Thiocyanate stabilizes AMPA binding to the quisqualate receptor

Calcium and chloride ions stimulated [3H]glutamate binding to quisqualate-sensitive [3H]glutamate binding sites 4-fold, as measured by quantitative autoradiography, whereas 100 mM potassium thiocyanate had no additional effect. In contrast, calcium and chloride had little effect on the binding of [3H](RS)-[alpha]-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid ([3H]AMPA), but 100 mM thiocyanate stimulated binding 4-fold. AMPA displace little [3H]glutamate binding from quisqualate-sensitive binding sites in the molecular layer of the cerebellum in the absence of thiocyanate. However, in the presence of thiocyanate AMPA became a more effective displacer, but still displaced only 44% of the quisqualate-sensitive [3H]glutamate binding. The distribution of [3H]glutamate binding to quisqualate-sensitive sites was similar to but not identical with that of [3H]AMPA binding. However, the distribution of AMPA-displaceable [3H]glutamate binding correlated highly (r = 0.97, P3H]AMPA binding. The results suggest that AMPA binds to a subclass of quisqualate-sensitive [3H]glutamate binding sites that are highly influenced by ionic environment and that quisqualate-sensitive binding sites exist in several states.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27061/1/0000051.pd

Helping alliance and unmet needs in routine care of people with severe mental illness across Europe: a prospective longitudinal multicenter study

The helping alliance (HA) refers to the collaborative bond between patient and therapist including shared goals and tasks. People with severe mental illness have a complex mixture of clinical and social needs. Using mixed-effects regression, this study examined in 588 people with severe mental illness whether an increase in the HA is associated with fewer unmet needs over time, and whether change in the HA precedes change in unmet needs. It was found that a reduction of unmet needs was slower in patients with higher HA (B=0.04, p<.0001) only for patient-rated measures. Improvement in both patient-rated and staff-rated HA over time was associated with fewer subsequent patient- (B=-0.10, p<0.0001) and staff-rated (B=-0.08, p=0.0175) unmet needs. With positive changes in the HA preceding fewer unmet needs, findings provide further evidence for a causal relationship between alliance and outcome in the treatment of people with severe mental illness

Ethyl 4-{1-[(2,4-dinitro­phen­yl)hydrazono]eth­yl}-5-(2-naphthyl­methoxy­meth­yl)isoxazole-3-carboxyl­ate

The title compound, C26H23N5O8, was prepared and its structure investigated to further develop a working hypothesis for the essential binding pharmacophore for ligands of the System Xc- transporter [Patel et al. (2004 ▶). Neuropharmacology, 46, 273–284]. The hydrazone group displays an E geometry and the isoxazole double bond and C=N group of the hydrazone are in an s-cis relationship. The secondary amino NH group forms an intra­molecular N—H⋯O hydrogen bond to a ring nitro group. There is a dihedral angle of 44.27 (5)° between the isoxazole plane and the hydrazone group plane

Synthesis of fluorine-18 labeled GABA uptake inhibitors

The first syntheses of fluorine-18 labeled inhibitors of GABA reuptake [(R,S)-1-{2-{4-[18F]fluorophenyl}phenyl}methoxyethyl]piperidine-3-carboxylic acid, (R,S)-1-{2-(4-[18F]fluorophenyl)(4-fluorophenyl)methoxyethyl}piperidine-3-carboxylic acid, and (R,S)-1-[2-{(4-[18F]trifluoromethyl)phenyl} {(4-trifluoromethyl)phenyl}-methoxyethyl]piperidine-3-carboxylic acid] are described. These N-substituted nipecotic acid derivatives were prepared in no-carrier-added form by the condensation of the appropriately substituted [18F]benzhydryl chlorides (prepared in three steps from [18F]fluoride ion) with N-(2-hydroxyethyl)nipecotic acid ethyl ester, followed by ester hydrolysis. Overall radiochemical yields were 17-28% (corrected, 150 min synthesis time). A simple new method for synthesis of a [18F]trifluoromethyl group by the nucleophilic substitution of a bromodifluoromethyl substituent has also been developed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28921/1/0000758.pd

ALA and ALA hexyl ester induction of porphyrins after their systemic administration to tumour bearing mice

The use of synthetic lipophilic molecules derived from 5-aminolevulinic acid (ALA) is currently under investigation to enhance cellular ALA penetration. In this work we studied the effect of systemic administration to mice of the hexyl ester of ALA (He-ALA) on porphyrin tissue synthesis as compared to ALA. In most normal tissues as well as in tumour, He-ALA induced less porphyrin synthesis than ALA after its systemic administration either intravenous or intraperitoneal, although explant organ cultures exposed to either ALA or He-ALA revealed equally active esterases. The only tissue that accumulated higher porphyrin levels from He-ALA (seven times more than ALA) was the brain, and this correlated well with a rapid increase in ALA/He-ALA content in brain after administration of He-ALA. This may be ascribed to a differential permeability to lipophilic substances controlled by the blood–brain barrier, a feature which could be further exploited to treat brain tumours

GABA ergic transmission in rat pontine reticular formation regulates the induction phase of anesthesia and modulates hyperalgesia caused by sleep deprivation

The oral part of the pontine reticular formation (PnO) contributes to the regulation of sleep, anesthesia and pain. The role of PnO γ‐aminobutyric acid ( GABA ) in modulating these states remains incompletely understood. The present study used time to loss and time to resumption of righting response (Lo RR and Ro RR ) as surrogate measures of loss and resumption of consciousness. This study tested three hypotheses: (i) pharmacologically manipulating GABA levels in rat PnO alters Lo RR , Ro RR and nociception; (ii) propofol decreases GABA levels in the PnO; and (iii) inhibiting GABA synthesis in the PnO blocks hyperalgesia caused by sleep deprivation. Administering a GABA synthesis inhibitor [3‐mercaptopropionic acid (3‐ MPA )] or a GABA uptake inhibitor [nipecotic acid ( NPA )] into rat PnO significantly altered Lo RR caused by propofol. 3‐ MPA significantly decreased Lo RR for propofol (−18%). NPA significantly increased Lo RR during administration of propofol (36%). Neither 3‐ MPA nor NPA altered Ro RR following cessation of propofol or isoflurane delivery. The finding that Lo RR was decreased by 3‐ MPA and increased by NPA is consistent with measures showing that extracellular GABA levels in the PnO were decreased (41%) by propofol. Thermal nociception was significantly decreased by 3‐ MPA and increased by NPA , and 3‐ MPA blocked the hyperalgesia caused by sleep deprivation. The results demonstrate that GABA levels in the PnO regulate the time for loss of consciousness caused by propofol, extend the concept that anesthetic induction and emergence are not inverse processes, and suggest that GABA ergic transmission in the PnO mediates hyperalgesia caused by sleep loss. The intravenous anesthetic propofol significantly decreases extracellular GABA levels in rat PnO. Pharmacologically increasing or decreasing extracellular GABA levels increases or decreases, respectively, the time to loss of consciousness caused by propofol. GABAergic transmission in the PnO does not modulate the resumption of consciousness after isoflurane‐ and propofol‐anesthesia. Administration of a GABA synthesis inhibitor into the PnO blocks the hyperalgesia caused by sleep deprivation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108018/1/ejn12571.pd