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Mini World: Block Art Activation Code [hack]
The command creates a folder called hello that contains a number of code files and one subfolder. Of these, you frequently work with views.py (that contains the functions that define pages in your web app) and models.py (that contains classes defining your data objects). The migrations folder is used by Django's administrative utility to manage database versions as discussed later in this tutorial. There are also the files apps.py (app configuration), admin.py (for creating an administrative interface), and tests.py (for creating tests), which are not covered here.
In code, too, you work exclusively with your model classes to store and retrieve data; Django handles the underlying details. The one exception is that you can write data into your database using the Django administrative utility loaddata command. This utility is often used to initialize a data set after the migrate command has initialized the schema.
As shown in the previous section, page templates can contain procedural directives like % for message in message_list % and % if message_list %, rather than only passive, declarative elements like % url % and % block %. As a result, you can have programming errors inside templates as with any other procedural code.
In the mouse head-twitch assay, 25I-NBOMe and a related analog were extremely potent in inducing this behavior, which was blocked by preadministration of the selective 5-HT2A antagonist M100907 [(R)-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol] (Halberstadt and Geyer, 2014). As discussed in the section on mouse models later in this review, the mouse head twitch has shown a high correlation with human psychedelic activity.
Kometer et al. (2013) assessed the effects of psilocybin (215 μg/kg) on both α oscillations that regulate cortical excitability and early visual evoked P1 and N170 potentials in 16 healthy human subjects. They employed a double-blind, placebo-controlled, within-subject, randomized design. Psilocybin generally significantly increased 5D-ASC scores after placebo pretreatment, but not after ketanserin pretreatment. Psilocybin strongly decreased both prestimulus parieto-occipatal α power and decreased N170 potentials associated with the appearance of visual perceptual alterations, including visual hallucinations. Preadministration of the 5-HT2A antagonist ketanserin (50 mg) blocked all of these effects. The authors conclude that 5-HT2A receptor activation by psilocybin profoundly modulates the neurophysiological and phenomenological indices of visual processing. They further propose that 5-HT2A receptor activation may induce a processing mode in which stimulus-driven cortical excitation is overwhelmed by spontaneous neuronal excitation through modulation of α oscillations.
Halberstadt et al. (2011a) examined the effects of several psychedelics on the mouse head twitch response (HTR) in wild-type (WT) male C57BL/6J or 5-HT2A knockout (KO) mice. They also assessed investigatory and locomotor activity in the mouse behavioral pattern monitor (BPM). Psilocin and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) produced the HTR in WT mice but not in KO mice. Psilocin and 5-MeO-DMT reduced locomotor activity, investigatory behavior, and center duration in the BPM, and these effects were blocked by the selective 5-HT1A antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridyl)cyclohexanecarboxamide), indicating that psilocin and 5-MeO-DMT act as mixed 5-HT1A/5-HT2A agonists. Halberstadt and Geyer (2011) reviewed the extensive literature covering various indoleamines as well as LSD and concluded that although the phenethylamines primarily exert their effects through activation of 5-HT2A receptors, indoleamines can have a significant behavioral component mediated by activation of 5-HT1A receptors.
Cussac et al. (2008) reported differential agonist action for a series of serotonergic ligands, including LSD and DOI, and using CHO cells stably expressing the human 5-HT2A receptor. [They also used cells transfected with the human 5-HT2B and 5-HT2C (VSV isoform) receptors, obtaining generally similar results, but the discussion here will focus on their work with the 5-HT2A receptor.] They measured specific activation of Gq/11 proteins using a scintillation proximity assay and used a fluorescent imaging plate reader assay to measure intracellular Ca2+ responses. Serotonin and 5-carboxytryptamine gave a 20- to 50-fold greater potency for Ca2+ release than measured for Gq/11 activation, whereas DOI showed only a modest 2-to 3-fold preference for Ca2+ release. As anticipated, M100907 potently blocked serotonin-stimulated Gq/11 proteins. LSD showed a 20-fold higher potency to stimulate Gq/11 than to induce Ca2+ release. The most striking separation between activities was for the nonhallucinogenic 5-HT2A agonist lisuride, which was as potent as DOI in stimulating Gq/11, more than 1000-fold more potent than at Ca2+ release, and was a partial agonist for the two pathways. Interestingly, Ca2+ mobilization is classically considered to be a downstream consequence of Gq/11 activation and subsequent PLC stimulation. Yet the results presented here suggest that Gq/11 signaling may not be the only determinant of Ca2+ signaling. The main result of this study, however, was the ability of different agonists to differentially activate two signaling pathways in the same cell type.
Extending this work further, Nichols and Sanders-Bush (2004) performed a second microarray screen using a different Affymetrix gene chip version, identifying and validating three additional transcripts increased by 1.0 mg/kg LSD in the rat PFC: MAP kinase phosphatase 1 (mkp1), core/enhancer binding protein β (C/EBP-β), and the novel gene, induced by lysergic acid diethylamide 1 (ilad1; subsequently renamed arrestin domain containing 2 or arrdc2). As with the other LSD-induced differentially expressed genes, these also followed a dose- and time-dependent expression pattern. At the highest 1.0-mg/kg dose of LSD, expression of mkp1, C/EBP-β, and ilad1 was only partially blocked by MDL100907, indicating that activation of multiple receptors probably contributes to the effects of LSD on gene expression at this dose. Indeed, LSD is a relatively nonselective serotonin and dopamine receptor ligand, with high to moderate affinity for a number of receptors that may contribute to its effects (Nichols, 2004).
In vivo microdialysis after systemic administration of DOI revealed significantly increased extracellular glutamate in the rat somatosensory cortex (Scruggs et al., 2003). Intracortical reverse dialysis of DOI also increased extracellular glutamate. The increase in glutamate after intracortical DOI was blocked by the selective 5-HT2A antagonist M100907. Similarly, using microdialysis, extracellular glutamate also was significantly increased in the rat PFC 30 minutes after 0.1 mg/kg intraperitoneal LSD administration and continued for 30 minutes. This glutamate release was blocked by preadministration of 0.05 mg/kg M100907 15 minutes prior to LSD administration (Muschamp et al., 2004). Reverse dialysis of LSD for 30 minutes into the rat PFC, followed by perfusion of drug-free solution for 45 minutes, led to a significant increase of glutamate that remained elevated for at least 45 minutes after the LSD perfusion ended. DOM (0.6 mg/kg, i.p.) similarly increased extracellular glutamate measured in the rat PFC (Muschamp et al., 2004).
In a subsequent study, Celada et al. (2008) reported that systemic administration of DOI markedly reduced the amplitude of low frequency oscillations in the mPFC, an effect that was completely blocked by preadministration of the selective 5-HT2A antagonist M100907. They also compared responses to DOI in control rats with rats that had been given electrolytic lesions of several thalamic nuclei that project to the mPFC. DOI was found to be equally effective in both control rats and in rats with thalamic lesions, again refuting the earlier hypothesis of the role of putative thalamocortical 5-HT2A receptors as mediators of hallucinogen action.
A second explanation for the increase in cortical glutamate after hallucinogens was offered by Lambe and Aghajanian (2001), who suggested that 5-HT2A receptor activation on postsynaptic cells might lead to release of a retrograde messenger. This substance would then diffuse out from the postsynaptic membrane and block K+ channels on presynaptic glutamate terminals, leading to glutamate release. Neither of these hypotheses survived further scientific scrutiny, however, because the ultimate source of glutamate was later identified by Béïque et al. (2007), as discussed later.
In particular, data indicate that group II mGluR agonists can counteract the effects of psychedelic 5-HT2A agonists. For example, DOI-induced rat head shakes mediated by 5-HT2A receptor activation were enhanced by pretreatment with either competitive or noncompetitive NMDA antagonists (Dall'Olio et al., 1999). Preadministration of the mGlu2/3 receptor agonist "type":"entrez-nucleotide","attrs":"text":"LY354740","term_id":"1257481336","term_text":"LY354740"LY354740 attenuated the frequency of DOI-induced head shakes in rats, whereas administration of the selective mGlu2/3 antagonist "type":"entrez-nucleotide","attrs":"text":"LY341495","term_id":"1257705759","term_text":"LY341495"LY341495 potentiated DOI-induced head shakes in rats (Gewirtz and Marek, 2000). As noted above, DOI-induced head twitches in mice were inhibited in a dose-dependent manner by the selective mGlu2/3 agonists "type":"entrez-nucleotide","attrs":"text":"LY354740","term_id":"1257481336","term_text":"LY354740"LY354740 and "type":"entrez-nucleotide","attrs":"text":"LY379268","term_id":"1257807854","term_text":"LY379268"LY379268 (Kłodzinska et al., 2002). This action is presumably due to a presynaptic effect on glutamate neurons, in which mGlu2/3 agonists suppress glutamate release and antagonists block the presynaptic autoreceptor agonist effect of endogenously released glutamate (Conn and Pin, 1997). 2ff7e9595c
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