#dopaminergic system

[csmsdust]

[tymkrs]

Ritalin and Dopaminergic System Part 4

Following article courtesy of @lmcomie:

http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0033693&representation=PDF

Sadasivan, S., Pond, B.B., Pani, A.K., Qu, C., Jiao, Y., & Smeyne R.J. (2012) Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice. PLOSONE, 7(3).

The wording keeps getting more and more jargony! Please be sure to check out parts 1, 2, and 3! 

Alterations in Gene Expression following Acute and Chronic MPH Exposure in SN:

They wanted to see whether there were any changes to gene expression and see what the genes were for.  They found that expression of 115 genes had changed between saline and the 1mg/kg Ritalin dose and expression of 54 genes had changed between saline and the 10mg/kg Ritalin dose.  Of these genes, 23 were expressing differently between the lower and higher Ritalin dose.

Since the larger changes in neuronal number and microglia (cells involved in fixing the brain after traumatic brain injury) occurred with the higher dose, they wanted to look at the gene expression in mice with only this dose.  They looked at specific genes associated with basal ganglia toxicity (note: the basal ganglia consists of structures involved in control of voluntary motor movements, procedural learning, routine behaviors or "habits", eye movements, cognition and emotion) including:

brain derived neurotropic factor (bdnf): support survival of neurons and growth of new ones

glial derived neurotopic factor (gdnf): promotes survival and differentiation of dopaminergic neurons

tyrosine hydroyxlase (th): creates precursors of dopamine (L-DOPA specifically)

dopamine transporter DAT1 (slc6a3): recycles dopamine

vesicular monoamine transporter VMAT2 (slc18a2): membrane protein that transports neuropeptides like dopamine

They found significant decreases in mRNA expression in gdnf, th, slc6a3, and slc18a2 after both acute and chronic administration of 10 mg/kg Ritalin while bdnf was only reduced after chronic 10 mg/kg Ritalin. 

Note - mRNA turns into proteins.  It's like a template that proteins get copied off of.  If there's less mRNA, there're fewer proteins that it's making.

Again, I think it would have been much more interesting had they also included the 1mg/kg dose and those results, even if they were no different than the saline mice.

Evidence for inflammation associated with acute doses of MPH:

They also wanted to see if since there was an increase in activated microglia following the higher dose of Ritalin, they wanted to see whether inflammatory genes had changed expression as well.  Specifically:

il-6: signaling protein that is usually activated in burn/tissue damage traumas

tnf-alpha: regulates immune cells by inducing fever or even cell death

cox-2: causes fevers in response to immune system attack

il1b: involved in cell proliferation, cell differentiation and cell death

They found that there were significant increases in mRNA expression of tnf-alpha and il-6 in those given a single dose of 10mg/kg MPH as compared to saline-injected mice.

And these were the results!  Tomorrow we'll start on the discussion section - which is usually where the researchers talk about why they think they saw what they saw.

@atdiy/@tymkrs  

[tymkrs]

Ritalin and Dopaminergic System Part 3

Still reading through the following article courtesy of @lmcomie:

http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0033693&representation=PDF

Sadasivan, S., Pond, B.B., Pani, A.K., Qu, C., Jiao, Y., & Smeyne R.J. (2012) Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice. PLOSONE, 7(3).

There are more results! Chronic MPH exposure sensitizes the SNpc to MPTP effects:

So since the higher dose of Ritalin (given over 90 days) lowered the dopaminergic neuron number in the substantia nigra, they wanted to see whether it also increased the sensitivity of the neurons to a parkinsonian agent MPTP.  That is, would giving MPTP after Ritalin cause the brain to be more likely to be in a state of stress and would there be additional dopaminergic neuronal death.

Reminders: Substantia nigra is a region of the brain involved in reward, addiction, and decreased neuron levels in this area lead to Parkinson's.

MPTP is a neurotoxin precursor to MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra.

It's interesting to note that normally these type of mice are not affected by MPTP and do not lose any neurons as a result of receiving this agent.  SO, whichever ones ARE lost, are because of the presence of Ritalin.

So what they found was that giving 1mg/kg or 10mg/kg of Ritalin DID make the neurons more sensitive to MPTP.  That is, where previously they would not have been damaged, they were now.  And MPTP was able to induce a 20% increase in cell death in mice that had RItalin.

They also looked to see how the microglia (cells involved in cleaning/fixing up after a brain injury) reacted to Ritalin and MPTP.  Since only an increase in activated microglia was seen in mice with the higher dose, they only gave this group MPTP (I think they should have given it with the 1mg/kg group as well).  And found that those given 10mg/kg Ritalin + MPTP showed a decrease in the number of resting microglia and a rise in the number of activated microglia.

Note that the increase in dopaminergic neuron loss was not large enough to result in the onset of parkinsonism, but certainly is a factor that should be considered in neurodegenerative disorders that involved the dopaminergic system.

@atdiy/@tymkrs

[tymkrs]

Ritalin + Dopaminergic System Part 1

Local buddy (though not for long) @lmcomie linked to an interesting article yesterday regarding Ritalin exposure and its effects on the basal ganglial system in mouse models.  So I thought I'd break down the article, and see what all it was saying, but maybe from a more reader-friendly perspective. Here's the citation and location of the article:

http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0033693&representation=PDF

Sadasivan, S., Pond, B.B., Pani, A.K., Qu, C., Jiao, Y., & Smeyne R.J. (2012) Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice. PLOSONE, 7(3). 

Introduction:

Ritalin has been prescribed for the management of ADHD and narcolepsy.  It's been shown to be addictive and an increasing number of adults/college students are using it for "cognitive enhancement".  A number of students feel Ritalin helps them "super-concentrate" so they are using it without regards for why it was brought on the market in the first place.

Previous studies have shown that in both ADHD and non-ADHD populations, Ritalin has been shown to increase scores on tests as well as increase working memory, and people have asked for it to become an over-the-counter drug.  But few studies have been published demonstrating the long-term consequences of using Ritalin.

Ritalin is a stimulant that blocks the dopamine transporter and norepinephrine transporter - much like cocaine.  

Note: Transporters are involved in the recycling of signaling neuropeptides.  So when your body signals that dopamine needs to be released, the neurons release them into the gap between neurons known as the synapse.  When they're done sending the message to the next neuron, transporters vacuum the dopamine back up (or any other neuropeptide), and save them for another day.  So by blocking the dopamine and norepi transporters, you end up with dopamine and norepi staying longer in those synapses, and therefore they act longer on the recipient neurons.

So Ritalin usage leads to an increase in dopamine levels but, be warned, excess levels of dopamine are toxic as it produces superoxide, hydrogen peroxide, and dopamine quinone.  

Those are some of the same items that your white blood cells use to kill invading microorganisms.  Great when they're being controlled by your white blood cells, toxic otherwise.  

Free ranging dopamine has also been shown to cause inflammation to occur in the brain which is shown by an increase in cytokines and chemokines - cell signaling proteins that say "Hey! Brain inflammation going on, take care of it!"  

Microgliosis is one of the processes induced by the increase in these signaling proteins and usually occurs when a person has a brain injury.  It involves microglial cells coming to the site of the injury, getting rid of any germs, getting rid of any dead/damaged neurons, and encourage growth of new neurons.  But, overactivation of the microglial cells leads to production of a number of toxic substances as well as inflammatory factors.

So, this study looks at whether long-term Ritalin usage in mice at 2 doses induces changes in the basal ganglia.  Per wiki, the basal ganglia consists of regions involved in control of voluntary motor movements, procedural learning, routine behaviors, eye movements, cognition, and emotion.  Interesting to note is that the dosages used in the mice - 1mg/kg and 10mg/kg - reflect the prescribed dosages that humans would receive for ADHD and recreational use/narcolepsy (respectively).

That is, 1mg/kg = ADHD and 10mg/kg = Narcoplepsy/Recreational 

They looked to see if short term or long term Ritalin changed dopamine neuron numbers and dopamine levels in the substantia nigra portion of the brain.  And since excessive dopamine has been shown to induce inflammation (as mentioned above), they looked to see if after Ritalin, neurons would be more sensitive to a drug MPTP that has been shown to cause neuron damage.

Note: substantia nigra is a portion of the brain that plays a role in reward, addiction, and movement.  Loss of dopaminergic neurons in this area leads to Parkinson's Disease.

Results tomorrow!

@atdiy/@tymkrs