Zebrafish Gene Expression Study Offers Clues to Drug Addiction

July 31, 2009
By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Genes involved in brain reward processes and adult neuron formation may be involved in drug addiction, according to a zebrafish gene expression study appearing online in Genome Biology today.

Researchers from Germany and the Netherlands used microarrays to compare gene expression in the brains of normal and mutant zebrafish that had or had not been exposed to amphetamine. Following amphetamine exposure, they found 139 transcripts that were differentially expressed between wild type zebrafish and mutant fish that don’t respond to the drug.

“Because a major step in the development of addiction is the switch from drug use to drug abuse,” lead author Katherine Webb, a neurogenetics researcher at the German Research Center for Environmental Health, said in a statement, “we aimed to gain insight into the mechanisms triggering the initiation of addictive behavior.”

Drug addiction affects tens of millions of people in the US, Webb and her team noted, leading to societal problems and significant related expenses. Although past studies suggest addiction involves the brain’s reward pathways, the molecular details of the transition from drug use to addiction for various drugs remain murky.

In an effort to learn more about this process, Webb and her colleagues focused on the process of amphetamine addiction in the zebrafish, a vertebrate model organism. They assessed zebrafish drug response using an assay called the conditioned place preference, in which the fish change their location in a tank as a result of amphetamine use.

By screening through zebrafish that had been exposed to a mutagenizing chemical called N-ethyl-N-nitrosourea, the researchers found a dominant mutation that renders zebrafish indifferent to amphetamine. They then used Agilent microarrays to compare the gene expression profile in this mutant, dubbed “no addiction”, with wild type zebrafish in the presence or absence of amphetamine.

In so doing, they identified 139 differentially expressed genes that appear to correspond to amphetamine action in fish brains. These genes belonged to pathways previously linked to the reward system, including neurotransmitter signaling genes, the authors noted. But they also found genes coding for transcription factors involved in brain development.

While the study did not directly assess amphetamine effects in mammalian brains, the researchers noted that at least 92 of the 139 genes resembled mammalian genes. When the team used quantitative PCR and in situ hybridization to verify their results and test some of the genes more thoroughly, they found that the transcription factor genes they detected tended to get expressed in parts of the zebrafish brain involved in neurogenesis, the formation of new neurons in the adult brain.

Additional experiments verified these genes might work together in a coordinated way to influence how individuals respond and become addicted to drugs such as amphetamines.

“[W]e propose that the re-use of a developmental transcription factor-mediated network accompanies or underlies the behavioral response to amphetamine in the adult brain,” Webb and her co-authors concluded. “Some of these factors … can further serve as valuable new entry points into studying the link between neurogenesis and addiction.”

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