| To date, FDA is yet to approve a medication for the treatment of cocaine dependence or for the prevention of cocaine relapse. One promising potential treatment is l-THP, primarily a modest dopamine antagonist. However, l-THP possesses unwanted sedative side effects, which could be difficult to overcome clinically. The present study aims to develop an improved cocaine relapse treatment, creating an l-THP based combination medication. Our preliminary experiments determined l-THP when co-administered with LDN, decreased the sedative effect and increased the efficacy of l-THP. As a result, the focus of this dissertation was placed on the development of l-THP & LDN as a combination medication for the prevention of cocaine relapse. Specific aims used to accomplish the objective were: 1) determine the efficacy of l-THP & LDN combination for attenuation of cocaine seeking behavior as well as minimization of sedative effect of l-THP and 2) investigate the mechanism of l-THP & LDN through beta-endorphin release and POMC expression. The combination of l-THP & LDN attenuated reinstatement of conditioned place preference as well as drug-seeking behavior in the reinstatement of cocaine self-administration. Additionally, the l-THP sedative effect observed at the 3mg/kg and 5mg/kg l-THP doses was ameliorated through co-administration of 0.1mg/kg LDN. Taken together, results of the behavioral studies indicate 3mg/kg l-THP & 0.1mg/kg LDN has the greatest potential as a cocaine relapse prevention treatment. This dosage was used to examine the effect of l-THP & LDN on endogenous beta-endorphin release and POMC expression. In animals treated with 3mg/kg l-THP & 0.1mg/kg LDN, we correlated the reduction of drug seeking with an increase of plasma beta-endorphin and hypothalamic POMC mRNA expression. This to our knowledge is the first study investigating the underlying mechanism of LDN. The research presented in this dissertation establishes l-THP & LDN as novel treatment for the prevention of cocaine relapse and dependence with great potential for future clinical translation. |
