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Dopamine receptors cannot be restored after amphetamine use?

dopamine amphetamine adderall

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#31 gamesguru

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Posted 02 November 2015 - 06:26 PM

So you've become somewhat dependent and use it as a bit of a crutch.  Are you to say had you never used it, you would now be unemployed and homeless?  I find it hard to believe amphetamines are the only thing which would able to function.

While someone taking 60mg daily may not technically be abusing adderall, they will start to feel the effects of damage, and cross over into the toxic regime.

 

Persistent Structural Modifications in Nucleus Accumbens and Prefrontal Cortex Neurons Produced by Previous Experience with Amphetamine
Experience-dependent changes in behavior are thought to involve structural modifications in the nervous system, especially alterations in patterns of synaptic connectivity. Repeated experience with drugs of abuse can result in very long-lasting changes in behavior, including a persistent hypersensitivity (sensitization) to their psychomotor activating and rewarding effects. It was hypothesized, therefore, that repeated treatment with the psychomotor stimulant drug amphetamine, which produces robust sensitization, would produce structural adaptations in brain regions that mediate its psychomotor activating and rewarding effects. Consistent with this hypothesis, it was found that amphetamine treatment altered the morphology of neurons in the nucleus accumbens and prefrontal cortex. Exposure to amphetamine produced a long-lasting (>1 month) increase in the length of dendrites, in the density of dendritic spines, and in the number of branched spines on the major output cells of the nucleus accumbens, the medium spiny neurons, as indicated by analysis of Golgi-stained material. Amphetamine treatment produced similar effects on the apical (but not basilar) dendrites of layer III pyramidal neurons in the prefrontal cortex. The ability of amphetamine to alter patterns of synaptic connectivity in these structures may contribute to some of the long-term behavioral consequences of repeated amphetamine use, including amphetamine psychosis and addiction.

Can a therapeutic dose of amphetamine during pre-adolescence modify the pattern of synaptic organization in the brain?
This treatment produced an increase in dendritic length and branches of pyramidal neurons of the medial prefrontal cortex, but not in the nucleus accumbens. These changes were associated with an increase in the expression of calcium/calmodulin-dependent protein kinase II, a highly abundant signalling protein in the postsynaptic densities of excitatory synapses. Interestingly, amphetamine pre-treatment did not alter the motor response to various dopamine agonists, including amphetamine. These data suggest that clinical doses of stimulant drugs may be acting as a trophic support at the glutamatergic synapses, thereby enhancing dopamine-glutamate interactions in the prefrontal cortex.

 

 

Heat shock protects cultured neurons from glutamate toxicity
http://www.sciencedi...896627391903484
NMDA receptor-mediated glutamate toxicity of cultured cerebellar, cortical and mesencephalic neurons: neuroprotective properties of amantadine and memantine
http://www.sciencedi...00689939390464X

Excitotoxic lesions of the pedunculopontine differentially mediate morphine- and d-amphetamine-evoked striatal dopamine efflux and behaviors.
http://www.ncbi.nlm....pubmed/11983320

 

A Mechanism for Amphetamine-Induced Dopamine Overload
http://www.ncbi.nlm....cles/PMC368179/
Dopamine-induced changes in neural network patterns supporting aversive conditioning.
http://www.ncbi.nlm....pubmed/19961836

Altered pattern of brain dopamine synthesis in male adolescents with attention deficit hyperactivity disorder
http://www.ncbi.nlm....les/PMC1698925/

See: ginkgo[1], ginseng[1], [2], green tea[1], [2], [3], [4], [5]

Dopamine Uptake Inhibitors but Not Dopamine Releasers Induce Greater Increases in Motor Behavior and Extracellular Dopamine in Adolescent Rats Than in Adult Male Rats
http://www.ncbi.nlm....les/PMC2957786/

Altered dopaminergic innervation and amphetamine response in adult Otx2 conditional mutant mice.
http://www.ncbi.nlm....pubmed/16256364

 

and you don't know what you may come down with later in life, say parkinsons, then even therapeutic doses of amphetamine might be regrettable

Chronic Amphetamine Use and Abuse
Neurotoxic Effects of Stimulant Drugs
Sustained high-dose administration of amphetamines (especially methamphetamine) to experimental animals produces a persistent depletion of DA which is associated with terminal degeneration (62, 182, 195), as well as neuronal chromatolysis in the brain stem, cortex and striatum (42, 182). In contrast, continuous dosing with extremely high doses of cocaine (100–250 mg/kg/day i.v.) did not induce terminal degeneration in frontal cortex and striatum (62, 183). Recently, Cubellis et al. (36) presented evidence that amphetamine, in contrast to cocaine, induces redistribution of DA from the vesicles into the cytosol; thus, the loss of the protection of the vesicles' relatively reducing environment results in cytosolic oxidative stress that may initiate amphetamine neurotoxicity. The DA depletion is reported to be permanent in the caudate of monkeys (196). The main hypotheses for underlying mechanisms have included 1) the conversion of DA into a hydroxy oxidative metabolite (195, 196); and 2) glutaminergic stimulation of toxicity, which can be inhibited by N-methyl-D-aspartate antagonist MK-801 (200).

Methamphetamine toxicity is inhibited by a variety of drug treatments, including: 1) DA synthesis inhibitor alpha-methyl-para-tyrosine; 2) DA receptor antagonists; 3) NMDA receptor antagonists, e.g., MK-801; 4) DA and serotonergic reuptake inhibitors protecting against DA and serotonin toxicity respectively (195). Even though most studies have found that serotonergic and DA reuptake inhibitors specifically protect these two sites, certain reuptake blockers (such as benztropine) do not (195). On the other hand, mazindol, a non-specific blocker, protects against both DA and serotonergic neurotoxicity. Ali et al. (1994) have further demonstrated in mice that a major factor for neurotoxicity is hyperthermia which is highly correlated with the degree of long-term DA depletion (21). Furthermore, haloperidol, diazepam and MK-801, all of which can reduce methamphetamine-induced hyperthermia, protect rats against DA depletion (4). They also demonstrated that reducing the ambient temperature (4°C) reduced neurotoxicity to the same levels found when phenobarbital, diazepam and MK-801 were present to protect the cell. Tolerance to methamphetamine induced by increasing doses also reduces the hyperthermic response and as well protects against neurotoxicity (89, 188).

An important caveat is that not all protective mechanisms act by preventing the hyperthermic effect; the monoamine uptake blockers inhibit neurotoxicity in the absence of inhibition of hyperthermia, e.g., fluoxetine blocks methamphetamine serotonin toxicity without reducing temperature (140). The monoamine protection from neurotoxicity by reuptake inhibition is emphasized by the unexpected discovery that even massive and 24-hour continuous dosing of cocaine, e.g., 100 mg/kg/day, does not result in DA system neurotoxicity (119, 182, 183). Hyperthermia has been well documented to increase amphetamine stereotypy (93, 220). Hyperthermia alone is well known to result in neuronal chromatolysis and has been previously proposed as a significant contributor to amphetamine-induced DA depletion and neuronal damage in clinical as well as experimental animal histopathology (52). Hyperthermia may have been one of the factors resulting in deaths among athletes taking moderate doses of amphetamine in the 1960s and 70s (145). Even in mild hyperthermia, increased body temperature induces a linear decrease in the inhibitory feedback of stimulants on somatodendritic autoreceptors (130). Thus, body temperature changes induced by amphetamine should be considered as one of the contributors to toxicity.

One of the hallmarks of amphetamine-induced neurotoxicity is the loss of DA uptake sites in the striatum and accumbens. These studies of transporters after chronic amphetamine have reported decreases in the range of 30–40% (158). Recently, Silvia et al. (198) addressed the functional significance of changes in transporters on amphetamine's behavioral effects. After seven days of infusion of transporter RNA antisense ODN into the SN/VTA nuclei, mazindol binding was reduced 32% in the caudate. Administration of 2 mg/kg of amphetamine at this time resulted in robust contralateral turning (an increase of 400%); in contrast, 10 mg/kg of cocaine induced no changes in the turning response. The lack of turning response to cocaine after transporter reduction contrasts with the substantial cocaine-induced contralateral turning after unilateral SN/VTA D2 ODN to reduce D2 autoreceptors in the striatum (199). Thus, the amphetamine-induced loss of DA uptake sites could have two consequences: 1) a protective mechanism reducing further neurotoxicity, and 2) reverse tolerance to subsequent amphetamine administration, perhaps resulting in adverse symptoms such as paranoid psychosis (see also the discussion on neurotoxicity in the habenular interpeduncular track and its possible relationship to augmentation amphetamine-induced adverse effects).

Recently, Fleckenstein et al. (68) reported that methamphetamine induced a dose-response sensitive reduction in [3H] DA uptake in washed striated synaptosomes which lasted for at least three hours; at 24 hrs the response had returned to normal. Since the decrease in intake was at maximum as early as 30 minutes after methamphetamine, this decrease in DA uptake is probably augmenting the amphetamine behavioral response and certainly not inducing tolerance. The decrease in DA uptake at doses up to 15 mg/kg could also provide some protection from neurotoxicity due to oxidative species.

These marked neurotoxic effects on the DA systems may underlie the mild Parkinson-like symptoms or "burned out" clinical picture in chronic, high-dose amphetamine abusers. These same individuals have a readily activated stimulant psychosis response. Similar re-activation of psychosis by L-dopa and direct agonists in Parkinson patients raises the question of whether the more severe psychosis resulting from amphetamine vs. cocaine abuse may have a partial basis in the greater toxicity induced by amphetamine.


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#32 Major Legend

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Posted 03 November 2015 - 02:30 PM

 

So you've become somewhat dependent and use it as a bit of a crutch.  Are you to say had you never used it, you would now be unemployed and homeless?  I find it hard to believe amphetamines are the only thing which would able to function.

While someone taking 60mg daily may not technically be abusing adderall, they will start to feel the effects of damage, and cross over into the toxic regime

 

 

 

 

 

 

 

 

 

 

Well real ADHD is a bitch, the kicker is that it just looks like you are eternally lazy to other people, but really you are like trapped in your mind unable to will yourself to do the right thing.

 

I assume he lives in a first world country, so unemployed and homeless might be excessive, but you can argue that wherever he is at now, perhaps he would not have reached his current position without Amphetamines.

 

Absolutely not endorsing Amphetamines in any way, as far as my understanding goes, both scientifically and from reading/watching other people's experiences - anything within the amphetamine class is "highly likely" IMO to cause neurotoxicity through not just one - but a variety of channels as mentioned already in this thread.

 

CDP Choline is meant to upregulate dopamine, but i've never really had much luck. Forksolin, and Tianeptine? Worth a shot, but I think it will be weird and probably not enough research on those to take long term.

 

The one thing that worked really well for me was NAC + Lions Mane + Jarrows' Carnit all with 3 types of carnitine).

 

The 3 types of carnitine, NAC and lions manes are self explanatory for neuroregeneration and there are lots of studies online you can find just googling any of them. 



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#33 gamesguru

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Posted 03 November 2015 - 02:54 PM

Well real ADHD is a bitch, the kicker is that it just looks like you are eternally lazy to other people, but really you are like trapped in your mind unable to will yourself to do the right thing.

I assume he lives in a first world country, so unemployed and homeless might be excessive, but you can argue that wherever he is at now, perhaps he would not have reached his current position without Amphetamines.

erdos-photo-1.gifFacts+you+need+to+know_da5d62_5496053.jp
 


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#34 Axmann8

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Posted 05 November 2015 - 10:53 PM

 

So you've become somewhat dependent and use it as a bit of a crutch.  Are you to say had you never used it, you would now be unemployed and homeless?  I find it hard to believe amphetamines are the only thing which would able to function.

While someone taking 60mg daily may not technically be abusing adderall, they will start to feel the effects of damage, and cross over into the toxic regime.

 

 

"Dependent" in the same way a schizophrenic patient is "dependent" on their antipsychotics, or that a patient with Parkinson's is "dependent" on their levodopa/dopamine agonist.

I have tried methylphenidate, dexmethylphenidate, atomoxetine, a ridiculous number of procognitive supplements (very high doses fish oil that caused bruising, virtually every racetam, tianeptine, curcumin, SAMe, DMAE, sulbutiamine, huperzine A, L-theanine, inositol, vinpocetine, mucuna dopa, ashwagandha, rhodiola rosea, amino acids [e.g. L-Tyrosine, N-Acetyl-Tyrosine], antioxidants [pycnogenol, NAC, ALCAR, etc.]), several off-label medications for ADD (venlafaxine, duloxetine, levomilnacipran, bupropion, etc), whacko adjunctive therapies (chromium to try to control blood sugar fluctuations, coconut oil, testosterone injections, high-dose fexofenadine [it has stimulant properties], probiotics), and other things I can't even think of at the moment.

None of it improves my cognitive abilities like Adderall, even at fairly low doses (talking the ~10 mg range).

A significant increase in quality of life when on medication could indeed create a state of what you call "dependency."

Either you *really* don't understand the dopaminergic system or you simply think schizophrenics should "deal with" their psychosis, those with Parkinson's should "deal with" their tremors, and those with ADD should "deal with" a near-complete absence of motivation and attention.


Edited by Axmann8, 05 November 2015 - 11:08 PM.


#35 gamesguru

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Posted 05 November 2015 - 11:59 PM

Too much dopamine long-term is bad.  Does not matter much if you are correcting an imbalance, or a hypodopaminergic state.

And suppressing hyperdopaminergic states with neuroleptics also comes at a cost, usually creative thought.  Perhaps this has to do with reduced activity and neurogenesis.

Effect of antipsychotic drugs on brain-derived neurotrophic factor expression under reduced N-methyl-D-aspartate receptor activity.
Reduced serum BDNF levels in schizophrenic patients on clozapine or typical antipsychotics

 

The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and d-amphetamine
One of the prime findings in amphetamine abuse is the induction of psychotic episodes that are almost indistinguishable from the positive symptoms seen in schizophrenic patients (Ujike and Sato, 2004; Hermens et al., 2009). This supports the conjecture that there might be a link between amphetamine abuse and the psychopathic traits observed in schizophrenia. Although the aetiology of schizophrenia is very complex and comprises multiple genetic and environmental risk factors (Karam et al., 2010), psychostimulants such as d-AMPH or METH can increase the susceptibility of users to psychotic symptoms either during acute amphetamine abuse or during withdrawal (Ujike and Sato, 2004; Hermens et al., 2009). There are reports that DAT levels are not reduced in the striata of schizophrenic patients (Seeman and Niznik, 1990). However, others report that there is a reduction in DAT and tyrosine hydroxylase levels in the prefrontal cortex of postmortem specimens of schizophrenic subjects (Akil et al., 1999).

It has been recently shown that impulsive antisocial behaviours (a possible ‘negative symptom’ that can occur in schizophrenia) correlates with an increase in amphetamine-induced DA release in the NAc measured by [18F]fallypride PET and functional magnetic resonance imaging. These observations provide evidence for an association between substance abuse and psychopathic traits (Buckholtz et al., 2010). To obtain an animal model for the psychotic symptoms of schizophrenia, animals are subjected to amphetamine-induced sensitisation and observed during withdrawal periods after the sensitisation regimen (Paulson and Robinson, 1995; Peleg-Raibstein et al., 2009). Sensitised animals show an increase in subsequent amphetamine-induced DA release in the striatum and an increase in locomotor activity (Paulson and Robinson, 1995; Iwata et al., 1997). Thus, sensitisation is not only a model for addiction but also for psychosis (Gainetdinov et al., 2001). Abi-Dargham et al. (2009) have shown using [123I]IBZM (a DAT antagonist) single photon emission computed tomography that schizophrenic patients demonstrate a higher striatal DA release after challenge with d-AMPH and increased D2 receptor occupancy compared to control subjects (Abi-Dargham et al., 2009). Schizophrenia is a collection of presumably heterogeneous disease entities. Hence, many findings are controversial and difficult to reproduce. Nevertheless, at this stage it seems safe to conclude that there is sufficient evidence to substantiate the claim that DAT plays a role in the pathogenesis of schizophrenia.
Amphetamines are the second most commonly abused drugs in Europe after cannabis (EMCDDA, 2009) and the devastating effects of METH addiction are obvious in many parts of the world (Karila et al., 2010). All three drugs (METH, d-AMPH and MDMA) have been reported to induce psychotic episodes or ‘seizures’ in humans (Ujike and Sato, 2004; Karlsen et al., 2008). Furthermore, the loss of nigrostriatal dopaminergic neurons observed following repeated METH administration in animals has been associated with the pathogenesis of PD (Sonsalla et al., 1996; Harvey et al., 2000; Granado et al., 2010). These unintended (‘side’) effects should be carefully assessed when considering the long-term effects of amphetamine abuse on mental health and well-being. Conversely, both d-AMPH and METH are used in the treatment of ADHD, narcolepsy and obesity

 

Story of antipsychotics is one of myth and misrepresentation
People (both with mental illness and volunteers) who’ve taken antipsychotics also report a state of physical, mental and emotional suppression. Those suffering from mental disorders describe how the drugs can help to diminish disturbing thoughts and experiences, but at the cost of stifling important aspects of their personality such as initiative, motivation, creativity and sexual drive.
 

Levodopa‐induced dyskinesia in Parkinson's disease: clinical features, pathogenesis, prevention and treatment
Levodopa is the most effective drug for treating Parkinson's disease. However, long‐term use of levodopa is often complicated by significantly disabling fluctuations and dyskinesias negating its beneficial effects. Younger age of Parkinson's disease onset, disease severity, and high levodopa dose increase the risk of development of levodopa‐induced dyskinesias (LID). The underlying mechanisms for LID are unclear though recent studies indicate the importance of pulsatile stimulation of striatal postsynaptic receptors in their pathogenesis. The non‐human primates with MPTP‐induced parkinsonism serve as a useful model to study dyskinesia. Once established, LID are difficult to treat and therefore efforts should be made to prevent them. The therapeutic and preventative strategies for LID include using a lower dosage of levodopa, employing dopamine agonists as initial therapy in Parkinson's disease, amantadine, atypical neuroleptics, and neurosurgery. LID can adversely affect the quality of life and increase the cost of healthcare.

 


Edited by gamesguru, 06 November 2015 - 12:10 AM.

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#36 mwl987

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Posted 06 November 2015 - 06:00 AM

I mean logically speaking if amphetamine is shown to cause damage at high doses, it very possible it can cause some damage at normal doses too. 

 

You can't really use logic to make this jump here.  Just because something causes damage at high doses does not imply that it will cause damage, albeit to a lesser degree, at a therapeutic dose.  Consider, for example, that chronic high dose (i.e. overdose) vitamin A can lead to intracranial hypertension and other symptoms of hypervitaminosis A; however, it does not follow that normal doses of vitamin A lead to lesser versions of the same conditions.



#37 drg

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Posted 06 November 2015 - 11:46 AM

I won't get into a semantic argument about what I said. But the fact that amphetamines is shown to cause neurotoxicity at high doses makes it much more POSSIBLE that SOME damage COULD be caused at therapeutic doses. Damage that just hasn't been identified or studied. Not saying that it does just that there is a reasonable possibility.

Anyways logically you can't prove something doesn't exist so yeah neurotoxicity could be there just we haven't proven it.



#38 gamesguru

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Posted 06 November 2015 - 12:03 PM

Even low dose does damage, if given long enough.  Obviously never as damaging as abuse.  But, say 10mg per day for 40 years, that's no good.

Some combination of ginkgo, ginseng, and green tea might not be as effective, but it's more sustainable?

A few low doses can prime or protect against future damage, and given infrequently and not for an extended period, can paradoxically boost dopamine and BDNF.

Long-lasting effects of escalating doses of d-amphetamine on brain monoamines, amphetamine-induced stereotyped behavior and spontaneous nocturnal locomotion.
The repeated intermittent administration of relatively low doses of amphetamine (AMPH) produces an enduring hypersensitivity to the motor stimulant effects of AMPH (behavioral sensitization), and this is accompanied by enhanced mesotelencephalic dopamine (DA) utilization/release. In contrast, chronic treatment with very high doses of AMPH does not produce sensitization, but is neurotoxic, resulting in the depletion of brain DA (and often other monoamines). However, gradually escalating doses of AMPH provide protection against the neurotoxic effects of higher doses given later. Therefore, the purpose of the present experiment was to determine if a regimen of gradually escalating doses of AMPH, culminating in much higher doses than usually used to study sensitization, would produce neural and behavioral changes associated with AMPH neurotoxicity (DA depletion) or behavioral sensitization (increased DA utilization). Female rats were given 60 injections (2/day) of increasing (1 to 10 mg/kg) doses of d-AMPH, culminating in rats receiving 20 mg/kg/day for four consecutive days. This treatment did not deplete brain DA or serotonin, but did produce a long-lasting enhancement (at least 12 days) in striatal and nucleus accumbens DOPAC concentrations, and DOPAC/DA ratios. These neurochemical changes were accompanied by an enduring hypersensitivity to the stereotypy-producing effects of a subsequent AMPH 'challenge.' In contrast to this enhanced response to a challenge, AMPH-pretreated rats showed a marked reduction in spontaneous nocturnal motor activity. It is concluded that rats can be given escalating doses of AMPH, which mimic to some extent the AMPH 'runs' common in addicts and that this produces neural and behavioral changes consistent with the development of sensitization; not neurotoxicity.

 

Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders
3. Long-Term Amphetamine Administration.
Investigators have focused on the role of dopamine in positive SZ symptoms such as psychosis, hallucinations, and paranoia because antipsychotic therapies target the dopaminergic system (Tamminga and Holcomb, 2005). Long-term amphetamine administration is used as a pharmacological model for psychotic symptoms of SZ (Ellison, 1994; Pillai, 2008) and has predictive validity for antipsychotics that typically inhibit dopaminergic receptors (Tordjman et al., 2007). Mice or rats given doses of amphetamine for a minimum of 7 days show psychosis-related behaviors reminiscent of SZ (Featherstone et al., 2007). Long-term amphetamine administration decreases BDNF protein levels in the hypothalamus and cortical regions (Angelucci et al., 2007a). This treatment also affects NGF in cortical areas, the hypothalamus, and the hippocampus (Angelucci et al., 2007a). These data suggest that long-term amphetamine exposure has a nonspecific effect on growth factors. Nevertheless, all of these animal models report BDNF decreases in corticolimbic brain regions although specificity of these changes is uncertain. Given that these models each replicate behavioral aspects of SZ and that serum and post mortem brain studies have reported decreased BDNF levels, these data all seem to suggest that BDNF may be important in the pathological features of SZ. Nonetheless, as stated previously, it remains to be tested whether the nature of BDNF changes and their relationship to SZ are causative or incidental.

Chronic amphetamine treatment reduces NGF and BDNF in the rat brain
Amphetamines (methamphetamine and d-amphetamine) are dopaminergic and noradrenergic agonists and are highly addictive drugs with neurotoxic effect on the brain. In human subjects, it has also been observed that amphetamine causes psychosis resembling positive symptoms of schizophrenia. Neurotrophins are molecules involved in neuronal survival and plasticity and protect neurons against (BDNF) are the most abundant neurotrophins in the central nervous system (CNS) and are important survival factors for cholinergic and dopaminergic neurons. Interestingly, it has been proposed that deficits in the production or utilization of neurotrophins participate in the pathogenesis of schizophrenia. In this study in order to investigate the mechanism of amphetamine-induced neurotoxicity and further elucidate the role of neurotrophins in the pathogenesis of schizophrenia we administered intraperitoneally d-amphetamine for 8 days to rats and measured the levels of neurotrophins NGF and BDNF in selected brain regions by ELISA. Amphetamine reduced NGF levels in the hippocampus, occipital cortex and hypothalamus and of BDNF in the occipital cortex and hypothalamus. Thus the present data indicate that chronic amphetamine can reduce the levels of NGF and BDNF in selected brain regions. This reduction may account for some of the effects of amphetamine in the CNS neurons and provides evidences for the role of neurotrophins in schizophrenia.


D-Amphetamine withdrawal-induced decreases in brain-derived neurotrophic factor in sprague-dawley rats are reversed by treatment with ketamine.

one conflicting study or incongruent finding:
?>>Brain-derived neurotrophic factor expression is increased in the rat amygdala, piriform cortex and hypothalamus following repeated amphetamine administration.<<?

 

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Persistent gene expression changes in NAc, mPFC, and OFC associated with previous nicotine or amphetamine exposure.
Highly addictive drugs like nicotine and amphetamine not only change an individual's behaviour in the short and long-term, they also induce persistent changes in neuronal excitability and morphology. Although research has started to examine the epigenetic changes that occur immediately after drug exposure, there has been little investigation into the persistent modifications to the epigenome that likely moderate the stable maintenance of the neurological changes. Male Long-Evans rats were administered amphetamine, nicotine, or saline for 14 consecutive days, given a 14 day withdrawal period, and then sacrificed. DNA from the mPFC, OFC, and nucleus accumbens (NAc) was used for global DNA methylation analysis and RNA from the same brain regions was used for gene expression analysis. Following the two-week withdrawal period, exposure to amphetamine or nicotine was associated with a decrease in global DNA methylation in each brain region examined. Previous exposure to nicotine was associated with changes in expression of 16 genes (NAc:6, mPFC:5, OFC:5) whereas exposure to amphetamine was associated with changes in expression of 25 genes (NAc:13, OFC:8, mPFC:4). The persistent epigenetic changes associated with exposure to amphetamine and nicotine were region and drug dependent, and differ from the latent epigenetic changes that occur immediately after drug exposure. The changes in DNA methylation are consistent with the gene expression results and provide further support to the notion that DNA methylation is the key regulatory mechanism for experience dependent changes.

 

Mouse brain gene expression changes after acute and chronic amphetamine.
Arrays display robust hybridization for about 3600 transcripts. One hundred and seventeen of these expressed transcripts are candidate positives for drug-related changes, displaying > 1.8-fold differences from SS control values in whole brains of either SA or AA mice. Five transcripts reveal altered expression in both AA and SA mice. SA mostly enhances expression while AA treatments largely reduce expression. Fourteen SA and four AA changes in whole brain mRNA were replicated by > 1.8-fold changes in independent microarray assessments of either cerebral cortical or brainstem mRNAs, with more changes identified in frontal than in entorhinal/parietal cortical samples. About one-quarter of these changes persist in initial studies of mice killed 20 h after the last amphetamine injection. Each of these genes, including transcription factor, cellular regulatory, structural and other gene family members, are candidates to contribute to brain adaptations to psychostimulants.

Selective changes in gene expression in cortical regions sensitive to amphetamine during the neurodegenerative process.
Changes in gene expression in the cortical regions were all between 1.2- and 1.5-fold 14 days after AMPH but some of these changes, such as annexin V increases, may be relevant to neurotoxicity. Gene expression was not affected by more than 1.5-fold at the time points in the striatum, although 65% dopamine depletions occurred, but the plasma membrane-associated dopamine transporter and dopamine D2 receptor were decreased about 40% in the substantia nigra at 64 h and 14 days post-AMPH. Thus, the 2-day AMPH treatment produced a few changes in gene expression in the two-fold range at time points 16 h or more after exposure but the majority of expression changes were less than 1.5-fold of control. Nonetheless, some of these lesser fold-changes appeared to be relevant to the neurotoxic process.

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Dopamine partial agonist reverses amphetamine withdrawal in rats.
Decreased motivation to work for a natural reward is a sign of amphetamine withdrawal and is thought to be associated with hypofunction of the mesolimbic dopamine system. During withdrawal from repeated amphetamine administration, rats showed reduced responding for a sweet solution in a progressive ratio schedule. Repeated systemic treatment with terguride (0.2 and 0.4 mg/kg, i.p.) twice daily during the first four days of amphetamine withdrawal reversed the decrease in responding for the sweet solution. These results suggest that dopamine partial agonists, possibly due to their agonistic-like actions under these conditions, are a potential therapeutic approach for the acute withdrawal stage of the amphetamine addition cycle.

The effect of chronic administration and withdrawal of amphetamine on cerebral dopamine receptor sensitivity
Mice with a 6-hydroxydopamine induced unilateral nigro-striatal lesion received (+)-amphetamine sulphate (2.5–20 mg/kg) over a 3-month period by daily incorporation into the drinking water. During this period the circling response to apomorphine hydrochloride (0.01–0.5 mg/kg, s.c.) was increasingly suppressed in comparison to control animals, while spontaneous locomotor activity increased. Following drug withdrawal the circling response to apomorphine remained suppressed two months later. However, spontaneous locomotor activity was also reduced up to 1 month following drug removal.
The dopamine content of the lesioned side of the forebrain was 25% of the intact side in control animals and was not further reduced by amphetamine administration. The dopamine content of the intact forebrain was reduced by 43% during amphetamine administration and remained 18% depressed 1 month following drug withdrawal. No changes in 5-hydroxytryptamine or noradrenaline concentrations were observed in either the intact or lesioned side.
This data, while showing that chronic amphetamine treatment can induce persistent changes in dopamine receptor sensitivity, can be interpreted in terms of increased striatal receptor sensitivity or as a decreased response of dopamine receptors in the nucleus accumbens.

Regional differences in the effects of amphetamine withdrawal on dopamine dynamics in the striatum. Analysis of circadian patterns using automated on-line microdialysis.
The purpose of the study is to determine the relationship between behavioral symptoms of amphetamine withdrawal and the extracellular concentration of dopamine (DA) in the dorsolateral caudate nucleus and the nucleus accumbens across the entire light-dark cycle. This was accomplished using automated on-line microdialysis sampling in behaving rats. Animals were pretreated with escalating doses of d-amphetamine (or saline) over a 6-week period and then were withdrawn from amphetamine for 3, 7, or 28 days before testing. There were regional differences in the effects of amphetamine withdrawal on the concentrations of DA and DA metabolites in dialysate. Early during withdrawal (3 and 7 days), when animals showed postamphetamine withdrawal behavioral depression (nocturnal hypoactivity), there was a significant decrease in DA and DA metabolites in the dorsolateral caudate nucleus and a disruption in the normal circadian pattern of DA activity. In contrast, there was no effect of amphetamine withdrawal on DA dynamics in the nucleus accumbens. By 28 days after the discontinuation of amphetamine pretreatment, after basal DA in the caudate returned to normal, there was a significant increase in basal DA metabolism in both the caudate and the accumbens. This increase in DA metabolism may be related to the expression of sensitization, including a hypersensitivity to an amphetamine challenge. It is concluded that the role of the dorsal striatum in psychostimulant drug withdrawal syndromes deserves further consideration.


Edited by gamesguru, 06 November 2015 - 12:37 PM.

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#39 Andersen

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Posted 12 January 2018 - 12:07 AM

Did anybody ever find anything that would help this situation. I have had very severe effects from taking prescription amphetimines I had no business doing. I’m looking for any information that my help. Is my brain permanently messed up. I can hardly function and have severe anhedonia.





Also tagged with one or more of these keywords: dopamine, amphetamine, adderall

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