There are no approved medications for preventing relapse to cocaine abuse. Previous clinical evaluations of drug candidates have been disappointing. Stress has often been implicated in relapse to drug abuse. Converging evidence from genetic, neuroanatomical and pharmacological studies suggest that the kappa opioid receptor (KOR) system interacts with the hypothalamic-pituitary-adrenocortical axis and modulates the effects of stress on behavior. Importantly, KOR agonists have been reported to exacerbate, and KOR antagonists have been reported to attenuate the behavioral effects of environmental stressors. We have synthesized a novel, KOR antagonist, (3R)-7-Hydroxy-N-{(1S)-1-{[(3R,4fR)-4-(3-hydroxyphenyl)-3,4-dimethyl- 1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic) which has shown high potency and selectivity for the KOR and potent and extremely long-lasting KOR antagonist activity. Recently, we found that JDTic was able to block footshock-induced stress reinstatement of cocaine-seeking in rats, an effect hypothesized predictive of medications which would be useful in treating cocaine relapse. These observations, and others, have led us to propose JDTic as a candidate medication for treating relapse to cocaine abuse. The purpose of this project is to evaluate four JDTic analogs identified in Project 1. In this project, the four analogs will be evaluated at least three doses each in footshock-induced reinstatement procedures using Long-Evans hooded rats with histories of self-administering 0.5 mg/kg cocaine during daily, 2-h experimental sessions. Candidates demonstrating an ability to significantly attenuate the effects of footshock-induced stress will then be evaluated in cocaine-prime reinstatement procedures to assess their specificity and to delineate their range of effectiveness. Candidates attenuating stress-induced reinstatement of cocaine seeking which minimally affect cocaine-prime reinstatement or attenuate it will be promoted onto toxicity studies for further evaluation as a backup to JDTic. JDTic is an exciting compound which offers a novel mechanism for potentially treating relapse to cocaine abuse, an unfilled therapeutic niche. This project will identify successors to JDTic in the event future studies during its development necessitate a replacement for it.