Rats are the smart choice: Rationale for a renewed focus on rats in behavioral genetics

• Rat models have been used for decades to study physiology and behavior.
• Superior genetic techniques (i.e., knockout technology) caused a shift toward mice.
• Tools for forward genetics are readily available in rats (HS, commercial outbreds).
• Tools for reverse genetics are now quite good (ZFN, TALENs).
• Rats can now be used for quantitative genetic studies of sophisticated behaviors.

Due in part to their rich behavioral repertoire rats have been widely used in behavioral studies of drug abuse-related traits for decades. However, the mouse became the model of choice for researchers exploring the genetic underpinnings of addiction after the first mouse study was published demonstrating the capability of engineering the mouse genome through embryonic stem cell technology. The sequencing of the mouse genome and more recent re-sequencing of numerous inbred mouse strains have further cemented the status of mice as the premier mammalian organism for genetic studies. As a result, many of the behavioral paradigms initially developed and optimized for rats have been adapted to mice. However, numerous complex and interesting drug abuse-related behaviors that can be studied in rats are very difficult or impossible to adapt for use in mice, impeding the genetic dissection of those traits. Now, technological advances have removed many of the historical limitations of genetic studies in rats. For instance, the rat genome has been sequenced and many inbred rat strains are now being re-sequenced and outbred rat stocks are being used to fine-map QTLs. In addition, it is now possible to create “knockout” rats using zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs) and related techniques. Thus, rats can now be used to perform quantitative genetic studies of sophisticated behaviors that have been difficult or impossible to study in mice.This article is part of a Special Issue entitled ‘NIDA 40th Anniversary Issue’.