Posted by Shawn. T. on August 24, 2004, at 22:44:13
In reply to Re: is Ritalin neurotoxic? » Shawn. T., posted by Dave001 on August 24, 2004, at 17:29:02
I apologize; I thought that I had included an article by Jones et al. (2000) in that list of abstracts (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10820189). They found that nomifensene, a dopamine reuptake inhibitor, prevented dopamine- induced apoptosis in 60-70% of PC12 cells. The cells were incubated with a relatively large (300 microM) amount of dopamine; I speculate that nomifensene would have prevented apoptosis in a larger percentage of cells if a lower concentration of dopamine had been added to the medium. The assumption is that most of the dopamine added would enter the cell via the dopamine transporter; if nomifensene had not protected a majority of the cells from apoptosis, then we could have assumed that extracellular dopamine was playing the more important role.
I should have said that dopamine- induced neurotoxicity is primarily a result of processes involving free intracellular dopamine. The oxidation of dopamine could be the primary causal factor in some but not all cases of dopamine- induced neurotoxicity. For example, Rochet et. al (2004) recently found that a reaction between dopamine and alpha-synuclein could play a key role in the degeneration of dopamine neurons in Parkinson's disease (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15126689). Peter Jenner (2003) has argued that it is not possible to separate the roles of oxidative stress and other events involved in dopaminergic cell death (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12666096). However, I assume that in the future, more will be known about the possible sequences of events that can lead to dopamine- induced neurotoxicity.
Johnson-Davis et al. (2004) found that methamphetamine pretreatment attenuates the decrease in function of the vesicular monoamine transporter-2 (VMAT-2) as well as the persistent dopamine deficits that are induced by the drug (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14747615). Guilarte et al. (2003) have suggested that "Brain regions exhibiting DAT and 5-HTT deficits that co-localize with decreased VMAT-2 levels and glial cell activation may represent monoaminergic terminal degeneration" (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14614914). If tolerance to the effects of methamphetamine on VMAT-2 actually does reduce the neurotoxic effects of the drug, then the addition of a drug that can further decrease VMAT-2 activity would be expected to increase toxicity. Reserpine is a vesicular monoamine transporter inhibitor, so the two articles that you cited add further support to the hypothesis that VMAT-2 inhibition is involved in methamphetamine- induced neurotoxicity. Resperine prevents the transfer of monoamines into storage vesicles; this inhibits the exocytotic release of dopamine, but it does not deplete intracellular dopamine. See Mosharov et al. (2003) for a discussion of the effects of reserpine on cytosolic levels of catecholamines and catechols in cultured chromaffin cells (http://www.jneurosci.org/cgi/content/full/23/13/5835).
Thanks for pointing out the misstatement.
Shawn
poster:Shawn. T.
thread:380741
URL: http://www.dr-bob.org/babble/20040821/msgs/381967.html