An important focus of our laboratory is the elucidation of long term effects of drugs in the brain. We previously showed that repeated administration of cocaine followed by withdrawal for at least 10 days resulted in a downward regulation of the dopamine transporter protein. In a recent study, we sought to determine, as the previous work showed this down regulation occurred in the nucleus accumbens, whether or not the down regulation occurred in the shell or in the core of the nucleus accumbens. After preparing animals in the same way as previously described, we showed that the decrease occurred in the shell of this nucleus. This is not surprising as this is the limbic pathway and is the one associated mainly with reward and reinforcement. Another important issue in the field of addiction is the effect of rate of entry of drugs into the brain and its influence on abuse liability of these drugs. Intuitively, it seems obvious that drugs that enter the brain rapidly would be the most rewarding and reinforcing. Accordingly, we have developed a method, using in vivo receptor binding competition, that allows a calculation of the rate of entry of a substance into brain, but not only the rate of entry but also its occupancy of the transporter or receptor site. By using this method, we show that cocaine enters the brain quite rapidly as do some other compounds. However, interestingly, all of the RTI compounds enter the brain somewhat more slowly than cocaine, with quite a bit of variation. Some of the compounds do not occupy significant numbers of receptors for at least 15 minutes after intravenous injection. These results show that RTI compounds, which enter the brain more slowly than cocaine, might be good treatment medications, because a desirable property of treatment medications is that they enter the brain more slowly than cocaine; this would correspondingly reduce the abuse liability of these compounds. Secondly, it provides a mouse model by which rate of entry of drugs and occupancy of receptors can be determined. Furthermore, as it is an in vivo labeling model in the mouse, it certainly could be extended to nonhuman primates and humans utilizing brain imaging. Overall, results continue to be interesting and we continue to develop capabilities to look at additional variables in drugs of abuse and their physiological mechanisms.
