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Penn State Team IDs Expression Changes Linked To Drug Relapse in Rats

NEW YORK (GenomeWeb News) – A team of researchers from Pennsylvania State University has identified dozens of genes whose expression in rat brains changes in concert with drug relapse behavior in heroin-addicted animals.

The team used microarrays and quantitative PCR to evaluate gene expression in rat brains, both for rats exhibiting drug relapse behavior and control rats, focusing on the medial prefrontal cortex of rat brains — a region of the brain believed to govern goal-directed behavior. The research, which appeared online in the journal BMC Neuroscience last night, turned up 66 genes that appear to be involved in heroin relapse. Among them: genes that are thought to contribute to processes such neuroplasticity and learning.

"As data accumulate, the existence of a single 'relapse gene' is looking increasingly unlikely," lead author Kara Kuntz-Melcavage, a pharmacology researcher at Pennsylvania State University, said in a statement, "it is likely to be a constellation of different genes. Therefore, large scale views of gene expression, like this one, will prove very useful for guiding research into human drug-associated behavior."

The biological changes associated with drug exposure can provide clues about drug addiction, Kuntz-Melcavage explained. But, she added, understanding physiological changes associated with drug relapse is also important.

"Physiological and gene expression changes that may increase an individual's likelihood to relapse are known to exist well into a period of abstinence," the authors wrote. "Therefore, relapse to drug use is currently being investigated on both the molecular and behavioral levels."

To investigate drug-relapse in rats, the team rigged up self-administration chambers in which rats received an intravenous dose of heroin into their jugular whenever they licked a spout. Meanwhile, rats in the control group received an intravenous saline solution whenever their matched rat got a heroin dose.

After providing rats with this self-administered heroin or saline three hours a day for two weeks, the researchers removed the drug for up to two weeks and then put the rats back in the self-administration chamber for an hour and a half.

"The session with the inactive spout served not only to provide an opportunity to observe drug-seeking behavior, but also mimicked a real-life situation in which environmental cues precipitate relapse behavior following an extended period of abstinence," Kuntz-Melcavage said in a statement.

As expected, the rats that had been exposed to heroin previously showed greater goal-oriented behavior in the self-administration chamber than the control rats, even though heroin was no longer available.

When the researchers sacrificed the rats and compared gene expression patterns in the medial prefrontal cortex of rat brains using Agilent 4x44 rat whole genome microarrays, they found 66 genes whose expression was up or down-regulated at least 1.4 times in the drug-relapsed rats compared with control rats.

The team then verified their results using quantitative real-time PCR, identifying six genes — bdnf, calb1, dusp5, dusp6, npy, and rgs2 — whose expression was significantly altered in both microarray and RT qPCR experiments.

Based on their ontological analyses, the researchers concluded that drug relapse behavior in rats is linked to expression changes in many gene pathways, including some involved in intracellular signaling, neuroplasticity, learning, and behavior.

"This study provides the first report of whole genome analysis of [medial prefrontal cortex] gene expression in rats that have expressed behavioral incubation and expands our knowledge of gene expression changes that exist after abstinence and during the time of relapse liability," the researchers wrote. "This study has produced data that are relevant not only for future studies involving heroin, but also for understanding the molecular underpinnings of incubation of drug-seeking."

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