Role of Reactive Oxygen Species on Chronic Methamphetamine- Induced Dopamine Transmission in the Nucleus Accumbens

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Devin Bradshaw and Scott Steffensen, Psychology

Introduction

Methamphetamine is a highly addictive substance with many negative effects on the user. These effects include detriments to physical health such as “…extreme weight loss, severe dental problems (“meth mouth”), and skin sores caused by scratching. Methamphetamine use also raises the risk of contracting infectious diseases like HIV and hepatitis B and C.” (“DrugFacts: Methamphetamine”, 2014). Negative health effects like this come from long term abuse of methamphetamine due to addiction to the substance. Reducing the cause of the addictive behavior (dopamine (DA) overstimulation causing neuronal damage) can help to prevent these negative effects of METH abuse. As the effects of ROS scavengers on DA release are studied we can more fully understand the relationship between METH addiction and ROS and possibly find a way to counteract and even reverse the negative effects of METH use.

Methodology

Chronically Affected Rats
In our experiment rats were addicted chronically to methamphetamine. This was done through a daily administration of the drug to the rats via an intraperitoneal injection. These injections were paired with another drug, TEMPOL, which is a known reactive oxygen species (ROS) scavenger. One group of rats were given TEMPOL chronically with the methamphetamine injections, while the other group received saline injections in place of the TEMPOL. This group served as the control group. After 5 days of injections two days of withdrawal were given and then DA release data was collected on the rats.
Fast Scan Cyclic Voltammetry
Fast scan cyclic voltammetry was used to measure the average differences in DA release between the two different groups of rats. In order to do this an electrode was inserted into the medial forebrain bundle (MFB) which stimulated the brain electrically. Another electrode was inserted into the nucleus accumbens (NAc) to record the DA release in the brain. This is a common pathway indicated in the addiction process for it’s modulatory DA response to drug administration. The levels of DA released were taken before and after one final administration of both TEMPOL (or saline), and methamphetamine. In this way we were able to obtain baseline levels of DA release in each animal so as to compare the percent increase of DA release in their brain. A 1 mg/kg dosage was used for methamphetamine in all trials, and a 25 mg/kg dosage was used for administration of TEMPOL. During the process the rats were anesthetized with isoflurane, and IUCAC procedures were followed as to the care and treatment of the rats.

Results

In rats given chronic TEMPOL injections before the injections of methamphetamine DA release was significantly reduced after injection of methamphetamine on test day. In rats only given saline injections (control) methamphetamine increased DA release by an average of 445.5%, while those rats who were treated with TEMPOL only experienced a DA release percent change of 195.6% on average. This data is with a p value of .308 and was done with n=3 for the saline/methamphetamine rats and n=2 for TEMPOL/methamphetamine rats.

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Discussion

TEMPOL clearly influences the levels of DA released upon electrical stimulation of the MFB in rats chronically addicted to methamphetamine. The drug has the effect to reduce the levels of DA which directly contrasts the effects of methamphetamine. Part of the addiction process with methamphetamine is shown by an increase of DA in this pathway from the MFB to the NAc. In reducing or reversing these effects that methamphetamine has on the brain TEMPOL shows promise to help reduce the effects of addiction.

Conclusion

This study helps us to understand the general model of addiction and the role that dopamine plays in it. We know that DA release in increased in response to addictive substances such as methamphetamine. This indicates that DA dysregulation plays a major role in the addiction process. A drug such as TEMPOL that can inhibit or reduce these particular effects of addiction will allow us to understand just how big of a role the DA release in the NAc plays in the actual process of addiction. Further studies showing the behavioral results of treatment with TEMPOL or other drugs that acts as ROS scavengers will help us to determine if the reversal of these physiological effects can help to reduce or reverse the behavioral effects seen in addiction.

References

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