Recent reports have demonstrated that the selective cannabinoid CB1 receptor antagonist SR141716A attenuates the ability of drug-associated conditioned cues and drug priming injections to reinstate extinguished drug-seeking behavior. Remarkably this effect of SR141716A has been observed across a wide range of drug classes including psychostimulants, opiates, nicotine and ethanol. This broad spectrum of influence suggests that the endocannabinoid system has great potential as a therapeutic target for the treatment of relapse. However, the neural substrates and neuropharmacological mechanisms through which endocannabinoids modulate relapse behavior have not been characterized, and direct evidence of altered endocannabinoid signaling during the reinstatement of extinguished drug-seeking behavior has not been shown. Thus, the goals of this project are to evaluate the influence of endocannabinoids on conditioned cue-induced heroin-seeking behavior in an operant response-reinstatement model of relapse. The neural substrates through which CB1 receptors modulate conditioned cue-induced heroin-seeking behavior will be investigated using site-directed microinfusions of a selective CB1 receptor antagonist, a selective inhibitor of endocannabinoid reuptake, and the endocannabinoid substances (R)-methanandamide and 2-arachidonoylglycerol. The brain regions to be investigated are the basolateral amygdala, the medial prefrontal cortex, and the nucleus accumbens core. In vivo microdialysis sampling will be employed to characterize alterations in interstitial endocannabinoid levels in these brain regions during conditioned cue-induced reinstatement of extinguished drug-seeking behavior, and additional neurochemcial studies will begin to characterize the neuropharmacological mechanisms through which endocannabinoids modulate drug-seeking behavior. [unreadable] [unreadable]