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Amphetamine Neurotoxicity and Tolerance Reduction/Prevention II

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NAChR induced neurotoxicity
Nicotinic receptors are broadly classified into two subtypes based on their primary sites of expression: muscle-type nicotinic receptors and neuronal-type nicotinic receptors. The neuronal subtypes are various homomeric or heteromeric combinations of twelve different nicotinic receptor subunits: α2 through α10 and β2 through β4. Examples of the neuronal subtypes include: (α4)3(β2)2, (α4)2(β2)3, and (α7)5. The neuronal forms of the receptor can be found both post-synaptically (involved in classical neurotransmission) and pre-synaptically where they can influence the release of multiple neurotransmitters.

The activation of receptors by nicotine modifies the state of neurons through two main mechanisms. On one hand, the movement of cations causes a depolarization of the plasma membrane (which results in an excitatory postsynaptic potential in neurons), but also by the activation of voltage-gated ion channels. On the other hand, the entry of calcium acts, either directly or indirectly, on different intracellular cascades leading, for example, to the regulation of the activity of some genes or the release of neurotransmitters.

Memantine is a useful drug to prevent the spatial and non-spatial memory deficits induced by methamphetamine.
http://www.ncbi.nlm.nih.gov/pubmed/20553881
Methamphetamine (METH) is a street drug that is abused by young people. In previous studies, we demonstrated the effectiveness of alpha-7 nicotinic receptor antagonists in preventing the neurotoxicity induced by this amphetamine derivative. The present study seeks to determine whether pre-treatment with memantine (MEM) (an antagonist of both NMDA and alpha-7 nicotinic receptors) counteracts the memory impairment induced by METH administration in male Long Evans rats. Non-spatial memory was tested in the object recognition test and spatial learning memory was tested in the Morris water maze. In our experimental conditions, rats that received the MEM (5 mg/kg, intraperitoneally) pre-treatment recovered the ability to discriminate between a familiar and a novel object. This ability had been abolished by METH (10 mg/kg, subcutaneously) at 72 h and 1 week after treatment. Moreover, MEM pre-treatment also inhibited the thigmotaxis behaviour induced by METH. Rats treated with METH showed impaired learning in the Morris water maze. The results of the probe trial demonstrated that METH-treated rats did not remember the location of the platform, but this memory impairment was also prevented by MEM pre-treatment. Moreover, MEM by itself improved the learning of the task. Finally, MEM significantly improved the learning and memory impairment induced by METH. Therefore, MEM constitutes the first successful approach to prevent the cognitive deficits induced by amphetamine derivatives which are frequently abused in western countries.

alpha-7 nicotinic receptors
Some centrally acting compounds such as bupropion, mecamylamine, and 18-methoxycoronaridine block nicotinic acetylcholine receptors in the brain and have been proposed for treating drug addiction.

The sensitizing effect of acute nicotine on amphetamine-stimulated behavior and dopamine efflux requires activation of β2 subunit-containing nicotinic acetylcholine receptors and glutamate N-methyl-D-aspartate receptors.

http://www.ncbi.nlm.nih.gov/pubmed/20971124

Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity

http://www.mdpi.com/1424-8247/4/6/822
Amphetamine derivatives such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) are widely abused drugs in a recreational context. This has led to concern because of the evidence that they are neurotoxic in animal models and cognitive impairments have been described in heavy abusers. The main targets of these drugs are plasmalemmal and vesicular monoamine transporters, leading to reverse transport and increased monoamine efflux to the synapse. As far as neurotoxicity is concerned, increased reactive oxygen species (ROS) production seems to be one of the main causes. Recent research has demonstrated that blockade of a7 nicotinic acetylcholine receptors (nAChR) inhibits METH- and MDMA-induced ROS production in striatal synaptosomes which is dependent on calcium and on NO-synthase activation. Moreover, a7 nAChR antagonists (methyllycaconitine and memantine) attenuated in vivo the neurotoxicity induced by METH and MDMA, and memantine prevented the cognitive impairment induced by these drugs. Radioligand binding experiments demonstrated that both drugs have affinity to a7 and heteromeric nAChR, with MDMA showing lower Ki value.

Dextromethorphan
α3β4-, α4β2-, and α7-nACh receptor antagonist. It inhibits the antinociceptive (pain killing) action of nicotine in the tail-flick test in mice, where mouse tails are exposed to heat, which makes the mouse flick its tail if it feels pain.

Mecamylamine
α3β4 nicotinic receptors antagonist. Sometimes used as an anti-addictive drug to help people stop smoking tobacco.

Varenicline
Varenicline is a partial agonist of the α4β2 subtype of the nicotinic acetylcholine receptor. In addition it acts on α3β4 and weakly on α3β2 and α6-containing receptors. A full agonism was displayed on α7-receptors. Partially stimulates, the α4β2 receptor without producing a full effect like nicotine. Varenicline does not greatly increase the downstream release of dopamine. It also acts as an agonist at 5-HT3 receptors, which may contribute to mood altering effects of varenicline.

Possible varenicline-induced paranoia and irritability in a patient with major depressive disorder, borderline personality disorder, and methamphetamine abuse in remission. http://www.ncbi.nlm.nih.gov/pubmed/19011454
 
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Neuroglycopenia cause excessive glutamate release, causing neurotoxicity.


Not exactly the cliffs I was looking for. What exactly does NAC have to do with anything here in in regards to therapeutic co-usage with amphetamine?
 
Not exactly the cliffs I was looking for. What exactly does NAC have to do with anything here in in regards to therapeutic co-usage with amphetamine?

Hypoglycemia unawareness
I believe that recurrent hypoglycemic state from insulin-induced methamphetamine cause hypoglycemic unawareness which develop into neuroglycopenia. Often glucagon secretion is inhibited. Methamphetamine alters blood brain barrier permeability & GLUT1-GLUT3
NAC prevents the impairment of the Counter-Regulatory response following recurrent Hypoglycemia.
NAC revert methamphetamine inhibition of glucose uptake by human neurons and astrocytes.
NAC revert glucose transporter impairment & blood-brain barrier dysfunction caused by methamphetamine.

NAC appear to reduce hyperinsulinaemia and promote insulin sensitivity.

Glutamate - NMDA antagonist
I believe that neuroglycopenia inhibit GABA output, which trigger glutamate-induced neurotoxicity. NMDA receptor, a glutamate receptor, is the predominant pathway of control in synaptic plasticity and memory function. Glutamate system is the core of reward-seeking addictive behaviors and is the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis.
NAC is exerting benefits by being a precursor to the antioxidant, glutathione, modulating glutamatergic, neurotropic and inflammatory pathways.
NAC assists in the regulation of neuronal intra- and extracellular exchange of glutamate through the cystine–glutamate antiporter.
NAC is a decreasing activity of central glutamatergic synapses, especially those involved in the reward system.
NAC influence Acquisition, Extinction and Reinstatement behavior.
NAC has therapeutic value in treating obsessive-compulsive disorder.
NAC reduce anxiety involved with dysfunctional GABA activity.


Dopamine modulation
NAC has been shown to protect against reductions in DA transporter levels following repeated methamphetamine administration

Misc
NAC inhibit hyperlocomotion, it is in my opinion ataxia induced by hypoglycemia and may be related to tolerence.
NAC reduce sensitization, important effect since it has been implied as a core mechanism in substance abuse and dependence.
NAC reduce amphetamine-related withdrawal symptoms and craving.
NAC reduce amphetamine seeking behavior.
 
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MAOB in the regulation of GABA
Tobacco smoke contains the monoamine oxidase inhibitors anatabine, harman and norharman. These beta-carboline compounds significantly decrease MAO activity in smokers. MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin. It is thought that the powerful interaction between the MAOI's and the nicotine is responsible for most of the addictive properties of tobacco smoking.

GAD67: the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis
http://www.ncbi.nlm.nih.gov/pubmed/12811640
Decreases in the 67 kDa isoenzyme of brain glutamic acid decarboxylase (GAD67) expression have been consistently found in patients with bipolar disorder and schizophrenia. In animals GAD67 expression is diminished by chronic, but not acute stimulation of dopamine D2 receptors and by short-term blockade of NMDA receptors. In contrast, chronic treatment with D2 receptor antagonists enhances GAD67 expression. Thus, antipsychotic treatment cannot explain the reduction in GAD67 levels in patients with psychotic disorders. Rather, pathophysiological findings such as reduced viability of cortical glutamatergic neurones (in schizophrenia) or enhanced dopamine sensitivity (in bipolar disorder) might explain the observed reduction in GAD67. Since reduction in GAD67 expression leads to reduced levels of GABA, the GABAergic inhibitory control over glutamatergic cells is reduced. Psychosis could result from AMPA receptor activation caused by overactivity of the glutamatergic system. GAD67 levels would thus be a surrogate marker for psychosis liability. Pharmacological principles that raise GAD67 expression levels could represent novel targets for antipsychotic therapy.

Amphetamine exposure down-regulated the levels of GAD.
Glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to GABA and CO2.
Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) stimulated GAD activity.

MAO-B is an enzyme that metabolises the dopamine neurotransmitter.
Monoamine Oxidase B inhibitors are used in the treatment of Parkinson's Disease. Nicotine, in tobacco addiction, has been shown to have weak addictive properties when administered alone, addictive potential increases after co-administration of an MAOI.


Monoamine Oxidase inhibitors
Harmala alkaloids, Resveratrol, Curcumin, Rhodiola rosea, Ruta graveolens, Ginkgo biloba, Anthocyanins, Proanthocyanidin, Catechin, Desmethoxyyangonin, Epicatechin, Emodin, Hydroxytyrosol, Piperine, Gentiana lutea, Liquorice, Myristicin, Siberian Ginseng, Yerba Mate, Yohimbe

Down-Regulated GABAergic Expression in the Olfactory Bulb Layers of the Mouse Deficient in Monoamine Oxidase B and Administered With Amphetamine
http://rd.springer.com/article/10.1007/s10571-009-9475-2
This study explores primarily the role of the activity of monoamine oxidase B (MAOB) in the regulation of glutamic acid decarboxylase67 (GAD67) expression in distinct layers of main olfactory bulb (OlfB), which links the limbic system. Moreover, the response of GAD67 was investigated to amphetamine perturbation in the absence of MAOB activity. Immunocytochemical analysis was performed on OlfB sections prepared from the adult wild type (WT) and the MAOB gene-knocked-out (KO) mice after receiving repeated intraperitoneal injections (two doses per day, total seven doses) of saline or amphetamine, 5 mg/kg. The levels of the GAD67 immunoreactivity were approximate 25 and 38% lower in respective glomerular (GloL) and mitral cell layers (ML) of saline-treated KO mice than that of WT, whereas similar in the external plexiform or granule cell layers (GraL) of the KO and WT. In the GloL, the level of tyrosine hydroxylase was 39% lower in the KO mice than WT, implicating different dopamine content in the KO from WT. The amphetamine exposure down-regulated the levels of GAD67 in the WT layers by 46 to 52%, and in KO layers 65 to 71%, except ML. The GraL GAD67 level may be regulated by the activation of CREB, as the phosphorylated (p) CREB coexisted with GAD67, and the percentage of GAD67-expressing pCREB neurons was decreased by the amphetamine exposure. The data indicate that the activity of MAOB could modulate the regular and amphetamine-perturbed expression of GAD67 and pCREB. Thus, interactions are suggested among the MAOB activity, GABA content of OlfB, and olfaction.

CREB is a cellular transcription factor.
It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the downstream genes. It play an important role in neuronal plasticity and long-term memory formation. It is a core mediator in late stage of long-term potentiation, a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. A major contributor in synaptic plasticity, causing synapse to change their strength a contributor in formation of memories. It has an important role in the development of drug addiction, emotional memory operate on fear conditioning, an amygdala-dependent behavior.
 
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Menthol: κ-Opioid agonism is neuroprotective against hypoxia/ischemia. What do you guys think?
 
Doubtful, menthol is a poor K-opi agonist as evidenced from almost total lack of psychoactivity.

The monoterpenoids in general seem to be incredibly poor g-protein ligands.
 
I came across a study on GLUT3 and Ascorbic Acid and was wondering what you guys think.

I know that the decrease in neuronal glucose uptake by METH was associated with reduction of glucose transporter protein-3 (GLUT3) which is the basis of my theory on acute psychosis.
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019258

Anybody can explain to me the impact of ascorbic acid on GLUT3?

Ascorbic acid-dependent GLUT3 inhibition is a critical step for switching neuronal metabolism.
http://www.ncbi.nlm.nih.gov/pubmed/21321936
Intracellular ascorbic acid is able to modulate neuronal glucose utilization between resting and activity periods. We have previously demonstrated that intracellular ascorbic acid inhibits deoxyglucose transport in primary cultures of cortical and hippocampal neurons and in HEK293 cells. The same effect was not seen in astrocytes. Since this observation was valid only for cells expressing glucose transporter 3 (GLUT3), we evaluated the importance of this transporter on the inhibitory effect of ascorbic acid on glucose transport. Intracellular ascorbic acid was able to inhibit (3)H-deoxyglucose transport only in astrocytes expressing GLUT3-EGFP. In C6 glioma cells and primary cultures of cortical neurons, which natively express GLUT3, the same inhibitory effect on (3)H-deoxyglucose transport and fluorescent hexose 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) was observed. Finally, knocking down the native expression of GLUT3 in primary cultured neurons and C6 cells using shRNA was sufficient to abolish the ascorbic acid-dependent inhibitory effect on uptake of glucose analogs. Uptake assays using real-time confocal microscopy demonstrated that ascorbic acid effect abrogation on 2-NBDG uptake in cultured neurons. Therefore, ascorbic acid would seem to function as a metabolic switch inhibiting glucose transport in neurons under glutamatergic synaptic activity through direct or indirect inhibition of GLUT3.
 
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Glucagon secretion that is often inhibited in long-term methamphetamine user and came across this plant has the potential to restore production. It also has neuroprotective effects. Eucommia is a non-selective beta-blocker, it would modulate excessive adrenalin.

Neuroprotective effects of Eucommia ulmoides Oliv. Bark on amyloid beta(25-35)-induced learning and memory impairments in mice.
http://www.ncbi.nlm.nih.gov/pubmed/20974223
Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
In the present study, we examined whether aqueous extract of Eucommia ulmoides Oliv. Bark (EUE) with graded doses exerted its neuroprotective effects on amyloid beta(25-35) (Aβ(25-35))-induced learning and memory impairments in mice. Mice received a single intracerebroventricular (i.c.v.) injection of Aβ(25-35) 6 nmol as the critical factor in Alzheimer's disease (AD), cognition was evaluated using Y-maze, passive avoidance, and Morris water maze tests. EUE significantly improved the Aβ(25-35)-induced memory deficit in the Y-maze test. Also, EUE increased step-through latency time with Aβ(25-35)-induced learning and memory deficits in the passive avoidance test. In addition, EUE decreased the escape latencies with Aβ(25-35)-induced cognitive impairments in the Morris water maze test. In the probe trial session, EUE increased time spent in the target quadrant. In the in vitro study, EUE was found to inhibit acetylcholinesterase (AChE) activity in a dose-dependent manner (IC50 value; 172 μg/ml). Ex vivo study, EUE significantly inhibited AChE activity in the hippocampus and frontal cortex. These results demonstrate that EUE possesses potent neuroprotective effects and that its beneficial effects are mediated, in part, by AChE inhibition, and therefore, might be a potential candidate in neurodegenerative diseases such as AD.
 
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Just curious -what form are you guys using for your Magnesium? And, what dose are you taking?

I have always used 450 mg of citrate BID...but don't know if I want to place another order.
 
Just curious -what form are you guys using for your Magnesium? And, what dose are you taking?

I have always used 450 mg of citrate BID...but don't know if I want to place another order.

300mg citrate myself, personally anything but oxide is ok in my opinion. I just get the cheapest stuff I can find.
 
I would go nothing that is not chelated. Magnesium glycinate, taurate, fumarate, orotate are the one you should be looking for. purebulk.com is a cheap source.
 
I use chelated, "Doctors Best". I must be deficient, or getting used to it. Even after one pill at night, I have trouble waking in the morning.

On the topic: What are thoughts on Aricept/Donepezil or Galantamine as an adjunct?
 
There is no reason that magnesium supplementation would cause extended drowsiness.

ebola
 
There is no reason that magnesium supplementation would cause extended drowsiness.

ebola

Actually. It would cause in the presence of neuroglycopenia/hypoglycemia.

[Effects of magnesium intake on expression of insulin receptor in type 2 diabetes rats].


OBJECTIVE:
To investigate the effects of magnesium intake on expression of insulin receptor in type 2 diabetes rats.

METHODS:
The models of type 2 diabetes rats were established by feeding with high-fat-diet and injecting streptozotocin (STZ). Rats were randomly assigned to four groups. The high-fat-diets were administrated magnesium at a dose of 2000 (high magnesium group), 1000 (medium magnesium group) and 200 (low magnesium group). Model control group was only fed with high-fat-diet. Normal control group was fed with common diet. Rats ate freely for four weeks. Fasting blood glucose was detected by glucose oxidase method.. Insulin was detected by radio-immunity method. The expression levels of IR of pancreas and skeletal muscle were detected by immunohistochemistry method.

RESULTS:
The immunohistochemistry pictures were analyzed by Image-Pro Plus. Compared with model control group, the expression levels of IR of pancreas and skeletal muscle were 0.341 +/- 0.001 and 0.346 +/- 0.002, increased and fasting blood glucose decreased significantly in high magnesium group (P < 0.05 ).

CONCLUSION:
Magnesium intake may increase the expression levels of IR of pancreas and skeletal muscle, and decrease fasting blood glucose in type 2 diabetes rats.

It is doing so by acutely reducing blood glucose in a dose-dependent manner. Magnesium can cause hypoglycemia/Neuroglycopenia.
 
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I f*cking love you.
Wonder what the implications for this is for the extremely common magnesium and amphetamine coadministration?
Perhaps a case to coadministrater with a source of complex carbs or easily converted lipids?

I know CoQ10 has some interesting effects on sugar metabolism I'll have to dig up when I get home
 
I f*cking love you.
Wonder what the implications for this is for the extremely common magnesium and amphetamine coadministration?
Perhaps a case to coadministrater with a source of complex carbs or easily converted lipids?

I know CoQ10 has some interesting effects on sugar metabolism I'll have to dig up when I get home

Be very careful as a very strong reactive hypoglycemia may arise from a insuline spike caused by refined sugar or most free form amino acid. You have to make sure that the muscles are not glycogen depleted before you ingest any dose of NAC or Magnesium.
 
Edit: On a side note, you have to munch a lot of antacids to take ALA with amphetamine (acidity inhibits absorption and such). Stuff's pretty damn hard on the stomach.

I've wondered if plugging ALA would be an effective ROA?
 
I've wondered if plugging ALA would be an effective ROA?

I have made subq injection of Bio-enhanced Na RALA.
Sorry no sourcing
Soluble in water: 1 g dissolves in 50 ml water at room temperature.
Significantly more bio-available than R-lipoic acid (RLA).
 
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I have made subq injection of Bio-enhanced Na RALA.
...
Soluble in water: 1 g dissolves in 50 ml water at room temperature.
Significantly more bio-available than R-lipoic acid (RLA).

very interesting! I am primarily interested in neuroprotection from MDMA. How much of this would you recommend taking and at what point in the roll (pre-, during, post)? And anything else you recommend?

(We take 150mg MDMA with no re-dosing with 90day breaks between rolls, so we're pretty responsible users; not sure how much damage we are doing but always interested in harm reduction!)



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