The long-term goal of this project is to assess functional changes in the brain that are associated with the transition from controlled to compulsive patterns of cocaine-use. Animal models used to study neuronal mechanisms of drug addiction most commonly rely upon drug-administration protocols that result in a stable pattern of drug-taking. In order to fully understand the transition to addiction in humans; a model that mimics more closely the condition of cocaine use in human addicts (i.e., in which animals show an escalating pattern of self-administration), is needed. Using such a model, we found that animals given short access to cocaine developed a controlled pattern of drug self-administration, and showed a sensitized c-Fos and locomotor response to the drug. However, when such animals were later given longer access to cocaine, they transitioned to escalating patterns of drug use and lost the sensitized c-Fos and locomotor responses to the drug. Functional changes of the dopaminergic pathway have been suggested to underlie the changes associated with chronic psychostimulant administration. Therefore, in order to further explore the neurological mechanisms that underlie the differential c-Fos and locomotor responses in animals following short vs. long access to cocaine, functional changes in this pathway will be monitored. More specifically, the technique of quantitative receptor autoradiography will be used to measure levels and coupling of the D1 and D2 dopamine receptors, and the technique of immunohistochemistry will be used to measure levels of CAMP in response to stimulation of the D1 or D2 dopamine receptor, at different time-points after the end of the self-administration protocol. This self-administration protocol includes three groups of animals: one group that will self-administer only saline, one group of animals that will self-administer cocaine for 1 hour a day (short access), and a third group of animals that will first self administer cocaine for one hour a day but after showing stable self-administration rates will transfer to longer daily access of 6 hours. The one specific aim of this grant, then, is to quantify changes in dopamine receptors function immediately after the last session of cocaine self-administration, after 14 days of withdrawal, or after 60 days of withdrawal. Together, these experiments will illuminate some of the changes in dopaminergic function that underlie the transition to compulsive drug-use.
