Use of SPECT and Perfusion fMRI to Examine the Role of DAT Genotype in Motivated Smoking Behavior

Lay Summary

Combined imaging and genetics studies may lead to genetically tailored aids to prevent smoking relapse

Researchers will use a newly developed SPECT imaging technique to explore whether a specific genetic factor helps to explain why some people have an especially hard time quitting smoking.

Annually, about 40 percent of the nation’s 36 million smokers try to quit. Only about seven percent of these succeed. Smoking cues play a major role in failure. Smoking cues –people, places, events—that have been repeatedly associated with smoking—powerfully promote relapse. Previously, the investigators found that craving elicited by smoking cues is associated with activation of areas involved in the brain’s “reward” responses. The neural networks in these regions use the chemical messenger dopamine to communicate. Nicotine cues elicit dopamine release. After neuron #1 releases dopamine into the synapse—the junction between two cells—it briefly attaches to a receptor on neighboring neuron #2. Then neuron #2 releases the dopamine back into the synaptic space, where it is transported back to neuron #1 by a molecule called a “dopamine transporter.” While MRI imaging showed increased brain activity in participants exposed to smoking cues, they found variability in the degree of response among participants. The investigators surmised that the levels of dopamine remaining in the synapse, available to excite the neurons, might account for the variation in brain activation and craving levels.

Since the tendency to smoke is highly heritable, the investigators concluded that genetic factors may explain this variability. They undertook genetic studies of participants, and found that those with higher brain activation and craving levels tended to have one form of the gene that regulates the dopamine transporter, compared to participants with the other form of the gene. They hypothesize that this one form of the gene, therefore, produces fewer dopamine transporter molecules; or, these molecules may be less effective in transporting dopamine out of the synapse. Conversely, the other gene may produce more dopamine transporters and therefore confer some protection against smoking cues. They have developed a molecule that binds to and labels the dopamine transporter. Now they will use SPECT imaging to visualize the tagged dopamine transporters and quantify dopamine transporter levels in both genetic groups. The findings are expected to help define how levels of dopamine transporter affect responses to smoking cues, and may establish that high vulnerability to smoking cues is a function of genetic susceptibility.