Posted by undopaminergic on June 10, 2008, at 12:21:57
In reply to Re: Question nr. 2!, posted by linkadge on June 6, 2008, at 11:18:16
> >Amphetamines and DAT-inhbitors produce some of >the same neurobiological adaptions, such as >downregulation of postsynaptic D2-receptors. >However, the pattern of damage to presynaptic >nerve terminals under discussion only occurs >with amphetamines - at high doses - and not with >cocaine or methylphenidate, even at massive >doses, far beyond those used recreationally.
>
> Cocaine and methyphenidate do have neurotoxic potential.
>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. A notable exception is a couple of old reports from an author claiming to have found signs of cocaine-induced neurodegeneration in the "lateral habenula", but these are unconfirmed - and indeed contradicted - by other researchers. 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.
However, the apparent lack of neurotoxicity should not be erroneously interpreted as a lack of other adverse effects, such as liver toxicity and cardiovascular complications. Heart attacks and strokes can easily have such consequences as severe brain damage and death.
> I havn't heard about what you are suggesting,
>That is remarkable, considering the amount of research on it published throughout the past few decades. I'll include a small subset of the relevant references below.
> You can still obviously grow tollerant to methylphenidate or cocaine.
>Since I already acknowledged that, I wonder why you deem it necessary repeat it.
> Ritalin and cocaine do enhance the release of monoamines as well as block their reuptake.
>Most of the studies suggesting such an effect of DAT inhibitors at the first glance no longer do upon closer investigation, but rather turn out merely to use sloppy and misleading language. The few reports on experiments actually designed to demonstrate a neurtransmitter-releasing effect of cocaine (I can't recall any on methylphenidate) only appear to succeed in the endevour under special experimental conditions that scarcely occur in nature. Under normal conditions, DAT inhibitors are more likely to reduce neurotransitter release due to increased stimulation of 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.
> Longer term use of higher doses may also lead to monoamine depletion.
>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. During withdrawal from long-term use - especially if abrupt - there is likely to be a relative or functional deficit of the affected neurotransmitters in the synapse, but to call this a depletion of monoamines would be very misleading.
> Cocaine and ritalin also lead to dopamine transporter upregulation in certain limbic regions with long term us.
>This is absolutely correct.
> Rats raised on ritalin show long term reward deficits and depressive behavior when they do not recieve the drug. This may be related to transporter upregulation.
>Yes, in addition to a variety of other adaptions, depending on the level of exposure to the drug in terms of dose and duration, as well as on other factors, including at least at which point in the life of the animal that treatment was started.
> Ritalin is also shows genotoxic potential. The long term effects of this are currenly not well established.
>I'm highly skeptical of that, although considering the endless genetic variety, there is a chance that Ritalin would be toxic to some subset thereof.
> >It is not a matter of dose, but a matter of >mechanisms of action.
>
> Are you arguing that euphoriant doses of ritalin or cocaine are in no ways neurotoxic? This is not true.
>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. However, it can never be absolutely guaranteed, for all time, that these drugs cannot possibly be neurotoxic under any circumstances - it only means that any neurotoxic effects are rare and elusive enough to have gone undetected through decades of research. It is almost certain, however, that other risks - aside from neurotoxicity - are much more significant and relevant in practice - these include, for instance, the consequences of drug induced behaviours, cardiovascular complications such as stroke and cardiac arrest, damage related to the routes of administration, toxic effects of contaminants accompanying the drug, heat stroke, seizures, and so on.
> I would argue that while amphetamines may produce a form of neurotoxicity not seen with cocaine, they likely have certain common mechanisms of toxicity. Euphoriant doses of stimulants place massive demands on the brain. The brain releases more glutamate. The cells are required to function harder and there is increased oxidative stress. The elevation of PKC can alter BCL-2 levels which can the cells more vulnerable to apoptosis. This coupled with excessive glutamate and insufficiant energy requirements can lead to cellular death. Excessive dopaminegic activity can also increase oxidative stress in certain cicumstances.
>While you are correct about much of the above, you seem to be overlooking several facts that are highly relevant to the outcome. First, the location of the elevated dopamine (DA): DAT-inibitors reduce cytosolic extravesicular DA, thus reducing intracellular oxidative stress from DA-[auto]oxidation (e.g. DA quinones), whereas amphetamines do the opposite. Second, the magnitude of DA elevation: only a relatively modest elevation of synaptic DA is possible by reuptake inhibition (by cocaine, etc.), whereas extensive synaptic release of neuronal stores of DA by amphetamines can produce DA concentrations that are several times higher. Third, you imply that the so-called euphoriant doses of stimulants are necessarily much higher than those used medically: this is actually somewhat true for amphetamines, especially following the development of tolerance, but the route of administartion is of great importance as to whether or not euphoria is felt. In contrast, therepeutic doses of methylphenidate generally produce levels of DAT-inhibition matching or exceeding those required - but not sufficient - to elicit feelings of euphoria if - and only if -the onset of DAT inhibition is rapid enough, which it rarely is following oral administration. On the other hand, experiments have demonstrated that comparable doses of intravenous methylphenidate are indistinguishable from cocaine even by experienced cocainists. The absolute level of DAT-inhibition - as long as it exceeds a critical point of about 50% - is of little significance to the induction and maintenance of a "rush", as opposed to the rapid rise and absence of decline in synaptic DA. Neither cocaine nor methylphenidate is potent and long-lasting enough to maintain synaptic DA levels at a sufficient level to satisfy the demanding abuser for long after peak levels of DAT-inhibition have been reached and the inevitable decline has begun, leading to binges, where new doses are administered before the effects of the previous ones have dissipated. The danger of such behaviour is not that it produces particularly harmful levels of DA, but other effects, such as hypertension from noradrenaline reuptake inhibition and - in the case of cocaine - possible cardiac arrythmias from interference with sodium channels.
> 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.
> I think dose is important because any stimulant will put dose dependant demands on brain cells.
>So will many other substances as well - regardless of whether they are classified as stimulants or otherwise. The demands a substance puts on the brain (and body in general) depends on its properties, which determine how it interacts with the organism and therefore its potential to produce beneficial or detrimental effects. Amphetamines are capable of producing some neneficial effects in many cases where the other stimulants are not, but they are likewise capable of causing certain adverse consequences that the other stimulants cannot.
The references that I promised you 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/3185100Brain 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/2461246Brain Res. 1990 Apr 16;513(2):274-9.
Dopamine uptake inhibitors block long-term neurotoxic effects of methamphetamine upon dopaminergic neurons.
http://www.ncbi.nlm.nih.gov/pubmed/2140952Brain 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/1975218Neurosci 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/8327196J 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/8095976Brain Res. 1993 Jul 9;616(1-2):263-72.
Cocaine neurotoxicity and altered neuropeptide Y immunoreactivity in the rat hippocampus; a silver degeneration and immunocytochemical study.
http://www.ncbi.nlm.nih.gov/pubmed/8358618J 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/8158268J 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/7996441Brain Res. 1995 Apr 24;677(2):345-7.
Methamphetamine-induced serotonin neurotoxicity is mediated by superoxide radicals.
http://www.ncbi.nlm.nih.gov/pubmed/7552263J 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/9694971Brain 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/10433983Neurology. 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/10746608J 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/11861820J 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/12604695Synapse. 2003 Aug;49(2):89-96.
Neurotoxic methamphetamine regimen severely impairs recognition memory in rats.
http://www.ncbi.nlm.nih.gov/pubmed/12740864Psychopharmacology (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/16518646J 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/17683483Synapse. 2008 Feb;62(2):91-100.
Persistent cognitive and dopamine transporter deficits in abstinent methamphetamine users.
http://www.ncbi.nlm.nih.gov/pubmed/17992686
poster:undopaminergic
thread:833007
URL: http://www.dr-bob.org/babble/20080606/msgs/833991.html