Adam Bevan and Dr. Scott Steffensen, Psychology
Alcoholism is a problem that affects almost the whole world. The purpose of our proposed study was to record neuronal activity of the ventral tegmental area (VTA) of male Wistar rats during self-administration of sucrose, which is a natural reward for rats. Although sucrose administration seems far from alcoholism, our goal was to see how these neurons act in during a behavior known to be pleasurable since past literature suggested that rats would not self-administer ethanol to dependence. Our research did take a turn, however, and we developed a system where we saw rats self-administer ethanol intravenously. We decided to stay with ethanol self-administration as long as we could to get direct information about the brain’s reward pathway activity during ethanol self-administration. We found data that suggests that VTA γ-aminobutyric acid (GABA) neurons are involved in anticipation of reward from self-administration of ethanol.
The overall objective of Dr. Steffensen’s lab is to continue and extend the evaluation of the role of mesocorticolimbic (major reward pathway) GABA neurons in mediating the intoxicating and rewarding properties of ethanol. The core thesis underlying this project is that adaptive changes in VTA GABA neuron excitability and electrical coupling result from repeated exposure ethanol and contribute to the dysregulation of mesolimbic homeostasis that accompanies ethanol reward. We implanted all our subjects with femoral-vein catheters and some with chronic VTA recording electrodes. The subjects were allowed to recover for a period of 8-10 days before their first exposure to the ethanol chambers. The chambers used are equipped with both an active nosepoke hole and an inactive (sham) nosepoke hole. The system responded to active pokes by delivering a dose (.10-.15 g/Kg/poke) of ethanol via the femoral catheter. Behavioral data was based on responses to the active nosepoke vs. the inactive nosepoke. Those with recording electrodes were also subject to firing rate analysis from 10 seconds before the nosepoke event to 10 seconds after the event. The neuronal data collected was averaged over the entire session.
Our main difficulty was getting the recording electrodes to last through the recovery and training periods to record activity when subjects experienced addiction. Signs of addiction were usually seen about 30 days post surgery. The electrodes are extremely sensitive and would often give poor quality signals by that time. Another difficulty was getting the catheters to stay patent long enough for the subjects to learn the behavior. We found that using polyurethane tubing helped to reduce clots in the catheter. Also, we changed our schedule from one-hour sessions once a day to half-hour sessions twice daily. This increased attention given to catheters and also enabled us to observe the behavior of the subjects 6-8 hours after the morning dose of ethanol. We expected to see more signs of withdrawal/dependence before the afternoon session, but we found that the subjects wouldn’t poke for ethanol enough to reach such symptoms until about 60 days post surgery. Few rats were observed for this long of a period.
Despite these difficulties, we obtained some very good data from a few subjects. We did find that VTA GABA neuron activity would increase about 4 seconds prior to the active nosepoke event (see Fig. 1). We have also seen that rats will alter their activity to make up for changes in dose given (i.e. if less alcohol is given, rats will poke more to make up for the difference). This is a recent finding, and it is based on only a few subjects with large variance. More trials are required to really see if this is true.
We have not yet published our findings, as the number of successful trials is rather small. We are continuing to implant subjects with electrodes, trying to make secure them better so they can last long enough to get clear, reliable neuronal data after addiction. We are starting to record neurons from the first naïve trial through addiction, and we hope to find a significant difference between naïve trials and trials after rats have learned the connection between poking the correct hole and receiving ethanol (i.e. exploration vs. anticipation of reward). We plan on publishing our findings in Alcoholism: Clinical and Experimental Research or a similar journal by summer 2005.