Component 6: Psychostimulant reward and sensitization
Tamara J. Phillips, Ph.D., Principal Investigator
John K. Belknap, Ph.D., Chris Cunningham, Ph.D., Suzanne H. Mitchell, Ph.D., and Robert J. Hitzemann, Ph.D., Co-Investigators
Lay-language summary
This component uses a technique called selective breeding to study the biological mechanisms and genes that influence methamphetamine addiction. Mice are used in this research to model certain aspects of addiction found in humans. Because drug addiction is uniquely human, it cannot be completely modeled in animals. However, important features can be modeled, such as the amount of drug an individual will self-administer, or changes in sensitivity to the drug.
To identify mice that voluntarily self-administer high levels of methamphetamine, and conversely, those that avoid methamphetamine, researchers offered the mice the opportunity to drink a methamphetamine solution offered alongside plain tap water. Like humans, some mice will consume more methamphetamine than others. Mice that drank a lot were then bred to each other, and those that did not drink much were interbred.
When their offspring were tested for methamphetamine drinking, the offspring of the high- drinking parents consumed more methamphetamine than the offspring of low-drinking parents. This demonstrates that there are genes that influence methamphetamine drinking levels.
Now, after a few more generations of this selective breeding, we have two groups of mice with different levels of methamphetamine-drinking behavior that we are testing using other measures that tell us how much they like or dislike methamphetamine. We will also use gene-mapping and gene-expression techniques to see how the groups of mice differ genetically -- that is, to determine which genes have an influence on traits related to methamphetamine addiction.
We have followed the same selective breeding process to create mice that show high behavioral sensitization to methamphetamine. Sensitization is a measure that tells us how much the brain has changed in response to repeated methamphetamine exposure. A high level of sensitization may predict a higher probability that a person trying to abstain from taking methamphetamine will relapse compared to someone with a lower level of sensitization.
In mice, behavioral sensitization can be easily measured by examining how active they are when they receive their first exposure to methamphetamine and then after they receive additional exposures. Sensitization can be seen even after only one previous exposure, and can last for a year or longer, suggesting that some of the changes in the brain induced by methamphetamine may be relatively permanent. We have successfully bred a high- and a low-sensitization line, and they are being tested for methamphetamine drinking and being studied for genetic differences.
In conjunction with the other MARC components, we are also investigating whether the selected line mice differ in other important traits. For example, they are being studied for level of impulsivity; humans with methamphetamine and other drug problems have been shown to behave more impulsively than people that do not display excessive drug use. Both sets of lines are also being exhaustively evaluated for specific changes in the brain with regard to chemicals and brain proteins known to play a role in the effects of methamphetamine. This work is being done cooperatively with other components of the MARC.
Scientific abstract
Psychostimulant drugs like methamphetamine are addictive, and addicts have a high chance of relapsing even after prolonged periods of abstinence. Contributing to this, we think, are behavioral and neurochemical changes that evolve when methamphetamine exposure becomes chronic, and that change how an addict responds to methamphetamine after a period of abstinence.
A key hypothesis in this research component is that the many changes in the brain that are associated with addiction are coordinated in ways that are difficult to identify by studying each one independently. We hope, in conjunction with other research going on in the MARC, to integrate the information and identify important gene complexes and brain circuits that influence methamphetamine addiction and relapse.
To accomplish the specific research goals of this component, we will use mice that are selectively bred by the Animal Core (Component 3) for extreme responses to methamphetamine.
There will be a high methamphetmine-drinking line and a low methamphetamine-drinking line. There will also be lines that show large and small changes in response to methamphetamine, when the drug is administered several times over a several-day period. Larger changes in response (called sensitization) are thought to reflect larger changes in the brain circuitry that controls this methamphetamine response.
In Specific Aim 1, we will first examine whether some common genetic mechanisms influence methamphetamine sensitization and drinking. If the lines bred for high and low drinking also show a difference in the amount of sensitization they develop, this would suggest that some common genetic mechanisms are involved. A similar conclusion would be reached if the high- and low-sensitization lines drink different amounts of methamphetamine.
We will also use an operant methamphetamine self-administration model developed for Research Component 5 to see if our high- and low-methamphetamine drinking lines will also self-administrater different amounts of methamphetamine when it is directly infused into the brain.
In Specific Aim 2, we will examine the entire genome to identify positions on chromosomes that indicate where the genes are that influence the high and low responses of the selected lines. This approach is called gene mapping. We will also analyze the data in such a way that we can identify important interactions between genes, and therefore shed light on the genetic interplay that likely influences these complex traits.
In Specific Aim 3, we will use a technique called microarray analysis to examine gene expression patterns in brain tissue from specific parts of the brains from the selected mouse lines. This analysis will allow us to examine the expression of thousands of genes. This will yield a global picture of gene expression differences associated with our observed differences in drug sensitivity. By combining the gene expression results with the gene mapping results, we can identify genes that are most likely to be involved in methamphetamine drinking and sensitization. Component 5 and Component 7 will help us identify the most promising brain areas for the gene expression analyses.
Finally, Specific Aim 4 will look at other traits that may be influenced by some of the same genes we identify for methamphetamine drinking and sensitization.
We are particularly interested in sensitivity to stress and how it might lead to relapse to drug use. We are also interested in how impulsivity might be related to methamphetamine drinking and sensitization.
Finally, some of our research in collaboration with Component 5 will be focused on identifying specific neurochemical mechanisms that influence responses to methamphetamine.
We are very excited about the possibility of translating our findings into clinically-relevant investigations. The genetic and neurochemical findings from our preclinical investigations will be handed over to the MARC’s clinical components for follow-up.
What we learn here about the genetic regulation of methamphetamine responses and about the related neurochemical pathways may, in coordination with the other MARC projects, suggest new targets for novel methamphetamine addiction treatments.
> 2008 progress report summary
> Component 6 publications
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