A major goal of modern addiction research is to understand the neural adaptations that underlie the chronic, maladaptive and, for many, treatment-refractory behaviors produced by drugs of abuse, including opiates. Considerable optimism exists in this regard, as powerful preclinical tools and well-established animal models have dramatically advanced our understanding of the molecular and cellular mechanisms of opiate-related plasticity . Nonetheless, a considerable gap remains in the clinical-translational testing and validation of such preclinical findings in human opiate addiction. In seminal preclinical studies nearly 20 years ago, Robinson & Kolb [3-5] demonstrated enduring decreases in synaptic (i.e., dendritic spine) density in both the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) of rodents despite sustained (0-4 weeks) abstinence from chronic opiate administration. Their findings were compelling and suggested an important pathophysiological mechanism ? persistent aberrant structural synaptic plasticity ? whereby opiates might produce the chronic, recalcitrant behaviors (e.g., craving, compulsive use, and relapse) so seemingly ?hard-wired? in those suffering from the disorder. Our group has developed a novel radiotracer, 11C-UCB-J, for imaging synaptic density in the living human brain using positron-emission tomography (PET) [62, 63]. Thus, the current exploratory/development (R21) application seeks to apply this breakthrough methodology to explore whether observations of decreased synaptic density in the NAc and mPFC (and increases in orbitofrontal cortex) of rodents are recapitulated in abstinent opiate use disorder (OD) humans. If achieved, the current study would have a major impact, providing powerful clinical-translational support for aberrant brain structure at the synaptic level, setting the stage for future studies of the relationship of such aberrant synaptic density to risk for relapse, opiate-related behaviors and clinical prognosis/outcome.
Basic science research has shown that opiates produce abnormalities (i.e., decreases) in brain structures called synapses through which nerve cells communicate with each other. These decreases in synaptic density are thought to underlie the enduring, maladaptive patterns of behavior (e.g., drug craving, compulsive use and relapse) that make prescription and non-prescription opiate (e.g. heroin) addiction such a chronic, treatment-refractory disorder. The current study will test, for the first time in humans, whether synaptic density is decreased in specific brain regions (i.e., ventral striatum and medial prefrontal cortex) of human opiate abusers using a new (i.e., breakthrough) brain imaging tool, 11C-UCB-J positron emission tomography (PET).