5-Hydroxytryptamine (5-HT)(1A) receptors play an important role in multiple cognitive processes, and compelling evidence suggests that 5-HT(1A) antagonists can reverse cognitive impairment. We have ...examined the therapeutic potential of a potent (K(i) = 1.1 nM), selective (>100-fold), orally bioavailable, silent 5-HT(1A) receptor antagonist (K(B) = 1.3 nM) (R)-N-(2-methyl-(4-indolyl-1-piperazinyl)-ethyl)-N-(2-pyridinyl)-cyclohexane carboxamide (WAY-101405). Oral administration of WAY-101405 was shown to be effective in multiple rodent models of learning and memory. In a novel object recognition paradigm, 1 mg/kg enhanced retention (memory) for previously learned information, and it was able to reverse the memory deficits induced by scopolamine. WAY-101405 (1 mg/kg) was also able to reverse scopolamine-induced deficits in a rat contextual fear conditioning model. In the Morris water maze, WAY-101405 (3 mg/kg) significantly improved learning in a paradigm of increasing task difficulty. In vivo microdialysis studies in the dorsal hippocampus of freely moving adult rats demonstrated that acute administration of WAY-101405 (10 mg/kg) increased extracellular acetylcholine levels. The selective radioligand (3)HWAY-100635, administered i.v., was used for in vivo receptor occupancy studies, where WAY-101405 occupied 5-HT(1A) receptors in the rat cortex, with an ED(50) value of 0.1 mg/kg p.o. Taken together, these studies demonstrate that WAY-101405 is a potent and selective, brain penetrant, orally bioavailable 5-HT(1A) receptor "silent" antagonist that is effective in preclinical memory paradigms at doses where approximately 90% of the postsynaptic 5-HT(1A) receptors are occupied. These results further support the rationale for use of this compound class in the treatment of cognitive dysfunction associated with psychiatric and neurological conditions.
This 2023 Clinical Practice Guideline provides the biomedical definition of death based on permanent cessation of brain function that applies to all persons, as well as recommendations for death ...determination by circulatory criteria for potential organ donors and death determination by neurologic criteria for all mechanically ventilated patients regardless of organ donation potential. This Guideline is endorsed by the Canadian Critical Care Society, the Canadian Medical Association, the Canadian Association of Critical Care Nurses, Canadian Anesthesiologists’ Society, the Canadian Neurological Sciences Federation (representing the Canadian Neurological Society, Canadian Neurosurgical Society, Canadian Society of Clinical Neurophysiologists, Canadian Association of Child Neurology, Canadian Society of Neuroradiology, and Canadian Stroke Consortium), Canadian Blood Services, the Canadian Donation and Transplantation Research Program, the Canadian Association of Emergency Physicians, the Nurse Practitioners Association of Canada, and the Canadian Cardiovascular Critical Care Society.
Neurokinin-3 (NK3) receptors are concentrated in forebrain and basal ganglia structures within the mammalian CNS. This distribution, together with the modulatory influence of NK3 receptors on ...monoaminergic neurotransmission, has led to the hypothesis that NK3 receptor antagonists may have therapeutic efficacy in the treatment of psychiatric disorders. Here we describe the in vitro and in vivo characterization of the highly selective NK3 receptor antagonist talnetant (SB-223412). Talnetant has high affinity for recombinant human NK3 receptors (pKi 8.7) and demonstrates selectivity over other neurokinin receptors (pKi NK2 = 6.6 and NK1<4). In native tissue-binding studies, talnetant displayed high affinity for the guinea pig NK3 receptor (pKi 8.5). Functionally, talnetant competitively antagonized neurokinin B (NKB)-induced responses at the human recombinant receptor in both calcium and phosphoinositol second messenger assay systems (pA2 of 8.1 and 7.7, respectively). In guinea pig brain slices, talnetant antagonized NKB-induced increases in neuronal firing in the medial habenula (pKB = 7.9) and senktide-induced increases in neuronal firing in the substantia nigra pars compacta (pKB = 7.7) with no diminution of maximal agonist efficacy, suggesting competitive antagonism at native NK3 receptors. Talnetant (3-30 mg/kg i.p.) significantly attenuated senktide-induced 'wet dog shake' behaviors in the guinea pig in a dose-dependent manner. Microdialysis studies demonstrated that acute administration of talnetant (30 mg/kg i.p.) produced significant increases in extracellular dopamine and norepinephrine in the medial prefrontal cortex and attenuated haloperidol-induced increases in nucleus accumbens dopamine levels in the freely moving guinea pigs. Taken together, these data demonstrate that talnetant is a selective, competitive, brain-penetrant NK3 receptor antagonist with the ability to modulate mesolimbic and mesocortical dopaminergic neurotransmission and hence support its potential therapeutic utility in the treatment of schizophrenia.
Abstract Social isolation from weaning in rats produces behavioural and hippocampal structural changes at adulthood. Here, rats were group or isolation reared for eight-weeks. Following the initial ...four-week period of rearing, fluoxetine (10 mg/kg i.p.) was administered for 28 days. Changes in recognition memory, hippocampal monoamines, and cytoskeletal microtubules were investigated. Isolation-rearing for four- or eight-weeks produced recognition memory deficits that were not reversed by fluoxetine. Eight-weeks of isolation decreased α-tubulin acetylation (Acet-Tub) and the tyrosinated/detyrosinated α-tubulin ratio (Tyr/Glu-Tub), suggesting major alterations in microtubule dynamics and neuronal plasticity. In grouped rats, fluoxetine decreased Acet-Tub without changes in Tyr/Glu-Tub. In isolates, fluoxetine did not affect Acet-Tub but increased Tyr/Glu-Tub. Finally, fluoxetine altered serotonin metabolism in grouped, but not in isolated animals. Therefore, isolation-rearing changes the hippocampal responses of the serotonergic and microtubular system to fluoxetine. These findings show that early-life experience induces behavioural changes paralleled by alterations in cytoskeletal and neurochemical functions.
Neurokinin-3 (NK(3)) receptor distribution and its modulatory influence on dopaminergic and noradrenergic neurotransmission have lead to the hypothesis that NK(3) receptor antagonists may be a valid ...target to ameliorate the symptomatology of schizophrenia. This hypothesis has gained some clinical support as the selective NK(3) receptor antagonist osanetant has shown efficacy in schizophrenic patients. Talnetant (SB-223412) is a potent and selective NK(3) receptor antagonist able to modulate monoaminergic neurotransmission in both cortical and subcortical brain structures. Here we have used in vivo microdialysis to investigate the adjunctive effects of talnetant (10 and 30 mg/kg; i.p.) on typical (i.e. haloperidol, 0.3 and 1 mg/kg; i.p.) and atypical (i.e. risperidone, 0.3 and 1 mg/kg; i.p.) antipsychotic drug-induced changes in monoaminergic neurotransmission in forebrain structures of the guinea pig. As seen previously talnetant, produced a dose dependent increase in extracellular levels of both dopamine (DA) and norepinephrine (NE) in both prefrontal cortex (PFC) and hippocampus in a similar manner to the atypical risperidone. Combination studies revealed an additive effect of talnetant on risperidone-induced changes in both NE and DA levels in the PFC but not the hippocampus. Furthermore, addition of talnetant converted the neurochemical profile of the typical antipsychotic, haloperidol, to a profile more akin to that induced by an atypical antipsychotic. These data suggest that addition of talnetant to antipsychotic drugs may facilitate monoaminergic neurotransmission and hence potentially improve their clinical efficacy.
The Juno Microwave Radiometer (MWR) is a six-frequency scientific instrument designed and built to investigate the deep atmosphere of Jupiter. It is one of a suite of instruments on NASA’s New ...Frontiers Mission Juno launched to Jupiter on August 5, 2011. The focus of this paper is the description of the scientific objectives of the MWR investigation along with the experimental design, observational approach, and calibration that will achieve these objectives, based on the Juno mission plan up to Jupiter orbit insertion on July 4, 2016. With frequencies distributed approximately by octave from 600 MHz to 22 GHz, the MWR will sample the atmospheric thermal radiation from depths extending from the ammonia cloud region at around 1 bar to pressure levels as deep as 1000 bars. The primary scientific objectives of the MWR investigation are to determine the presently unknown dynamical properties of Jupiter’s subcloud atmosphere and to determine the global abundance of oxygen and nitrogen, present in the atmosphere as water and ammonia deep below their respective cloud decks. The MWR experiment is designed to measure both the thermal radiation from Jupiter and its emission-angle dependence at each frequency relative to the atmospheric local normal with high accuracy. The antennas at the four highest frequencies (21.9, 10.0, 5.2, and 2.6 GHz) have ∼12° beamwidths and will achieve a spatial resolution approaching 600 km near perijove. The antennas at the lowest frequencies (0.6 and 1.25 GHz) are constrained by physical size limitations and have 20° beamwidths, enabling a spatial resolution of as high as 1000 km to be obtained. The MWR will obtain Jupiter’s brightness temperature and its emission-angle dependence at each point along the subspacecraft track, over angles up to 60° from the normal over most latitudes, during at least six perijove passes after orbit insertion. The emission-angle dependence will be obtained for all frequencies to an accuracy of better than one part in
10
3
, sufficient to detect small variations in atmospheric temperature and absorber concentration profiles that distinguish dynamical and compositional properties of the deep Jovian atmosphere.
N 1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N 1-(6-chloroimidazo2,1-b1,3thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist ...(5-HT6 K i = 2 nM, EC50 = 6.5 nM, E max = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders.
Objectives
To test the novel nonimidazole histamine H
3
receptor antagonist 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1
H
-3-benzazapin-7-yl)oxy-
N
-methyl-2-pyrazinecarboxamide (GSK207040) in a series of ...behavioral and neurochemical paradigms designed to evaluate its antipsychotic potential.
Materials and methods
Acute orally administered GSK207040 was investigated for its capacity to reverse a 24-h-induced deficit in novel object recognition memory, deficits in prepulse inhibition (PPI) induced by isolation rearing, and hyperlocomotor activity induced by amphetamine. The acute neurochemical effects of GSK207040 were explored by analyzing rat anterior cingulate cortex microdialysates for levels of dopamine, noradrenaline, and acetylcholine and by c-
fos
immunohistochemistry. The potential for interaction with the antipsychotic dopamine D
2
receptor antagonist haloperidol was explored behaviorally (spontaneous locomotor activity and catalepsy), biochemically (plasma prolactin), and via ex vivo receptor occupancy determinations.
Results
GSK207040 significantly enhanced object recognition memory (3 mg/kg) and attenuated isolation rearing-induced deficits in PPI (1.0 and 3.2 mg/kg) but did not reverse amphetamine-induced increases in locomotor activity. There was no evidence of an interaction of GSK207040 with haloperidol. GSK207040 (3.2 mg/kg) raised extracellular concentrations of dopamine, noradrenaline, and acetylcholine in the anterior cingulate cortex and c-
fos
expression in the core of the nucleus accumbens was increased at doses of 3.2 and 10.0 mg/kg.
Conclusions
The behavioral and neurochemical profile of GSK207040 supports the potential of histamine H
3
receptor antagonism to treat the cognitive and sensory gating deficits of schizophrenia. However, the failure of GSK207040 to reverse amphetamine-induced locomotor hyperactivity suggests that the therapeutic utility of histamine H
3
receptor antagonism versus positive symptoms is less likely, at least following acute administration.
A liquid chromatography–tandem mass spectrometric method has been developed for measurement of
N-acetylaspartate,
N-acetylaspartylglutamate and glutamate. The analytes were separated within 5
min ...using an anion exchange/reverse phase column. The lower limit of quantification for Glu, NAA and NAAG was found to be 5, 50 and 6
nM, respectively, with a signal-to-noise ratio of 5:1. Using this methodology the basal levels of Glu, NAA and NAAG could be measured consistently in
in vitro superfusion samples from rat hippocampus. The assay was also used for measurement of the distribution of Glu, NAA and NAAG in different regions of the rat brain.
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