View Full Version : Methamphetamine treatment impairs spatial working memory in rats.


theta
05-21-08, 01:16 PM
1: Psychopharmacology (Berl). 2007 Sep;194(1):21-32. Epub 2007 May 20.
Links
Repeated methamphetamine treatment impairs spatial working memory in rats: reversal by clozapine but not haloperidol.
Nagai T, Takuma K, Dohniwa M, Ibi D, Mizoguchi H, Kamei H, Nabeshima T, Yamada K.

Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.

RATIONALE: Although chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans, there are few reports about an animal model that reflects METH-induced impairment of working memory. OBJECTIVES: In this study, we investigated the effect of repeated METH treatment on spatial working memory in rats. MATERIALS AND METHODS: Rats were repeatedly administered METH (2 mg/kg) once a day for 7 days, and their memory function was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. RESULTS: METH-treated animals showed an impairment of performance in the test phase when the delay time was increased from 5 to 30 min or longer. The effect of METH persisted for at least 14 days after the drug withdrawal. METH-induced impairment of working memory was reversed by clozapine (3 and 10 mg/kg, for 7 days), but not haloperidol (1 and 2 mg/kg, for 7 days). The improving effect of clozapine diminished 7 days after the withdrawal. Phosphorylated extracellular signal-regulated kinase1/2 (ERK1/2) levels were significantly increased in the hippocampus of saline-treated control rats from 5 to 60 min after the training phase. In contrast, hyperphosphorylation of ERK1/2 was abolished in the hippocampus of rats treated with METH. CONCLUSIONS: These findings suggest that repeated METH treatment induces impairment of working memory, which is associated with a dysfunctional ERK1/2 pathway in the hippocampus. Furthermore, clozapine may be effective for the treatment of METH-induced cognitive dysfunction.

PMID: 17514479 [PubMed - indexed for MEDLINE]

2 mg/kg once a day for 7 days in rats. The HED would be 0.3 mg/kg. Thats well in line with therupetuic doses for humans. (75kg * 0.3 = 22.5 mg).

http://en.wikipedia.org/wiki/Clozapine (atypical antipsychotic).

Might suggest methamphetamine would not be suitable for certain types of ADHD or occupations/course of study.

Mincan
05-21-08, 01:30 PM
What about dextroamphetamine man!? And how does one go without their only way of processing working memory? spatial-visual that is.

theta
05-21-08, 01:47 PM
What about dextroamphetamine man!?

Assuming their neurotoxic(or down-regulating) effecting zones are the same areas the drug works therapeutically on we can say dextroamphetamine and methamphetamine may have more differences than mere dose and half-lives.
It could be for example methamphetamine is a safer drug but less effective
than dextroamphetamine at treating ADHD. Lars has suggested he found dextroamphetamine more stimulating and suitable for work and study. A
toxicity study found dextroamphetamine caused dopamine deficits in three
regions of the brain compared to methamphetamine causing deficits in one region. That might explain some of the increase effectiveness of dextroamphetamine(it works in more areas).

I did not look up the full text but I'm sure the rats had a lot of spatial working memory left. It was just a reduction. ADHDers need no reduction at all they need improved working memory in most cases.

Mincan
05-21-08, 01:56 PM
Oh well, better this than getting hit by a bus later today. :)

fxfake
05-21-08, 03:00 PM
Needs more info, like when the doses were administered.

If you administered 22.5 mg (trusting the OP's numbers) to otherwise non-amphetamine using people for 7 days you'd very likely get impaired memory, among other things. Why? Because those people would probably get much less sleep. Lack of sleep can lead to memory problems and symptoms resembling schizophrenia; clozapine is a treatment for schizophrenia.

theta
05-21-08, 03:12 PM
Needs more info, like when the doses were administered.

If you administered 22.5 mg (trusting the OP's numbers) to otherwise non-amphetamine using people for 7 days you'd very likely get impaired memory, among other things. Why? Because those people would probably get much less sleep. Lack of sleep can lead to memory problems and symptoms resembling schizophrenia; clozapine is a treatment for schizophrenia.

Thats an interesting idea. I can not find the full text. But one thing I do know is a large percent of studies are flat out wrong. In the case of illegal drugs there is a lot money available to say they are dangerous and in the case of ADHD meds there is a lot money to say the opposite. And who pays for a study often effect its results.

1: Pharmacol Biochem Behav. 2007 Nov;88(1):55-63. Epub 2007 Jul 20.
Links
Modafinil restores memory performance and neural activity impaired by sleep deprivation in mice.
Piérard C, Liscia P, Philippin JN, Mons N, Lafon T, Chauveau F, Van Beers P, Drouet I, Serra A, Jouanin JC, Béracochéa D.

Institut de Médecine Aérospatiale du Service de Santé des Armées, France. cpierard@imassa.fr

The original aims of our study have been to investigate in sleep-deprived mice, the effects of modafinil administration on spatial working memory, in parallel with the evaluation of neural activity level, as compared to non-sleep-deprived animals. For this purpose, an original sleep deprivation apparatus was developed and validated with continuous electroencephalography recording. Memory performance was evaluated using spontaneous alternation in a T-maze, whereas the neural activity level was estimated by the quantification of the c-Fos protein in various cerebral zones. This study allowed altogether: First, to evidence that a diurnal 10-h sleep deprivation period induced an impairment of spatial working memory. Second, to observe a decrease in c-Fos expression after sleep deprivation followed by a behavioural test, as compared to non-sleep-deprived mice. This impairment in neural activity was evidenced in areas involved in wake-sleep cycle regulation (anterior hypothalamus and supraoptic nucleus), but also in memory (frontal cortex and hippocampus) and emotions (amygdala). Finally, to demonstrate that modafinil 64 mg/kg is able to restore on the one hand memory performance after a 10-h sleep deprivation period, and on the other hand, the neural activity level in the very same brain areas where it was previously impaired by sleep deprivation and cognitive task.

PMID: 17698177 [PubMed - indexed for MEDLINE]

Base on that I say they do the methamphetamine /spatial memory study again and try modafinil after a delay. And do a test on sleep deprivation alone and see if clozapine improves spatial working memory.
If the answer is yes to both those then the first study is wrong based on leaving out a variable.

SuzzanneX
05-21-08, 03:51 PM
poor rats...

TygerSan
06-05-08, 03:30 PM
2 mg/kg once a day for 7 days in rats. The HED would be 0.3 mg/kg. Thats well in line with therupetuic doses for humans. (75kg * 0.3 = 22.5 mg).


Interesting calculation there. Those doses do seem somewhat low, and I know once i weaned off of Adderall, I had even worse working memory than before!

One thing you have to consider, though, is that rats process drugs very differently than humans, and the route of administration can cause very different plasma (blood) and brain concentrations of drugs.

Subcutaneous injection (under the skin) or intraparitoneal (into the abdominal cavity) administration is common in rats (easier to do), but results in faster drug absorption and elimination than oral administration. This has been demonstrated for methylphenidate (Ritalin).

The therapeutic and stimulant properties of methylphenidate (MP), a drug commonly prescribed for the treatment of attention deficit hyperactivity disorder, have been attributed to increases in synaptic dopamine (DA) concentrations resulting from the blockade of DA transporters. In addition to obvious difficulties inherent in any interspecies comparison, interpretation of preclinical studies done with MP is further complicated by different routes of administration in animals (i.v. and i.p.) compared with humans (oral). In the present study we compared the effects of i.p. and intragastric (oral) MP both on rat nucleus accumbens DA assessed by in vivo microdialysis and on locomotor activity measured in a photocell apparatus. We also compared regional brain uptake and plasma levels of [(3)H]MP after administration of 5 mg/kg via both routes. Intraperitoneal MP (5 and 10 mg/kg) was approximately twice as potent as intragastric MP in terms of increasing extracellular DA levels and in stimulating locomotion. This was consistent with the higher brain uptake of [(3)H]MP when given i.p. rather than intragastrically. The dose of 2 mg/kg produced significant increases in both measurements when administered i.p., but not intragastrically. This study shows that relatively low doses of MP (2 mg i.p. and 5 mg intragastric) significantly increase extracellular DA and locomotor activity and indicates that the differences in the neurochemical and behavioral effects of MP between the intragastric and the i.p. routes are due to central drug bioavailability.

http://www.ncbi.nlm.nih.gov/pubmed/10991960?ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVDocSum

PS. If you want a copy of that paper, PM me and I'll see what I can do.

TygerSan
06-05-08, 03:32 PM
poor rats...

Aww, I feel for you . . . I thank the ones that contribute to our understanding of how our brains work often. They are cool critters, aren't they!

theta
06-05-08, 03:50 PM
Interesting calculation there. Those doses do seem somewhat low, and I know once i weaned off of Adderall, I had even worse working memory than before!

I would guess it would take a few months of no drug use to up-regulate your
receptors to get back to your pre-Adderall working memory.

TygerSan
06-10-08, 12:46 PM
I would guess it would take a few months of no drug use to up-regulate your
receptors to get back to your pre-Adderall working memory.

Yep, exactly; thank goodness it didn't last forever (I was a little worried). Actually one of the reasons I stopped taking it was that when it wore of (during rebound), I literally couldn't remember anything. I don't think I've ever had such fuzzy brain in my life (and that's saying something!)

SuzzanneX
06-10-08, 01:43 PM
getting hit by a bus sounds more appealing, than the out come of my personal experiance
as a labritory rat on meth.

theta
06-10-08, 02:33 PM
I have a different hypothesis that might explain the observation in the study.

Stimulants can increase anxiety (http://www.ncbi.nlm.nih.gov/pubmed/18195452?ordinalpos=14&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVDocSum) ---> Anxiety selectively impairs visual-spatial working memory. (http://www.ncbi.nlm.nih.gov/pubmed/16637749?ordinalpos=39&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVDocSum)That same study showed increased anxiety from stimulnats was reduced with l-type calcium channel blockers. (http://www.ncbi.nlm.nih.gov/pubmed/16637749?ordinalpos=39&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_RVDocSum) So the same study should be preformed to eliminate the anxiety variable.

amu_d
08-24-08, 02:48 AM
These studies worry me about the long term side-effects of stimulants =/

SuzzanneX
08-24-08, 04:07 AM
....as well, they should.
that's why you wanna keep those doses LOW.

Colin
08-24-08, 07:25 AM
you need to weigh up the consequences of untreated adhd, wich for me is quite high, and i dont respond to anything but quite high doses.

the long term dangers are worrying, but there doesnt seem to be anyone claiming evidence of long term damage in humans who take it becuase they have a definate need to. the damage in rats is probably more consistent with damage in humans who abuse it.

lets face it stimulants have been prescribed for a very long time, and far newer drugs are being withdrawn for all sorts of effects, so the fact that theres no evidence for long term damage of medicinal use of stimulantes in humans could mean that there isnt any.

do rats get adhd ? or some equivalent dopamine deficiency related problem ? can they induce some thing like that ?

amu_d
08-25-08, 02:41 AM
Also, it took 7 days for the rats to have this affect. How long would this be in humans, 7 years minimum? I hope it's a long time =/

qinkin
08-25-08, 04:32 PM
chronic use of methamphetamine (METH) leads to long-lasting cognitive dysfunction in humans,chronic usage... MEANING problematic usage.. means like overdosaging, abusive use.. . . . ANYWAY--> Desoxyn is a different compound, though it does have the METH molecule in it..

The active salt of Desoxyn is dextro (http://en.wikipedia.org/wiki/Dextrorotation)-methamphetamine hydrochloride.
safer meds are better, but they need to be quite effective at low to mid-range doses.. i do think the doses last longer, than regular Adderall, in Desoxyn


Desoxyn also has a higher benefit relative to the incidence of side-effects than other amphetamines.There is no evidence to suggest it is clinically distinguishable from other amphetamines in either abuse potential, drug preference, sensitization, or tolerance.Just the fact, that this was the ORGINAL formulation to treat the disorder, ADD/HD.. gives it ALOT of cred

jaxze
12-15-08, 11:38 PM
from my experience my working memory is way worse after using stimulants, it is incredibly frustrating, almost infuriating. i get stuck in thought loops for minutes at a time trying to remember the word i'm thinking of, but to no avail. any semblance of eloquence has been shot down the drain, it's an obvious rebound effect for me

Contrapunctus
12-16-08, 01:17 PM
ANYWAY--> Desoxyn is a different compound, though it does have the METH molecule in it..

safer meds are better, but they need to be quite effective at low to mid-range doses.. i do think the doses last longer, than regular Adderall, in Desoxyn

Where does this person get this from?

Desoxyn is not a "different compound", it is simply the more active enantiomer of methamphetamine. In many cases, street methamphetamine is solely d-meth...

Jonas1H
03-17-09, 09:33 PM
everything >50mg is playing russian roulette with the memory system cause meth is neurotoxic in some way