Joseph Linzey and Dr. Scott Steffensen, Neuroscience

Research concerning whether or not D2 receptors can be used as an accurate biomarker for drug addiction is still currently underway. Unfortunately, this semester I was unable to engage in research nearly as much as I had planned. I spent a lot of time this semester interviewing at medical schools. The majority of my time at BYU was spent catching up on work and material covered in lectures I missed while I was interviewing. However, the interview session is nearly complete (with wonderful results) and I will be devoting a substantial amount of time this coming semester towards completing this project. The final research will hopefully be incorporated into a paper that Dr. Steffensen is working to publish in the near future and it will make up the content of my Honors Thesis.

However, even with the delays that occurred as a result of my interviews, we had substantial discoveries with additional prospects for the future. The lab has shown previously that GABA neurons in the ventral tegmental area (VTA), which regulate the activity of dopamine (DA) neurons, are activated by DA via D2 receptors and that D2 receptors are down-regulated in VTA GABA neurons during withdrawal from chronic ethanol. We have also shown that D2 receptor expression in the VTA is enhanced by eticlopride (chemical that markedly enhances DA release) and reduced by ethanol. Figure 1 shows that D2 receptor expression in the VTA after administration of eticlopride and ethanol causes a rapid adaptation of the D2 receptors in the brain.

This finding, in conjunction with the confirmation that D2 receptors can be found on leukocytes, as shown by Figure 2, sets the premise for the continued work we will pursue. Interestingly, previous research has shown that D2 receptors were primarily found on lymphocytes. However, our research to this point has found that most D2 receptors are found on activated monocytes. We have also evaluated the expression of D2 receptors in WBCs and found that ~13% of WBCs express D2 receptors.

As I said at the beginning, we are continuing to research the possibilities of examining D2 receptor concentration on blood leukocytes. In order to finish the research, we have a number of experiments that are going to be conducted throughout the course of this upcoming semester. We will be using rats throughout the course of these studies. Our aim for this series of experiments is to determine that blood D2 receptors can be used as an accurate biomarker for DA level changes in the mesolimbic DA system in reference to acute ethanol exposure. Our first experiment will consist of examining the effect of acute exposure to eticlopride and ethanol by examining the DA release in the nucleus accumbens (NAc) and D2 receptor expression in white blood cells (WBCs) sampled every 15 minutes for 2-4 hours. This will all be done in vivo. This will allow us to determine if the level of DA in the brain corresponds to the adapted D2 receptor concentrations on WBCs. The next experiment will be a control experiment for direct effects on WBC D2 receptors. We will examine acute eticlopride and ethanol exposure in relation to D2 receptor expression in vitro. This experiment will show whether or not the brain is involved with the regulation of D2 receptors on WBCs. For example, if there is a change in vitro, we know that the brain is not involved with the regulation of D2 receptors. On the other hand, if changes do occur, we know that the brain must be sending a signal to the WBCs to regulate the concentration of D2 receptors on their surfaces. The third experiment will consist of examining acute eticlopride and ethanol effects on D2 receptor expression in the VTA, NAc, and PFC after 1 and 2 hours. This last experiment would provide even more solid evidence that the activity in the brain mirrors what is occurring in the peripheral blood. As a result, we could use peripheral blood samples as an effective biomarker for drug addiction and DA levels in the brain.

I want to sincerely thank those who have generously donated so that I could work on this project. It truly has the potential to make a major difference in the treatment of addiction in the future. In addition, once this methodology has been perfected, it will be a logical result of this research to eventually extend these results into efforts to more effectively diagnose and treat many diseases including Parkinson’s disease, depression, and schizophrenia. This research has opened my eyes to how much I enjoy research. I plan on building on the foundation of basic science research skills I have developed in medical school and through my career as a physician.