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111.
Rationale Binocular rivalry occurs when different images are simultaneously presented to each eye. During continual viewing of this
stimulus, the observer will experience repeated switches between visual awareness of the two images. Previous studies have
suggested that a slow rate of perceptual switching may be associated with clinical and drug-induced psychosis.
Objectives The objective of the study was to explore the proposed relationship between binocular rivalry switch rate and subjective changes
in psychological state associated with 5-HT2A receptor activation.
Materials and methods This study used psilocybin, the hallucinogen found naturally in Psilocybe mushrooms that had previously been found to induce psychosis-like symptoms via the 5-HT2A receptor. The effects of psilocybin (215 μg/kg) were considered alone and after pretreatment with the selective 5-HT2A antagonist ketanserin (50 mg) in ten healthy human subjects.
Results Psilocybin significantly reduced the rate of binocular rivalry switching and increased the proportion of transitional/mixed
percept experience. Pretreatment with ketanserin blocked the majority of psilocybin’s “positive” psychosis-like hallucinogenic
symptoms. However, ketanserin had no influence on either the psilocybin-induced slowing of binocular rivalry or the drug’s
“negative-type symptoms” associated with reduced arousal and vigilance.
Conclusions Together, these findings link changes in binocular rivalry switching rate to subjective levels of arousal and attention. In
addition, it suggests that psilocybin’s effect on binocular rivalry is unlikely to be mediated by the 5-HT2A receptor. 相似文献
112.
HR Arias H Xing K MacDougall MP Blanton F Soti WR Kem 《British journal of pharmacology》2009,157(2):320-330
Background and purpose
Benzylidene-anabaseines (BAs) are partial agonists of the α7 nicotinic acetylcholine receptor (nAChR) but their mechanism(s) of action are unknown. Our study explores several possibilities, including direct interactions of BAs with the nAChR channel.Experimental approach
Functional and radioligand-binding assays were used to examine the interaction of two BA analogues, 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA) and its primary metabolite 3-(4-hydroxy-2-methoxybenzylidene)-anabaseine (4OH-DMXBA) with both agonist and non-competitive antagonist (NCA)-binding sites on muscle-type nAChRs.Key results
Both BAs non-competitively inhibited ACh activation of human fetal muscle nAChRs and sterically inhibited the specific binding of the NCAs [piperidyl-3,4-3H(N)]-(N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([3H]TCP) and [3H]dizocilpine to Torpedo nAChRs in the desensitized state. These compounds modulated [3H]tetracaine, [14C]amobarbital and [3H]TCP binding to resting nAChRs by allosteric mechanisms. Both BAs enhanced [3H]TCP binding when the nAChR was initially in the resting but activatable state, suggesting that both compounds desensitized the Torpedo nAChR. Although DMXBA failed to activate human fetal muscle nAChRs, 4OH-DMXBA was found to be a partial agonist. [3H]Nicotine competition-binding experiments confirmed that 4OH-DMXBA has higher affinity than DMXBA for the agonist sites, and that DMXBA is also a competitive antagonist.Conclusions and implications
3-(4-hydroxy-2-methoxybenzylidene)-anabaseine is a partial agonist for human fetal muscle nAChRs, whereas DMXBA only has competitive and NCA activities. The NCA-binding site for BAs overlaps both the phencyclidine-and dizocilpine-binding sites in the desensitized Torpedo nAChR ion channel. The desensitizing property of BAs suggests another possible mode of non-competitive inhibition in addition to direct channel-blocking mechanisms. 相似文献113.
Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines 总被引:1,自引:1,他引:0
Winter JC 《Psychopharmacology》2009,203(2):251-263
Background Although man’s first encounters with hallucinogens predate written history, it was not until the rise of the sister disciplines
of organic chemistry and pharmacology in the nineteenth century that scientific studies became possible. Mescaline was the
first to be isolated and its chemical structure determined. Since then, additional drugs have been recovered from their natural
sources and synthetic chemists have contributed many more. Given their profound effects upon human behavior and the need for
verbal communication to access many of these effects, some see humans as ideal subjects for study of hallucinogens. However,
if we are to determine the mechanisms of action of these agents, establish hypotheses testable in human subjects, and explore
the mechanistic links between hallucinogens and such apparently disparate topics as idiopathic psychosis, transcendental states,
drug abuse, stress disorders, and cognitive dysfunction, studies in animals are essential. Stimulus control by hallucinogens
has provided an intuitively attractive approach to the study of these agents in nonverbal species.
Objective The intent of this review is to provide a brief account of events from the time of the first demonstration of hallucinogen-induced
stimulus control to the present. In general, the review is limited to lysergic acid diethylamide (LSD) and the hallucinogenic
derivatives of phenethylamine and tryptamine.
Results The pharmacological basis for stimulus control by LSD and hallucinogenic phenethylamines and tryptamines is serotonergic in
nature. The 5-HT2A receptor appears to be the primary site of action with significant modulation by other serotonergic sites including 5-HT2C and 5-HT1A receptors. Interactions with other neurotransmitters, especially glutamate and dopamine, are under active investigation.
Most studies to date have been conducted in the rat but transgenic mice offer interesting possibilities.
Conclusions Hallucinogen-induced stimulus control provides a unique behavioral tool for the prediction of subjective effects in man and
for the elucidation of the pharmacological mechanisms of the action of these agents. 相似文献
114.
Oxytocin: The great facilitator of life 总被引:1,自引:0,他引:1
Oxytocin (Oxt) is a nonapeptide hormone best known for its role in lactation and parturition. Since 1906 when its uterine-contracting properties were described until 50 years later when its sequence was elucidated, research has focused on its peripheral roles in reproduction. Only over the past several decades have researchers focused on what functions Oxt might have in the brain, the subject of this review. 相似文献
115.
Tura C. Camilli 《Biochemical pharmacology》2010,80(5):702-1551
Wnt signaling can be divided into three pathways, namely the canonical Wnt/β-catenin pathway, and the non-canonical (or heretical) Wnt/Ca2+ and planar cell polarity (PCP) pathways. Although the canonical Wnt/β-catenin pathway is the best described in cancer, increasing data points to the importance of the heretical Wnt pathways in several aspects of tumor progression. The recent advances in understanding the players and mechanisms by which these Wnt pathways contribute to cancer progression have led to the identification of numerous molecules that are already, or could be considered, targets for cancer therapy. 相似文献
116.
Phencyclidine is an N-methyl d-aspartate receptor (NMDAR) blocker that has been reported to induce neuronal apoptosis during development and schizophrenia-like behaviors in rats later in life. Brain-derived neurotrophic factor (BDNF) has been shown to prevent neuronal death caused by NMDAR blockade, but the precise mechanism is unknown. This study examined the role of the phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways in BDNF protection of PCP-induced apoptosis in corticostriatal organotypic cultures. It was observed that BDNF inhibited PCP-induced apoptosis in a concentration-dependent fashion. BDNF effectively prevented PCP-induced inhibition of the ERK and PI-3K/Akt pathways and suppressed GSK-3β activation. Blockade of either PI-3K/Akt or ERK activation abolished BDNF protection. Western blot analysis revealed that the PI-3K inhibitor LY294002 prevented the stimulating effect of BDNF on the PI-3K/Akt pathway, but had no effect on the ERK pathway. Similarly, the ERK inhibitor PD98059 prevented the stimulating effect of BDNF on the ERK pathway, but not the PI-3K/Akt pathway. Co-application of LY294002 and PD98059 had no additional effect on BDNF-evoked activation of Akt or ERK. However, concurrent exposure to PD98059 and LY294002 caused much greater inhibition of BDNF-evoked phosphorylation of GSK-3β at serine 9 than did LY294002 alone. Finally, either BDNF or GSK-3β inhibition prevented PCP-induced suppression of cyclic-AMP response element binding protein (CREB) phosphorylation. These data demonstrate that the protective effect of BDNF against PCP-induced apoptosis is mediated by parallel activation of the PI-3K/Akt and ERK pathways, most likely involves inhibition of GSK-3β and activation of CREB. 相似文献
117.
118.
119.
Joanna J. Rowell Atul K. Mallik Jennifer Dugas‐Ford Clifton W. Ragsdale 《The Journal of comparative neurology》2010,518(16):3272-3289
Molecular markers that distinguish specific layers of rodent neocortex are increasingly employed to study cortical development and the physiology of cortical circuits. The extent to which these markers represent general features of neocortical cell type identity across mammals, however, is unknown. To assess the conservation of layer markers more broadly, we isolated orthologs for 15 layer‐enriched genes in the ferret, a carnivore with a large, gyrencephalic brain, and analyzed their patterns of neocortical gene expression. Our major findings are: 1) Many but not all layer markers tested show similar patterns of layer‐specific gene expression between mouse and ferret cortex, supporting the view that layer‐specific cell type identity is conserved at a molecular level across mammalian superorders; 2) Our panel of deep layer markers (ER81/ETV1, SULF2, PCP4, FEZF2/ZNF312, CACNA1H, KCNN2/SK2, SYT6, FOXP2, CTGF) provides molecular evidence that the specific stratifications of layers 5 and 6 into 5a, 5b, 6a, and 6b are also conserved between rodents and carnivores; 3) Variations in layer‐specific gene expression are more pronounced across areas of ferret cortex than between homologous areas of mouse and ferret cortex; 4) This variation of area gene expression was clearest with the superficial layer markers studied (SERPINE2, MDGA1, CUX1, UNC5D, RORB/NR1F2, EAG2/KCNH5). Most dramatically, the layer 4 markers RORB and EAG2 disclosed a molecular sublamination to ferret visual cortex and demonstrated a molecular dissociation among the so‐called agranular areas of the neocortex. Our findings establish molecular markers as a powerful complement to cytoarchitecture for neocortical layer and cell‐type comparisons across mammals. J. Comp. Neurol. 518:3272–3289, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
120.
Glutamate plays an important role in the psychotomimetic effects of both channel blocking N-methyl D-aspartate (NMDA) receptor antagonists and hallucinogenic drugs which activate 5-hydroxytryptamine2A (5-HT2A) receptors. Previous work suggested that activation of non-NMDA ionotropic glutamate receptors mediates the effects of 5-HT-induced excitatory post-synaptic potentials/currents (EPSPs/EPSCs) when recording from layer V pyramidal cells in the rat medial pre-frontal cortex (mPFC). However, those effects are mediated by either alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate receptors of the iGluk5 subtype. To test whether activation of AMPA receptors is sufficient to mediate 5-HT-induced EPSCs, a 2,3-benzodiazepine that selectively blocks AMPA receptors was assessed. This selective AMPA receptor antagonist potently suppressed 5-HT-induced EPSCs. Since phenethylamine hallucinogens induce head shakes by activating 5-HT2A receptors in the mPFC and this action is modulated by glutamate, we also examined whether selective blockade of AMPA receptors would suppress DOI-induced head shakes. As predicted, we found that selective blockade of AMPA receptors suppressed DOI-induced head shakes. Given evidence that activation of AMPA receptors is an important downstream effect for both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens, we also tested multiple doses of DOI with a sub-anesthetic dose of MK-801. Synergistic action between these two classes of psychotomimetic drugs was demonstrated by MK-801 enhancing DOI-induced head shakes and locomotor activity. These findings expand the dependence of both channel blocking NMDA receptor antagonists and phenethylamine hallucinogens on enhancing extracellular glutamate. 相似文献