155 replies to this topic

[Doc Psychoillogical]

[topic='http://www.longecity...lants/?p=745416']My goal is to compile as much information as possible, so I may make it easier on me as well as others to find any and all data and information regarding this topic.
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[gamesguru]

Some of the neurotoxicity is from sleep deprivation I heard.

 

Does anyone have an opinion of the effect of NGF and BDNF enhancers - such as bacopa and lion's mane - on amphetamine tolerance? Hypothetically, increased activity in the learning centers of the brain would also serve to increase tolerance faster. What about using NGF/BDNF enhancers during "break" periods, when one isn't using amphetamines?

Bump...

 

Evidence that sleep deprivation downregulates dopamine D2R in ventral striatum in the human brain.
Dopamine D2 receptors are involved with wakefulness, but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [(11)C]raclopride in controls) in striatum, but could not determine whether this reflected dopamine increases ([(11)C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (a drug that increases dopamine by blocking dopamine transporters) during sleep deprivation versus rested sleep, with the assumption that methylphenidate's effects would be greater if, indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [(11)C]raclopride after rested sleep and after 1 night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared with rested sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans.

Dopamine in neurotoxicity and neuroprotection: what do D2 receptors have to do with it?
Accurate control of dopamine levels and/or the resulting dopamine-receptor interaction is essential for brain function. Indeed, several human neurological and psychiatric disorders are characterized by dysfunctions of the dopaminergic system. Dopamine has been reported to exert either protective or toxic effects on neurons, yet it is unclear whether these effects are receptor-dependent and, if so, which dopamine receptor could be involved. The D(2) dopamine receptor occupies a privileged position because its signalling might be neuroprotective in human diseases, such as Parkinson's disease, ischaemia and epilepsy. Unravelling the role of D(2) receptors in neuronal death and survival might be central to understanding the mechanisms that underlie several neuropathologies.

Neuroprotective effects of the dopamine D2/D3 agonist pramipexole against postischemic or methamphetamine-induced degeneration of nigrostriatal neurons.

Brain-derived neurotrophic factor in schizophrenia and its relation with dopamine.
The brain-derived neurotrophic factor (BDNF) belongs to the neurotrophins family and has a role in proliferation, differentiation of neurons but also as a neurotransmitter. This neurotrophin has received much attention during the last year in regard of the pathophysiology of schizophrenia. Results of genetic studies conducted in schizophrenia support a role for BDNF in schizophrenia and in brain function associated with the disorder. The changes of BDNF observed in the brain and in the plasma of patients with schizophrenia have generated results that can be interpreted either as a hallmark of the disease or a consequence of antipsychotic drugs. Antipsychotic drugs act by blocking the dopamine transmission at the dopamine D2-like receptors. BDNF controls the expression of one of these D2-like receptors, the dopamine D3 receptor. This raises the hypothesis of a link between cortical area, via BDNF, and the dopamine neurotransmission pathway in schizophrenia and its treatment.

The activation of dopamine D4 receptors inhibits oxidative stress-induced nerve cell death.
D4 dopamine receptor-specific antagonist improves reversal learning impairment in amphetamine-treated male rats.
The role of dopamine D4 receptor in the induction of behavioral sensitization to amphetamine and accompanying biochemical and molecular adaptations.
Dopamine D4 receptor-deficient mice, congenic on the C57BL/6J background, are hypersensitive to amphetamine.
Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors

"Haloperidol and clozapine were shown to down-regulate D1 and D4 dopamine receptor "

Dopamine neuron stimulating actions of a GDNF propeptide.
GDNF Selectively Protects Dopamine Neurons over Serotonin Neurons Against the Neurotoxic Effects of Methamphetamine
GDNF enhances the synaptic efficacy of dopaminergic neurons in culture.

Dopamine regulates brain-derived neurotrophic factor (BDNF) expression in cultured embryonic mouse striatal cells.
The differentiation of striatal GABAergic neurons coincides with the perinatal establishment of nigrostriatal dopaminergic synaptic connections. We have shown previously that dopamine stimulates the maturation of striatal GABAergic neurons. Since BDNF also regulates the development of GABAergic cells, we hypothesized that dopamine might affect striatal BDNF expression. The influence of dopamine on BDNF protein/mRNA and trkB mRNA levels was studied in neuronal and astroglia cultures of the mouse striatum. Stimulation with dopamine and a dopamine D1 receptor agonist increased BDNF mRNA and protein but not trkB mRNA in neuronal cultures. Our data indicate a potential role for dopamine in the developmental regulation of striatal BDNF expression and suggest that dopamine effects on GABAergic cells may be intertwined with BDNF action.

BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization.
Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.

Edited by gamesguru, 25 September 2015 - 02:12 AM.

[Area-1255]

These are the main concerns / guidelines with amphetamine.

 

• Adrenal Fatigue with long-term use; leading to burnout, lethargy and diminished energy / respiration in the future.
• Serotonin also increases leading to uncomfortable side-effects such as irregular heart beat, sweating, feeling hot etc and nausea/vomiting.
• Due to in part, the serotonin increasing effects coupled with the adenylyl cyclase increasing effects of amphetamine - which then increases thyroid hormones - the 'hot' feeling is even more so.
• Thus , amphetamine shouldn't be administered without a 5-HT3 and preferably also, a 5-HT7 antagonist...adding Lysine ; a 5-HT4 antagonist would also help.
• The other issue is amphetamine distorts the adrenergic system - it tricks your body into thinking it has more adrenaline than it does , meanwhile it stimulates alpha-2-receptors so your brain and body is telling itself to DECREASE noradrenaline (by autoreceptors) yet it is INCREASING noradrenaline uptake by other means as in TAAR1 activation.
• Don't use Yohimbine with amphetamine under any circumstances; unless you want your heart to explode.
• NEVER NEVER COMBINE FORSKOLIN WITH AMPHETAMINE - you will end up accumulating too much cAMP and the hot feelings will get worse due to thyroid hormone excess.
• Do not use any MAO inhibitors with amphetamine, EVER!
• ALWAYS KEEP AN ALPHA-1-ADRENERGIC BLOCKING AGENT ON HAND WHEN USING AMPHETAMINE; IN CASE BLOOD PRESSURE GOES TOO HIGH...AND KEEP SEROTONIN antagonists like Cyproheptadine on hand for other effects if needed...including psychosis. 
• Basically there are tons of benefits in the short-run with amphetamine but most people are too dumb to know how to augment it 'properly'.
• Take care of your adrenals while on it and keep cortisol under control.
• Same goes with Ecstasy; you can augment the pharmacological actions and reduce side-effects / chance of overdose symptoms by 'selectively' antagonizing certain receptors.
• Imagine if everyone always did this 'tactical approach' to augmentation - we would all be immune to drug toxicity / overdoses and needless spiking - practically inhuman. 
• I sure love the transhumanist / Imminist movement.
• In 2-3 years we will have super humans walking throughout major cities; but in all reality..they are around now.

I know these last few points weren't related to amphetamine but oh well , lmao!

 

 

Eur J Pharmacol. 2007 Sep 10;570(1-3):72-6. Epub 2007 Jun 5.

Effects of the serotonin 5-HT(7) receptor antagonist SB-269970 on the inhibition of dopamine neuronal firing induced by amphetamine.

Mnie-Filali O1, Dahan L, Zimmer L, Haddjeri N.

Author information

 

Abstract

Using extracellular unitary recordings in anaesthetized rats, this study examined the implication of the serotonin 7 (5-HT(7)) receptors in the inhibitory effect of amphetamine on ventral tegmental area and substantia nigra pars compacta dopamine neuronal activity. The acute administration of the selective 5-HT(7) receptor antagonist, SB-269970 (0.1, 0.5 and 1 mg/kg, i.p.), did not alter the firing activity of dopamine neurons. Interestingly, this antagonist prevented significantly the inhibition of dopamine neuronal firing activity induced by amphetamine (1 mg/kg, i.v.) in the ventral tegmental area, but not in the substantia nigra pars compacta. The present results suggest that 5-HT(7) receptors modulate the dopamine firing activity in the ventral tegmental area, thus affecting preferentially the mesocorticolimbic pathway.

PMID:   17586491   [PubMed - indexed for MEDLINE]

 

 

Involvement of presynaptic alpha 2-adrenoreceptors in the depressor response produced by repeated administration of dextro-methamphetamine.

Journal of Autonomic Pharmacology 07/1983; 3(2):79-88.

Source: PubMed

ABSTRACT The mechanism for the depressor response produced by the repeated administration of dextro-methamphetamine was studied in rats and rabbits. In the urethane anaesthetized and atropinized rat, the methamphetamine-induced depressor response was markedly inhibited by alpha-adrenoreceptor antagonists or by chronic reserpinization in combination with alpha-methyl-p-tyrosine, while it was not affected by propranolol. Yohimbine reversed the methamphetamine-induced depressor response to a pressor one when it was administered during the course of the depressor phase whilst prazosin or phentolamine caused only a further depressor response. In the pithed rat with electrical stimulation of the spinal cord, the first administration of methamphetamine elicited a marked pressor response whereas, following treatment with cocaine, the first administration of methamphetamine produced only a depressor response which was abolished by yohimbine. In the rabbit isolated aorta prelabeled with 3H-noradrenaline, methamphetamine enhanced the stimulation-evoked 3H-overflow and caused an enhanced contraction. However, in the presence of cocaine, methamphetamine reduced both stimulation-evoked 3H-overflow and neurogenic contractions. These findings suggest that the methamphetamine-induced depressor response results from the inhibition of catecholamine release from noradrenergic nerve terminals probably mediated by the activation of peripheral presynaptic alpha 2-adrenoreceptors.

Involvement of presynaptic alpha 2-adrenoreceptors in the depressor response produced by repeated administration of dextro-methamphetamine. - ResearchGate. Available from: http://www.researchg...methamphetamine [accessed Sep 25, 2015].

 

Edited by Area-1255, 25 September 2015 - 04:06 AM.

[Flex]

Maybe its not that relevant because of the therapeutic dose but anyway:

 

Regarding Vmat2 inhibition by AMPH and the consquences (oxidative stress, MPTP)

 

VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity

http://www.ncbi.nlm....icles/PMC23302/

 

Neuroprotective activities of catalpol on MPP+/MPTP-induced neurotoxicity.

http://www.ncbi.nlm....pubmed/18423111

 

Catalpol = Rehmannia Glutinosa = Sheng Di Huang

 

would use AMPH also maybe with PQQ or anything other like Catalpol* (though I´m not sure) that activates the ERK pathway

 

The neurotrophic factor pleiotrophin modulates amphetamine-seeking behaviour and amphetamine-induced neurotoxic effects: evidence from pleiotrophin knockout mice.

we used specific Akt and ERK1/2 inhibitors uncovering for the first time that PTN-induced protective effects against amphetamine-induced toxicity in PC12 cells are mediated by the ERK1/2 signalling pathway.

http://www.ncbi.nlm....pubmed/20192945

 

*Catalpol attenuates nitric oxide increase via ERK signaling pathways induced by rotenone in mesencephalic neurons.

http://www.ncbi.nlm....pubmed/19111870

 

+ it increases GDNF but not too much which is actually good because too much would decrease the dopaminergic transmission

 

Catalpol attenuates MPTP induced neuronal degeneration of nigral-striatal dopaminergic pathway in mice through elevating glial cell derived neurotrophic factor in striatum.

http://www.ncbi.nlm....pubmed/20123001

 

But I´m not sure about its effects on cortisol

Edited by Flex, 25 September 2015 - 09:38 PM.

[John250]

Bumping an old thread as this seems to be one of the most advanced amp neurotoxicity prevention threads I’ve ever seen. For example I had no idea how many benefits over the counter natural lithium supplements have. Curious if there is any new updated info on the subject?

Edited by John250, 30 March 2018 - 05:19 PM.

[BioHacker=Life]

NARALA would be my main pick.