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Ketamine salts solubility

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Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5-HT2A) receptor activity via ERK1/2 signaling

Recent behavioral studies suggest that nonselective agonists of cannabinoid receptors may regulate serotonin 2A (5-HT2A) receptor neurotransmission. Two cannabinoids receptors are found in brain, CB1 and CB2 receptors, but the molecular mechanism by which cannabinoid receptors would regulate 5-HT2A receptor neurotransmission remains unknown. Interestingly, we have recently found that certain cannabinoid receptor agonists can specifically upregulate 5-HT2A receptors. Here, we present experimental evidence that rats treated with a nonselective cannabinoid receptor agonist (CP 55,940, 50 µg/kg, 7 days) showed increases in 5-HT2A receptor protein levels, 5-HT2A receptor mRNA levels, and 5-HT2A receptor-mediated phospholipase C beta (PLCβ) activity in prefrontal cortex (PFCx). Similar effects were found in neuronal cultured cells treated with CP 55,940 but these effects were prevented by selective CB2, but not selective CB1, receptor antagonists. CB2 receptors couple to the extracellular kinase (ERK) signaling pathway by Gαi/o class of G-proteins. Noteworthy, GP 1a (selective CB2 receptor agonist) produced a strong upregulation of 5-HT2A receptor mRNA and protein, an effect that was prevented by selective CB2 receptor antagonists and by an ERK1/2 inhibitor, PD 198306. In summary, our results identified a strong cannabinoid-induced upregulation of 5-HT2A receptor signaling in rat PFCx. Our cultured cell studies suggest that selective CB2 receptor agonists upregulate 5-HT2A receptor signaling by activation of the ERK1/2 signaling pathway. Activity of cortical 5-HT2A receptors has been associated with several physiological functions and neuropsychiatric disorders such as stress response, anxiety and depression, and schizophrenia. Therefore, these results may provide a molecular mechanism by which activation of cannabinoid receptors might be relevant to the pathophysiology of some cognitive and mood disorders in humans.
 
I thought I'd never see a social thread here.....Well, truth be told, I knew some cunt-strap would start one....Negrogesic shakes his head in accepting disapproval.....
 
its not like the thread is filling up very fast. in most places on bluelight threads get closed when they hit 1000 posts. if this thread continues to fill at its current average rate then the next ADD social thread won't start until this one is closed in 2023A.D.
 
A chemical analysis examining the pharmacology of novel psychoactive substances freely available over the internet and their impact on public (ill)health. Legal highs or illegal highs?

A total of 22 products were purchased from five different internet sites, 18 months after the UK ban on substituted cathinones, like mephedrone, was introduced in April 2010. Each substance was screened to determine its active ingredients using accepted analytical techniques.

Despite amendments to legislation, prohibited class B substances are still readily available in large quantities over the internet. The findings suggest that these prohibited substances are being manufactured or imported into the UK on a large scale, which has serious implications for public health and clinicians who are ill equipped to deal with this newly emerging problem.
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A case of 25I-NBOMe (25-I) intoxication: a new potent 5-HT2A agonist designer drug


Abuse of synthetic stimulant compounds resulting in significant toxicity is being increasingly reported by poison centers. Toxicologic assessment is complicated by inconsistent manufacturing processes and limited laboratory testing. We describe a case of self-reported exposure to 25-I (25I-NBOMe), a novel phenethylamine derivative, with subsequent quantification in serum. Case details. An 18-year-old male presented to the emergency department (ED) with severe agitation and hallucinations after jumping out of a moving car. He was tachycardiac (150–160 bpm) and hypertensive (150–170 mm Hg systolic and 110 mg Hg diastolic), and required physical restraints and treatment with intravenous lorazepam administration. His symptoms gradually improved and vital signs returned to normal over 48 h, though he continued to have episodes of aggressiveness.

An assay was developed by our analytical toxicology laboratory for 25-I, and serum obtained during ED evaluation and treatment was found to contain 0.76 ng/ml of 25-I. Case discussion. For 25I-NBOMe, 25-I is a common abbreviation for 25I-NBOMe, which is a (n-benzyl) phenethylamine in the 2C “family.”Initially synthesized for research, cases of self-reported use of 25-I have recently appeared in the literature, some of which contain qualitative urine confirmation. There are no commercially available quantitative assays, and no previous reports have published serum concentrations. 25-I is a potent new synthetic drug with apparent significant behavioral toxicity that can be detected and quantified in serum.
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MDMA produces a delayed and sustained increase in the extracellular concentration of glutamate in the rat hippocampus.

Abstract

The neurochemical effects of MDMA (3,4-methylenedioxymethamphetamine) on monoaminergic and cholinergic systems in the rat brain have been well documented. However, little is known regarding the effects of MDMA on glutamatergic systems in the brain. In the present study the effects of multiple injections of MDMA on extracellular concentrations of glutamate in the striatum, prefrontal cortex, and dorsal hippocampus were examined. Two or four, but not one, injections of MDMA (10 mg/kg, i.p. at 2 h intervals) resulted in a 2-3 fold increase in the extracellular concentration of glutamate in the hippocampus; no increase was evident in the striatum or prefrontal cortex. Reverse dialysis of MDMA (100 μM) into the hippocampus also elicited an increase in extracellular glutamate. Treatment with the 5-HT reuptake inhibitor fluoxetine prevented the increase in extracellular glutamate in the hippocampus following the systemic administration of MDMA, as did treatment with the serotonin 5-HT2A/C receptor antagonist ketanserin. Moreover, reverse dialysis of the sodium channel blocker tetrodotoxin did not prevent the increase in extracellular glutamate in the hippocampus. These data support the view that stimulation of 5-HT2A/2C receptors on non-neuronal cells by 5-HT released by MDMA promotes glutamate efflux in the hippocampus.
 
Cortexiphan said:
Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5-HT2A) receptor activity via ERK1/2 signaling

Recent behavioral studies suggest that nonselective agonists of cannabinoid receptors may regulate serotonin 2A (5-HT2A) receptor neurotransmission. Two cannabinoids receptors are found in brain, CB1 and CB2 receptors, but the molecular mechanism by which cannabinoid receptors would regulate 5-HT2A receptor neurotransmission remains unknown. Interestingly, we have recently found that certain cannabinoid receptor agonists can specifically upregulate 5-HT2A receptors. Here, we present experimental evidence that rats treated with a nonselective cannabinoid receptor agonist (CP 55,940, 50 µg/kg, 7 days) showed increases in 5-HT2A receptor protein levels, 5-HT2A receptor mRNA levels, and 5-HT2A receptor-mediated phospholipase C beta (PLCβ) activity in prefrontal cortex (PFCx). Similar effects were found in neuronal cultured cells treated with CP 55,940 but these effects were prevented by selective CB2, but not selective CB1, receptor antagonists. CB2 receptors couple to the extracellular kinase (ERK) signaling pathway by Gαi/o class of G-proteins. Noteworthy, GP 1a (selective CB2 receptor agonist) produced a strong upregulation of 5-HT2A receptor mRNA and protein, an effect that was prevented by selective CB2 receptor antagonists and by an ERK1/2 inhibitor, PD 198306. In summary, our results identified a strong cannabinoid-induced upregulation of 5-HT2A receptor signaling in rat PFCx. Our cultured cell studies suggest that selective CB2 receptor agonists upregulate 5-HT2A receptor signaling by activation of the ERK1/2 signaling pathway. Activity of cortical 5-HT2A receptors has been associated with several physiological functions and neuropsychiatric disorders such as stress response, anxiety and depression, and schizophrenia. Therefore, these results may provide a molecular mechanism by which activation of cannabinoid receptors might be relevant to the pathophysiology of some cognitive and mood disorders in humans.
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Can anybody upload it?
 
Not a "recent" article, but haven't see this posted...

Nature said:
On a small table in his office at the Scripps Research Institute in La Jolla, California, Ray Stevens spreads out a sheet of paper covered with colourful branched lines, each sprouting and thinning before terminating in an esoteric code. “This is the dream,” he declares.

The intricate diagram represents the largest family of receptor proteins encoded in the genome — the G-protein-coupled receptors (GPCRs), ubiquitous cell-surface molecules that are activated by light, odours, hormones and neurotransmitters. Stevens wants to determine the atomic structures of receptors on all branches of the tree. This week, that goal moved two receptors closer: Stevens's group has solved the atomic structure of the κ-opioid receptor (κ-OR)1, and a team led by Brian Kobilka at Stanford University in California has solved the medically crucial μ-opioid receptor (μ-OR)2. The structures, published in Nature, bring the tally of GPCR structures solved this year alone up to five.
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http://www.nature.com/news/opioid-receptors-revealed-1.10273

Apparently the MOR structure has been solved. It's confirmed that mu-opioid exists as a dimer and also that its binding pocket is rather promiscuous. The Nature guys think that may be the reason it can respond so quickly to activation/antagonism.
 
sekio said:
Not a "recent" article, but haven't see this posted...


http://www.nature.com/news/opioid-receptors-revealed-1.10273

Apparently the MOR structure has been solved. It's confirmed that mu-opioid exists as a dimer and also that its binding pocket is rather promiscuous. The Nature guys think that may be the reason it can respond so quickly to activation/antagonism.
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Solving of GPCR crystal structures is really picking up: Here's the 5-HT1B receptor

STRUCTURAL BASIS FOR MOLECULAR RECOGNITION AT SEROTONIN RECEPTORS

Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT1B G protein–coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine.
 
Not a journal article but interesting anyway

Derek Lowe - Chemical probes vs drugs
A drug is defined by its effects in a living creature (I'm tempted to add "Preferably, one that is willing to pay for it"). A chemical probe, on the other hand, is defined by its specificity. It's important not to confuse the two - you can get all excited about how specific your drug candidate is, how exquisitely it hits its target, but (as we have proven over and over in this business) that means nothing if hitting that target isn't clinically meaningful. Being impressed by the specificity of a chemical probe compound, on the other hand, is entirely appropriate - but no one should think that this makes it closer to being a drug.
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Makes me think about, say, the NBOMes versus LSD.
 
X-ray diffraction, ~2.7A resolution. You can dig out the Materials and Methods section for the nitty gritty (and how to replicate it yourself! :p)
 
2.7Å isn't bad at all. really nice that we're finally seeing so much progress with gpcr structures. i chose a different specialisation, so all these details would likely be wasted on me and i couldn't even think about replicating their results ;)
 
http://www.ncbi.nlm.nih.gov/pubmed/23333502

Treatment with a clinically-relevant dose of methylphenidate alters NMDA receptor composition and synaptic plasticity in the juvenile rat prefrontal cortex.
Abstract
Methylphenidate (Ritalin, MPH) is the most commonly prescribed psychoactive drug for children. Used to treat attention-deficit/hyperactivity disorder (ADHD) and for cognitive enhancement in healthy individuals, its cellular mechanisms of action and potential long-term effects are poorly understood. We recently reported that a clinically relevant (1mg/kg i.p., single injection) dose of MPH significantly decreased neuronal excitability in the juvenile rat prefrontal cortical neurons. Here we further explore the actions of acute treatment with MPH on the level of NMDA receptor subunits and NMDA receptor-mediated short- and long-term synaptic plasticity in the juvenile rat prefrontal cortical neurons. We found that a single dose of MPH treatment (1mg/kg, intraperitoneal) significantly decreased the surface and total protein levels of NMDA receptor subunits NR1 and NR2B, but not NR2A, in the juvenile prefrontal cortex. In addition, the amplitude, decay time and charge transfer of NMDA receptor-mediated EPSCs were significantly decreased whereas the amplitude and short-term depression of AMPA receptor-mediated EPSCs were significantly increased in the prefrontal neurons. Furthermore, MPH treatment also significantly increased the probability and magnitude of LTP induction, but had only a small effect on LTD induction in juvenile rat prefrontal cortical neurons. Our data thus present a novel mechanism of action of MPH, i.e., changes in glutamatergic receptor-mediated synaptic plasticity following early-life treatment. Furthermore, since a single dosage resulted in significant changes in NMDA receptors, off-label usage by healthy individuals, especially children and adolescents, may result in altered potential for plastic learning.
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^^I suspect the NMDA-mediated 'plastic learning' is less about learning things you are studying and more about learning that methylphenidate is rewarding and the experience needs to be repeated. I mean, sensitization (and tolerance) to psychostimulants is a plastic learning process mediated by NMDA receptors.

But maybe I'm just cynical.
 
I have never seen a study that old before... 1899 Damn. Have some internet points man. That was interesting.
 
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