed in the macaques, distinguishing a “”core”" response to viral infection from a “”high”" response specific to severe disease. Proteome expression profiles revealed distinct temporal response kinetics between viral strains, with HPAI inducing the most rapid response. While proteins involved in the immune response, metabolism, and transport were increased rapidly in the lung by HPAI, the this website other viruses produced a delayed response, characterized by an increase in proteins involved in oxidative phosphorylation, RNA processing, and translation. Proteomic results were integrated with previous genomic and pathological analysis to characterize the dynamic nature of the influenza virus infection process.”
“Mutations in the receptor-binding site of the hemagglutinin of pandemic influenza A(H1N1) 2009 viruses have been detected sporadically. An Asp222Gly (D222G) substitution has been associated with severe or fatal disease.

) for 7 days (day 1-7), followed by a 7-day washout (day8-14) Su

) for 7 days (day 1-7), followed by a 7-day washout (day8-14). Subchronic treatment with PCP induced an enduring NOR deficit. Lurasidone (1 mg/kg) but not 0.1 mg/kg, which is effective to acutely reverse the deficit due to subchronic PCP, or tandospirone, but not pimavanserin or haloperidol, significantly prevented the PCP-induced NOR deficit on

day 15. The ability of lurasidone co-treatment to prevent the PCP-induced NOR deficit was enduring and still present at day 22. The preventive effect of lurasidone was blocked by WAY 100635, a selective 5-HT1A antagonists, further evidence for the importance of 5-HT1A receptor stimulation in the NOR deficit produced by subchronic PCP. Further study is needed to determine whether these results concerning mechanism and dosage can be the basis for selleck products prevention of the development of CIS in at risk populations. Neuropsychopharmacology (2012) 37, 2175-2183; doi:10.1038/npp.2012.64; published online 27 June 2012″
“Acromegaly is a chronic disease with increased morbidity and mortality, where usually multiple treatment modalities are used. The somatostatin analogs (SSAs) are the mainstay of medical therapy but, in many patients, including those with a germline mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene, disease activity cannot be controlled with these

drugs. Previous data have suggested the involvement selleck chemicals llc of the tumor-suppressor gene ZAC1 in the mechanism of action of SSAs, and more recent findings suggested that Leukotriene-A4 hydrolase SSAs could regulate AIP, which in turn can stimulate ZAC1, therefore suggesting the existence of a SSA-AIP-ZAC1 somatostatin effect pathway. The current review discusses these novel observations, highlighting their significance in the treatment of sporadic and familial somatotroph adenomas.”
“Mvo10b from the mesophilic archaeon Methanococcus voltae is a member of the Sac10b family which may play an important role in the organization

and accessibility of genetic information in Archaea. Since Mvo10b is a DNA-binding protein as the other member in the Sac10b family, to obtain a recombinant Mvo10b requires an efficient and inexpensive expression and purification system for producing the protein free of nucleic acid contamination. Previously, the hyperthermophilic archaeal Ssh10b of the Sac10b family was successfully purified. However, the protocol adopted to purify Ssh10b is not appropriate for purifying the mesophilic Mvo10b. This study describes the successful expression and purification of the recombinant Mvo10b. The expression of recombinant Mvo10b was carried out in Escherichia coli, and the target protein was expressed in the soluble form. The protein was purified by polyethyleneimine (PEI) precipitation followed by nickel ion metal affinity chromatography. The purity of Mvo10b was checked to insure being free of nucleic acid contamination. The final protein yield is about 30 mg/l of LB culture.

(C) 2009 IBRO Published by Elsevier Ltd All rights reserved “

(C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Purpose: To improve the understanding of the etiological relation between type 2 diabetes and urinary incontinence, we examined associations between diabetes and urinary incontinence type in 71,650 women 37 to 79 years old in the Nurses’

Health Study and the Nurses’ Health Study II.

Materials and Methods: From 1976 to 2000 in the Nurses’ Health Study and 1989 to 2001 in the Nurses’ Health Study 11 participants reported diagnoses of type 2 diabetes. Women with incident urinary incontinence at least weekly were identified from 2000 to 2002 in the Nurses’ Health Study and 2001 to 2003 in the Nurses’ Health Study 11, We pooled data from the 2 cohorts, ML323 purchase and estimated odds ratios and 95% confidence intervals using multivariable logistic regression adjusting for age, parity, body check details mass index, smoking, hysterectomy, functional limitations, menopausal status, postmenopausal hormone use, incontinence promoting medications and study cohort.

Results: The incidence of at least weekly urinary incontinence was 5.3% (3,612 of 67,984) among women without type 2 diabetes and 8.7% (318 of 3,666) among women with diabetes. Overall the multivariable adjusted odds of incident urinary incontinence were increased 20% (OR 1.2, 95% Cl 1.0-1.3, p = 0.01) among women with vs without type 2 diabetes. This increase appeared largely explained

by significantly greater odds of urge urinary incontinence (OR 1.4, 95% CI 1.0-1.9, p = 0.03). There was no apparent association between diabetes and stress (p = 0.3) or mixed (p = 0.6) urinary incontinence, although confidence intervals were somewhat wide.

Conclusions: Our findings suggest that type 2 diabetes may especially influence urge urinary incontinence. Further research is needed to confirm this finding and identify pathways linking these conditions.”
“Purpose: We studied urodynamic characteristics and bladder sensory function in the early stages of diabetic bladder dysfunction in diabetic Erastin women.

Materials and Methods: A total of 86 consecutive type 2 diabetic women with minimal confounders of voiding dysfunction followed

at a diabetes clinic were prospectively enrolled and subjected to urodynamic studies. The sensory response of AS and C fibers of the bladder was measured by intravesical current perception threshold testing at frequencies of 250 and 5 Hz, respectively.

Results: Of these 86 women 30 (34.9%) were classified as having detrusor un-deractivity, 12 (14.0%) presented signs of detrusor overactivity, 11 (12.8%) were referred to as having bladder outlet obstruction and 33 (38.4%) showed normal detrusor function on urodynamics. The normal detrusor function group was the reference group. The detrusor underactivity group showed impaired emptying function and decreased sensation on cystometry and intravesical current perception threshold testing.

By using a new genetic technique to screen libraries expressing a

By using a new genetic technique to screen libraries expressing artificial transmembrane proteins for activators of the PDGF beta receptor, we isolated eFT508 much smaller proteins, from 32 to 36 residues, that lack all three of these features yet still dimerize noncovalently, specifically activate the PDGF beta receptor via its transmembrane domain, and transform cells efficiently. The primary amino acid sequence of BPV E5 is virtually unrecognizable in some of these proteins, which share as few

as seven consecutive amino acids with the viral protein. Thus, small artificial proteins that bear little resemblance to a viral oncoprotein can nevertheless productively interact with the same cellular target. We speculate that similar buy ATM Kinase Inhibitor cellular proteins may exist but have been overlooked due to their small size and hydrophobicity.”
“Pituitary adenylate cyclase activating polypeptide (PACAP) is a multifunctional neuropeptide, showing widespread occurrence in the nervous system and also in peripheral organs. The neuroprotective effects of PACAP are well-established in different neuronal systems against noxious stimuli in vitro and in vivo. Recently, its general cytoprotective actions have been recognized, including renoprotective effects. However, the effect of endogenous PACAP in the kidneys is not known. The main aim of the present study was to investigate

whether the lack of this endogenous neuropeptide influences survival of kidney cells against oxidative stress. First, we determined the presence of endogenous PACAP from mouse kidney homogenates by mass spectrometry and PACAP-like immunoreactivity by radioimmunoassay. Second, primary cultures were isolated from wild type and PACAP deficient mice and cell viability was assessed following oxidative stress induced by 0.5, 1.5 and 3 mM H(2)O(2). Our mass spectrometry and radioimmunoassay results show that PACAP is endogenously present in the kidney. The main part of our study revealed that the sensitivity of cells

from PACAP deficient mice was increased to oxidative stress: both after 2 or 4 h of exposure, cell viability was significantly reduced compared to that from control wild type mice. Buspirone HCl This increased sensitivity of kidneys from PACAP deficient mice could be counteracted by exogenously given PACAP38. These results show, for the first time, that endogenous PACAP protects against oxidative stress in the kidney, and that PACAP may act as a stress sensor in renal cells. These findings further support the general cytoprotective nature of this neuropeptide. (C) 2009 Elsevier Ireland Ltd. All rights reserved.”
“Suicidality is a life-threatening symptom in patients with bipolar disorder (BD). Impulsivity and mood instability are associated with suicidality in mood disorders.

Response latencies of dopaminergic neurons were reliably longer t

Response latencies of dopaminergic neurons were reliably longer than those of parabrachial neurons. Intra-parabrachial injections of the local anasethetic lidocaine or the GABA(A) receptor antagonist muscimol reduced tonic parabrachial activity and the amplitude (and in the case of lidocaine, duration) of the phasic response to footshock. Suppression of parabrachial activity with lidocaine reduced the baseline firing rate of dopaminergic neurons, while both lidocaine and muscimol reduced the amplitude of the phasic inhibitory response to footshock, in the case of lidocaine sometimes abolishing it altogether.

Considered together, these results suggest that the parabrachial nucleus is an important source of short-latency nociceptive PDGFR inhibitor input to the dopaminergic neurons. (C) 2010 IBRO. Published GSI-IX by Elsevier Ltd. All rights reserved.”

To develop a haemolysin (hly) gene-based species-specific multiplex PCR for simple and rapid detection of Vibrio campbellii, V. harveyi and V. parahaemolyticus.

Methods and Results:

The complete hly genes of three V. campbellii strains isolated from diseased

shrimps were sequenced and species-specific PCR primers were designed based on these sequences and the registered hly gene sequences of Vibrio harveyi and Vibrio parahaemolyticus. Specificity and sensitivity of the multiplex PCR was validated with 27 V. campbellii, 16 V. harveyi, and 69 V. parahaemolyticus, 18 other BCKDHA Vibrio species, one Photobacterium damselae and nine other bacterial species. The detection limits of all the three target species were in between 10 and 100 cells per PCR tube.


Specificity and sensitivity of the multiplex PCR is 100% each and sufficient to be considered as an effective tool in a prediction system to prevent potential disease outbreak by these Vibrio species.

Significance and Impact of the Study:

Because there is lack of simple, rapid and cost-effective method to differentiate these closely related V. campbellii, V. harveyi and V. parahaemolyticus species, the multiplex PCR developed in this study will

be very effective in epidemiological, ecological and economical points of view.”
“We analyzed the effects of different treadmill running protocols on the functional recovery after chronic constriction injury (CCI) of the sciatic nerve in mice. We found that a treadmill protocol of short-lasting running (1 h/d for 5 days after CCI) reduced the neuropathy-induced mechanical allodynia and normalized the weight bearing and the sciatic static index of the injured hindpaw. At difference, a treadmill protocol of long-lasting running (1 h/d for more than 5 days after CCI) was unfavorable both for allodynia and for functional recovery. Behavioral results were correlated with immunofluorescence assays of microglia and astrocytes activation in L4/L5 lumbar spinal cord sections.

We investigated

We investigated ABT263 the effect of Skp2 on VSMC proliferation and neointimal formation in vivo.

Methods and Results. Firstly, we demonstrated that Skp2-null mice developed significantly smaller neointimal areas than wild-type mice after carotid ligation. Secondly, to further identify, a local rather than a systemic effect of Skp2 alteration, we demonstrated that adenovirus-mediated expression of dominant-negative Skp2 in the balloon-injured

rat carotid artery significantly increased medial p27(Kip1) levels, inhibited VSMC proliferation, and the subsequent neointimal thickening. Lastly, to determine if Skp2 alone is sufficient to drive VSMC proliferation and lesion development in vivo, we demonstrated that adenovirus-delivery of wild-type Skp2 to the minimally-injured rat carotids

is sufficient to downregulate p27(Kip1) protein levels, enhanced medial VSMC proliferation, and the neointimal thickening.

Conclusion: This data provides, we believe for the first time, a more comprehensive understanding of Skp2 in the regulation of VSMC proliferation and neointimal formation and suggests that see more Skp2 is a promising target in the treatment of vasculoproliferative diseases. (J Vasc Surg 2009;50:1135-42.)”
“OBJECTIVE: A spinal perimedullary arteriovenous fistula (PMAVF) is a direct fistula of one or more spinal arteries into the perimedullary venous network with reversed venous flow and subsequent venous congestion of the spinal cord. The therapeutic goal of surgery is to normalize the venous drainage by obliterating the fistula. Strictly ventral lesions typically require an anterior approach to ensure adequate exposure of the fistula FER as well and the preservation of the physiological blood supply to the spinal cord.

CLINICAL PRESENTATION: We present a case of a ventral PMAVF at the level of T10 with feeders from the anterior spinal artery, caudally draining veins on the ventral spinal cord, and a dilated transmedullary vein filling

cranially draining veins on the dorsal aspect of the spinal cord.

TECHNIQUE: The dilated transmedullary vein was approached by a laminectomy. The vein was coagulated, and the gliotic channel was used to approach the ventral fistula site from the dorsal surface of the spinal cord. Complete obliteration of the fistula was achieved, and the preoperative neurological deficit improved.

CONCLUSION: We conclude that transmedullarly draining veins offers a possible dorsal approach for the occlusion of some ventral PMAVFs, thus avoiding more complex anterior approaches to the ventral spinal cord.”
“Objective: Image-guided surgery provides a mechanism to accurately and quickly assess the location of surgical tools relative to a preoperative image.

Several NDV vaccine vectors have been generated, and their immuno

Several NDV vaccine vectors have been generated, and their immunogenicities have been investigated with different animal models. However, a systematic study to evaluate the optimal insertion site of the foreign antigens into NDV that results in enhanced immune responses specific to the antigen has not yet been conducted. In this article, we describe the ability of NDV expressing HIV Gag to generate a Gag-specific immune response in mice. We also have determined the optimal selleck compound insertion site into the NDV genome by generating recombinant NDV-HIVGag

viruses in which HIV gag was located at different transcriptional positions throughout the NDV viral genome. All recombinant viruses were viable, grew to similar titers in embryonated chicken eggs, and expressed Gag in a QNZ stable manner. Our in vivo experiments revealed that higher HIV Gag protein expression positively correlates with an enhanced CD8(+) T-cell-mediated immune response and protective immunity against challenge with vaccinia virus expressing HIV Gag. We also inserted a codon-optimized version of HIV gag in the described best location,

between the P and M genes. Virus expressing the codon-optimized version of HIV gag induced a higher expression of the protein and an enhanced immune response against HIV Gag in mice. These results indicate that strategies directed toward increasing antigen

expression by NDV result in enhanced immunogenicity and vaccine efficacy.”
“Reelin plays critical roles in brain formation by binding to apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein Florfenicol receptor. Several isoforms and fragments of Reelin are generated by alternative splicing and proteolytic cleavage. In addition, two splice variants of ApoER2 have been recognized, namely, LA1237 and LA12378, that differ in the number of ligand-binding type A (LA) repeats.

Here, we quantitatively investigated the affinity between various isoforms/fragments of Reelin and the ApoER2 splice variants. ApoER2-LA1237 bound rather strongly to the Reelin central fragment than to the fragment bearing Reelin repeat 8 (RR8). ApoER2-LA12378 bound comparably to all Reelin fragments without the C-terminal region. These findings suggest that LA8 of ApoER2 and RR8 interfere with the interaction between the Reelin central fragment and ApoER2. Using a monoclonal antibody that only recognizes ApoER2-LA12378, we found that this variant of ApoER2 was expressed in the cerebral cortical wall and in the internal granule cells of the cerebellum during development. Primary-cultured cortical neurons did not express ApoER2-LA12378, and the extent of signal activation by Reelin fragments was well correlated with their affinity for ApoER2-LA1237.

Methods: The AmBaSar was synthesized in four steps starting from

Methods: The AmBaSar was synthesized in four steps starting from (1,8-diamine-Sar) cobalt(III) pentachloride ([Co(DiAmSar)]Cl-5) using an improved synthetic method. The AmBaSar was labeled with Cu-64(2+) in pH 5.0 ammonium acetate buffer solution at room temperature, followed by analysis and purification with HPLC. The in vitro stability of Cu-64-AmBaSar complex was evaluated in phosphate buffered saline (PBS), fetal bovine serum and mouse blood. The microPET imaging and biodistribution studies of Cu-64-AmBaSar were performed in Balb/c mice, and

the results were compared with Cu-64-DOTA.

Results: The AmBaSar was readily prepared and characterized by MS and H-1 NMR. The radiochemical yield of Cu-64-AmBaSar was >= 98% after 30 min of incubation at 25 degrees C. The Cu-64-AmBaSar complex was analyzed and purified by HPLC with a retention Nirogacestat research buy time of 17.9 min. The radiochemical purity of Cu-64-AmBaSar was more than 97% after 26 h of incubation in PBS or serum. The biological evaluation of Cu-64-AmBaSar in normal mouse demonstrated renal clearance as the primary mode of excretion, with improved stability in vivo compared to Cu-64-DOTA.

Conclusions: The new cage-like BFC AmBaSar was prepared using a simplified synthetic

method. The Cu-64-AmBaSar complex could be obtained rapidly with high radiochemical yield (>= 98%) under mild conditions. In vitro and in vivo evaluation of AmBaSar demonstrated its promising potential Selleck EPZ6438 Plasmin for preparation of 64 Cu radiopharmaceuticals. (C) 2010 Published by Elsevier Inc.”
“Highly active antiretroviral therapy (HAART) can reduce human immunodeficiency virus type 1 (HIV-1) viremia to clinically undetectable levels. Despite this dramatic reduction, some virus is present in the blood. In addition, a long-lived latent reservoir for HIV-1 exists in resting memory CD4(+) T cells. This reservoir is believed to be a source of the residual viremia and is the focus of eradication efforts. Here, we use

two measures of population structure-analysis of molecular variance and the Slatkin-Maddison test-to demonstrate that the residual viremia is genetically distinct from proviruses in resting CD4(+) T cells but that proviruses in resting and activated CD4(+) T cells belong to a single population. Residual viremia is genetically distinct from proviruses in activated CD4(+) T cells, monocytes, and unfractionated peripheral blood mononuclear cells. The finding that some of the residual viremia in patients on HAART stems from an unidentified cellular source other than CD4(+) T cells has implications for eradication efforts.”
“An ultrafast and efficient high-performance liquid chromatographic (LC) method was developed to purify positron emission tomography (PET) radiopharmaceuticals as well as for metabolite analysis of the plasma sample.

Cells were cultured from samples of BAL fluid collected from 51 p

Cells were cultured from samples of BAL fluid collected from 51 patients that had undergone bronchoscopy and BAL for diagnostic purposes. The cells were visualized by transmission electron microscopy and innmunoelectron microscopy to achieve ultrastructural localization of alpha-smooth muscle actin (alpha-SMA) and fibronectin. The levels of alpha-SMA protein and mRNA and fibronectin mRNA were measured by western blot and quantitative real-time reverse transcriptase polymerase chain reaction. The invasive capacities of the cells were evaluated. The cultured

cells were either fibroblasts or myofibroblasts. The structure buy CB-5083 of the fibronexus, and the amounts of intracellular actin, extracellular fibronectin and cell junctions

of myofibroblasts see more varied in different diseases. In electron and immunoelectron microscopy, cells cultured from interstitial lung diseases (ILDs) expressed more actin filaments and alpha-SMA than normal lung. The invasive capacity of the cells obtained from patients with idiopathic pulmonary fibrosis was higher than that from patients with other type of ILDs. Cells expressing more actin filaments had a higher invasion capacity. It is concluded that electron and immunoelectron microscopic studies of myofibroblasts can reveal differential features in various diseases. An analysis of rnyofibroblasts cultured from diagnostic BAL fluid samples may represent a new kind of tool for diagnostics and research into lung diseases. Laboratory Investigation (2012) 92, 1270-1284; doi:10.1038/labinvest.2012.95; Terminal deoxynucleotidyl transferase published online 18

June 2012″
“(-)Nicotine produces antinociceptive effects in rodents. meta-Chlorophenylguanidine (MD-354), an analgesia-enhancing agent, binds at 5-HT(3) and alpha(2)-adrenoceptors and potentiates the antinociceptive effects of an “”inactive”" dose of clonidine. The present study examined the actions of MD-354 on (-)nicotine-induced antinociception.

Mouse tail-flick and other assays were employed.

In the tail-flick assay, (-)nicotine (ED(50) = 1.66 mg/kg) but not MD-354 produced dose-related antinociceptive effects. Administered in combination with (-)nicotine (2.5 mg/kg), MD-354 (AD(50) = 3.4 mg/kg) did not potentiate, but effectively antagonized the antinociceptive actions of (-)nicotine. In a mouse hot-plate assay, MD-354 failed to modify (-)nicotine responses. In combination with a locomotor activity-suppressing dose of (-)nicotine, MD-354 (up to 17 mg/kg) failed to antagonize (-)nicotine-induced hypolocomotion. In a rat drug discrimination paradigm using (-)nicotine as training drug, MD-354 produced saline-appropriate responding; in combination with the training dose of (-)nicotine, MD-354 failed to antagonize the nicotine cue.