An international research group led by Vanderbilt University scientists has shown for the first time that a lipid, or fat molecule, can regulate “psychostimulant” behaviors in an animal model by interacting with a brain protein.
The finding, published online June 1 by Nature Chemical Biology, suggests that the lipid, called PIP2, could be the target for drugs to treat conditions as diverse as drug addiction and obesity.
“Fat can influence reward,” said Aurelio Galli, Ph.D., the paper’s co-senior author with Henrich J.G. Matthies, Ph.D., in the Vanderbilt Department of Molecular Physiology & Biophysics. “Fat in neurons (nerve cells) can influence how amphetamine and methamphetamine work.”
The discovery also gives new meaning to the well-worn phrase, “You are what you eat.” There is increasing evidence that the high-fat Western diet, by indirectly affecting the composition of lipids in the brain, can affect behavior, said Vanderbilt endocrinologist Kevin Niswender, M.D., Ph.D.
Niswender, associate professor of Medicine and Molecular Physiology & Biophysics, was not involved in the study but is collaborating with Galli to investigate how dopamine “reward” signaling in the brain may be involved in the risk of obesity as well as addiction.
“There is a tremendous parallel between psychostimulant abuse and obesity,” said Galli, professor of Molecular Physiology & Biophysics and Medicine.
The current study, led by Vanderbilt graduate students and first authors Peter Hamilton and Andrea Belovich, focused on the dopamine transporter (DAT), a protein that plays a key role in the reward pathway.
Embedded in the plasma membrane of certain neurons, DAT is responsible for “re-uptake” of the neurotransmitter dopamine from the synapse, or space between nerve cells. In this way, it regulates the supply of dopamine and dopamine signaling in the brain.
Drugs like amphetamines, however, can cause DAT to release dopamine. This dopamine “efflux” can over-excite the brain’s reward circuitry, and can lead to addiction. Vanderbilt scientists and others have found that lipids in the membrane regulate this efflux process offering a novel pharmacological target for amphetamine abuse.
In the current study, the researchers generated a fruit fly model in which the human DAT was molecularly modified to alter its interaction with PIP2.
Modifying the DAT-PIP2 interaction prevented amphetamine from causing dopamine efflux, but did not affect dopamine reuptake or normal transporter function.
Most significantly, the researchers showed that “locomotive behaviors” induced by exposure to amphetamine were “significantly reduced” in these modified flies. “These data demonstrate for the first time the behavioral importance of the interaction of PIP2 with a plasma membrane protein,” they reported.
“The brilliance of this work is how they molecularly defined this mechanism,” Niswender said.
There’s probably a genetic susceptibility to modified DAT-PIP2 interaction, he added, but the environment, including diet, may change the composition of lipids inside the cell, which then can alter how this molecular mechanism works.
Researchers from Weill Cornell Medical College and Columbia University in New York City and the Medical University of Vienna in Austria contributed to the study. The research was supported in part by National Institutes of Health grants DA035535, DA035263 and DA012408.
