Drug-Resistant Zebrafish Provide Clues to Drug Addiction
"Addictive drugs all trigger a sequence of widespread long-lasting consequences on brain physiology, most of which are only partially understood. Because a major step in the development of addiction is the switch from drug use to drug abuse, we aimed to gain insight into the mechanisms triggering the initiation of addictive behavior,” Webb said.
The researchers used the mutagenic chemical ENU to generate hundreds of mutant zebrafish. From these, they bred a line of fish that appeared to be normal but did not respond to amphetamine administration (despite the presence of the drug in the fish’s brain). Because amphetamine is usually experienced as pleasurable, amphetamine response was determined by measuring whether fish chose to move to a half of the tank where the drug had been administered.
By comparing these drug-proof mutants to fish with a normal response, Webb and her colleagues discovered a set of 139 genes that respond inappropriately to amphetamine in mutants, without being altered under normal conditions in either genotype. In addition to genes involved in pathways classically associated with reward, this gene set shows a striking enrichment in transcription factors that are specifically known for their involvement in brain development.
Several of these genes are expressed in neurogenic domains of the adult fish brain, where neurons are generated from neural stem cells during adulthood. “These factors, which are also dramatically down-regulated by amphetamine, can serve as valuable new entry points into studying the link between adult neurogenesis and addiction,” the researchers note.
They conclude that these results identify a new network of coordinated gene regulation that influences the response to amphetamine and may underlie the susceptibility to addiction.