Studies by other researchers had suggested that the proteins produced by the Homer genes might play a role in cocaine addiction. Members of the family were known to be activated by cocaine, and reduction of activity in the genes had been linked to cocaine withdrawal.
So, to unequivocally test the involvement of the Homer genes in cocaine addiction, Kalivas and his colleagues individually knocked out the genes in mutant mice and tested the behavioral and biological effects. In one behavioral test, they placed the knockout mice in one of two linked chambers after cocaine administration. One was a "comfortable" darkened chamber with nesting material, and the other was an "uncomfortable" bare, white, brightly lit chamber. The researchers found that the mice lacking Homer1 or Homer2 genes showed greater preference for the chamber that they associated with receiving cocaine, compared to normal controls. The knockout mice also showed hyperactivity characteristic of withdrawal.
The Homer2 knockout animals also showed a greater motivation to self-administer cocaine by pressing a lever than did normal mice. Also, the knockout animals showed neurochemical changes associated with cocaine addiction, including reduced base levels of the neurotransmitter glutamate in the region of the brain known to be involved in addiction. They also showed increased levels when receiving cocaine. Such brain chemical changes are characteristic of addiction, since glutamate is known to be a key neurochemical in cocaine response.
Finally, the knockout animals could be restored to an essentially normal condition by reintroduction of the Homer2 gene.
The Homer genes appear to be specific for cocaine, found Kalivas and his colleagues. When they tested the effects of heroin or caffeine on the knockout mice, the animals did not respond behaviorally as they did with cocaine.
"While it can be anticipated that additional genetic models may be discovered that mimic or block behaviors associated with cocaine addiction, the striking concordant neurochemical phenotype between Homer2 deletion and withdrawal from chronic cocaine treatment indicates that Homer is a particularly good candidate to play a central role in cocaine addiction," wrote the researchers.
Since the Homer proteins are known to be regulated by cocaine and the proteins are known to rise or fall in response to environmental cues and distress "not only does Homer provide an important window to understand cocaine-induced neuroplasticity and addiction, but also to study the molecular basis of the important link between environmental stress and cocaine addiction," they wrote.
Karen K. Szumlinski, Marlin H. Dehoff, Shin H. Kang, Kelly A. Frys, Kevin D. Lominac, Matthias Klugmann, Jason Rohrer, William Griffin III, Shigenobu Toda, Nicolas P. Champtiaux, Thomas Berry, Jian C. Tu, Stephanie E. Shealy, Matthew J. During, Lawrence D. Middaugh, Paul F. Worley, and Peter W. Kalivas: "Homer Proteins Regulate Sensitivity to Cocaine"
Publishing in Neuron, Volume 43, Number 3, August 5, 2004, pages 401-413.
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