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Re: Question nr. 2!

Posted by linkadge on June 6, 2008, at 11:18:16

In reply to Re: Question nr. 2!, posted by undopaminergic on June 6, 2008, at 9:25:17

>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. I havn't heard about what you are suggesting, but glutamatergic neurotoxicity is still a concern. Cocaine and ritalin also downregulate bcl-2 (among other antiapoptotic enzymes) in certain neural strucutres. These changes are generally dose dependant however.

>In fact, the DAT-inhibitors protect against the >toxic effects of high doses of amphetamines. >High doses of DAT-inhibitors have the opposite >effects of amphetamines in several respects - >for instance, they produce increases in >intracellular (vesicular) dopamine content, >whereas amphetamines produce a depletion - >including non-neurotoxic depletions at >therapeutic doses, and this is one of the >mechanisms underlying tolerance.

You can still obviously grow tollerant to methylphenidate or cocaine. The studies you are referring to are generally discussing the short term ability of ritalin to prevent some of the monoamine disturbances of high doses of amphetamines. Ritalin and cocaine do enhance the release of monoamines as well as block their reuptake. Longer term use of higher doses may also lead to monoamine depletion. Cocaine and ritalin also lead to dopamine transporter upregulation in certain limbic regions with long term us. 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.

Ritalin is also shows genotoxic potential. The long term effects of this are currenly not well established.

>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.

>It's also possible that they might >promote >certain types of neurotoxicity - but they are >not capable of causing some of the types of >damage seen with amphetamines.

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.

With cocaine abuse you still see things like cellular atrophy, loss of cortical grey matter, glial pathologies etc which are shared in meth abuse.

I think dose is important because any stimulant will put dose dependant demands on brain cells.





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