Posted by linkadge on June 10, 2008, at 19:08:04
In reply to Re: Question nr. 2!, posted by undopaminergic on June 10, 2008, at 12:21:57
>Such a possibility cannot be ruled out, but an >extensive - albeit not exhaustive - review of >the available data suggests that any neurotoxic >potential of cocaine - and probably >methylphenidate - is subtle enough to routinely >escape detection even after extreme conditions >of exposure to massive mounts of cocaine.
Cocaine is not necessarily directly neurotoxic to serotonergic and dopaminergic neurons in the way that amphetamines are, but this does not imply it is not neurotoxic. There are many studies demonstrating the ways in which cocaine is neurotoxic.
This study used clozapine in an animal model of cocaine neurotoxicity. They theorized that clozapine had some ability to reduce the cocaine induced glutamate release.
http://jpet.aspetjournals.org/cgi/content/full/312/1/297
Nextly cocaine has been shown to be neurotoxic to the medium spiny neurons in the neucleus accumbens (i.e. it directly damages the pleasure centres of the brain). This in conjunction with DAT transporter upregulation could be responsible for cocaine associated depression.
http://cocaine.org/reward/pleasure.html
The neurotoxic effects of cocaine are evident in regular users. The following study concluded that cocaine was directly neurotoxic to the frontal cortex as evidenced by glial activation and specific loss of choline, creatine and inositol containing compounds in the frontal cortex, in comparison to healthy control subjects.
http://cocaine.org/longterm/index.html
The next study examines the effects of cocaine and methamphetamine separately for their ability to deplete striatal dopamine concentrations. It concluded that cocaine and methamphetamine led to significant depletion of striatal dopamine as well as coenzyme q10. The study also found that q10 adminstration ameliorated the dopamine depletion. The study concluded that q10 administration appears to attentuate cocaine neurotoxicity.
http://cocaine.org/coq10/index.html
The next article describes certain changes in the brains of cocaine users. It finds indication of presynaptic degeneration to dopamine neurons (page 4). It describes a neuroleptic malignant like syndrome as an indicator of extreme dopamine depletion. (page5) The article then extensivly describes long term cognitive deficits and cerebral atrophy in cocaine users (page 5). It also states (with reference to the ability of cocaine to deplete dopamine): "Although some investigators reported lack of long-term monoamine depletion following chronic treatment
of rats with cocaine (Kleven et al. 1987), the majority of studies point to the existence of DA deficiency (page 9). The article then gives reference to several studys describing the detrimental effects of cocaine on monoamine levels and synthesis.Additional reference to the neurotoxic effects of cocaine (page 12)
Recent findings of Ellison (1992; Ellison et al., this volume) clearly established that cocaine is also neurotoxic: Continuous exposure to cocaine for 3 to 5days (pellets releasing 103 milligrams (mg) of cocaine over 5 days), in a regimen that mimics bingeing in addicts, produced strik-ing axonal degeneration extending from lateral habenula along the fascic-ulus retroflexus toward the ventral tegmentum. In rats exposed to continuous cocaine, persistent changes in acetylcholine (ACh) and GABA receptors in the caudate were observed, implying damage to structures postsynaptic to DA neurons (Ellison et al., this volume). These neurodegenerative changes resembled effects of amphet-amine and were observed 30 days after removal of cocaine pellets, sugges-ting that they were long lasting or permanent. Neurochemical evidence of cocaine-induced neurodegeneration was also furnished by other investigators. Hurd and colleagues (1990)
showed that repeated cocaine self-administration produced decreased levels of extra-cellular ACh in rat caudate-putamen in addition to DA deficiency. Contin-uous administration of cocaine was also shown to produce a persistent reduction in binding of the muscarinic receptor ligand and an increase in binding of the central benzodiazepine receptor ligand in the caudate, NA, olfactory tubercle, dorsal hippocampus, amygdala, and cerebral cortex (Zeigler et al. 1991). The upregulation of benzodiazepine receptors (coupled to the GABAA receptors) could result from decreased GABA synthesis and may suggest degeneration of GABAergic neurons. The brain regions that degenerated after continuous cocaine exposure are very rich in ACh and are the crossroads for DA, GABA, and ACh inner-vations (Angevine and Cotman 1981); therefore their lesions are likely to cause impairment of neuronal functions mediated by these 12
neurotrans-mitters. Such effects were, in fact, observed behaviorally in rats in the forms of exaggerated fear, anxiety, and reduced exploratory behavior (Zeigler et al. 1991).
http://www.nida.nih.gov/pdf/monographs/Monograph163/Monograph163.pdf(I could go on, the above link is 344 pages)
>Furthermore, there are numerous reports >confirming the lack of any detectable >neurotoxicity from cocaine under various >conditions - often following one or more of a >variety of different experiments designed to >provoke it.I think I know the *study* you are referring to :)
>Under normal conditions, DAT inhibitors are more >likely to reduce neurotransitter release due to >increased stimulation of autoreceptors.
Yes, but cocaine is a monoamine releaser on its own right, so it will release dopamine in spite of messages from autoreceptors.
>Nevertheless, I'm open to the possibility that >in certain situations, depending on a number of >factors, reuptake inhibitors may have release->facilitating actions, but not through the same >mechanisms - and almost certainly not to the >same level - as the amphetamines.
Cocaine is a monoamine releaser, just like ritalin is.
>Most data indicate enhanced intracellular >monoamine content following reuptake inhibition, >in addition to the well known elevation of >synaptic neurotransmitter concentrations - the >very opposite of depletion.
Read the above and certainly request more if you want it. Like I said, ritalin is a norepinephrine/dopamine reuptake inhibitor with NE and DE releasing actions. Cocaine is a triple uptake inhibitor with monoamine releasing actions.
>I can only conclude that there is extremely >little evidence of neurotoxicity of >methylphenidate or cocaine at doses far >exceeding those used for euphoria or other >recreational purposes.
There is as much evidence as you are willing to consider.
>>
>> With cocaine abuse you still see things like >>cellular atrophy, loss of cortical grey matter, >>glial pathologies etc which are shared in meth >>abuse.
>>>Be careful not to erroneously attribute >generalised, inspecific findings to particular >causes - whether drug abuse or otherwise - >without adequate supporting evidence in favour >of such an interpretation.
That is refeneced above.
>Life Sci. 1988;43(17):1403-9.
>Cocaine, in contrast to D-amphetamine, does not >cause axonal terminal degeneration in >neostriatum and agranular frontal cortex of Long->Evans rats.
>http://www.ncbi.nlm.nih.gov/pubmed/3185100This was only a 3 day study.
>Brain Res Bull. 1988 Aug;21(2):233-7.
>Lack of long-term monoamine depletions following >repeated or continuous exposure to cocaine.
>http://www.ncbi.nlm.nih.gov/pubmed/2461246Ok, one study shows no monoamine depletion. There are starkly contrasting studies above. Also this is not evidence of lack of neurotoxicity.
>Brain Res. 1990 Jun 4;518(1-2):67-77.
>Histological and ultrastructural evidence that D->amphetamine causes degeneration in neostriatum >and frontal cortex of rats.
>http://www.ncbi.nlm.nih.gov/pubmed/1975218This study says absolutely nothing about cocaine or ritalin (?)
>Neurosci Lett. 1993 Apr 30;153(2):210-4.
>Long-term cocaine administration is not >neurotoxic to cultured fetal mesencephalic >dopamine neurons.
>http://www.ncbi.nlm.nih.gov/pubmed/8327196This is a very specific cell culture.
>J Neurochem. 1993 Apr;60(4):1444-52.
>Differing neurotoxic potencies of >methamphetamine, mazindol, and cocaine in >mesencephalic cultures.
>http://www.ncbi.nlm.nih.gov/pubmed/8095976Again, a very specific cell culture. The study is incontrast to some of the above mentioned (in vivo) studies.
>J Neurosci. 1994 Apr;14(4):2260-71.
>Methamphetamine neurotoxicity involves >vacuolation of endocytic organelles and dopamine->dependent intracellular oxidative stress.
>http://www.ncbi.nlm.nih.gov/pubmed/8158268Again, this study says absolutely nothing about cocaine or ritalin.
>J Pharmacol Exp Ther. 1994 Dec;271(3):1320-6.
>Protection against methamphetamine-induced >neurotoxicity to neostriatal dopaminergic >neurons by adenosine receptor activation.
>http://www.ncbi.nlm.nih.gov/pubmed/7996441Again, this study says nothing about cocaine or ritalin.
>Brain Res. 1995 Apr 24;677(2):345-7.
>Methamphetamine-induced serotonin neurotoxicity >is mediated by superoxide radicals.
>http://www.ncbi.nlm.nih.gov/pubmed/7552263How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>J Pharmacol Exp Ther. 1998 Aug;286(2):1074-85.
>Long-term effects of amphetamine neurotoxicity >on tyrosine hydroxylase mRNA and protein in aged >rats.
>http://www.ncbi.nlm.nih.gov/pubmed/9694971How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>Brain Res. 1999 Aug 7;837(1-2):15-21.
>Methamphetamine generates peroxynitrite and >produces dopaminergic neurotoxicity in mice: >protective effects of peroxynitrite >decomposition catalyst.
>http://www.ncbi.nlm.nih.gov/pubmed/10433983How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>Neurology. 2000 Mar 28;54(6):1344-9.
>Evidence for long-term neurotoxicity associated >with methamphetamine abuse: A 1H MRS study.
>http://www.ncbi.nlm.nih.gov/pubmed/10746608How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>J Pharmacol Exp Ther. 2002 Mar;300(3):1093-100.
>Methylenedioxymethamphetamine decreases >plasmalemmal and vesicular dopamine transport: >mechanisms and implications for neurotoxicity.
>http://www.ncbi.nlm.nih.gov/pubmed/11861820How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>J Pharmacol Exp Ther. 2003 Mar;304(3):1181-7
>Methylphenidate alters vesicular monoamine >transport and prevents methamphetamine-induced >dopaminergic deficits.
>http://www.ncbi.nlm.nih.gov/pubmed/12604695Ok. This point was made above. It does not show that ritalin is non neurotoxic. It does not mention the dose or the duration of treatment with ritalin.
>Synapse. 2003 Aug;49(2):89-96.
>Neurotoxic methamphetamine regimen severely >impairs recognition memory in rats.
>http://www.ncbi.nlm.nih.gov/pubmed/12740864How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>Psychopharmacology (Berl). 2006 Apr;185(3):327->38. Epub 2006 Mar 3.
>Cognitive function and nigrostriatal markers in >abstinent methamphetamine abusers.
>http://www.ncbi.nlm.nih.gov/pubmed/16518646How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>Neurochem. 2007 Nov;103(3):1219-27. Epub 2007 >Aug 7.
>A rapid oxidation and persistent decrease in the >vesicular monoamine transporter 2 after >methamphetamine.
>http://www.ncbi.nlm.nih.gov/pubmed/17683483How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
>Synapse. 2008 Feb;62(2):91-100.
>Persistent cognitive and dopamine transporter >deficits in abstinent methamphetamine users.
>http://www.ncbi.nlm.nih.gov/pubmed/17992686How does providing evidence that methamphetamine is neurotoxic support your argument that cocaine and ritalin are not neurotoxic??
Linkadge
poster:linkadge
thread:833007
URL: http://www.dr-bob.org/babble/20080606/msgs/834048.html