Dissecting the role of amygdalo-striatal circuits in the regulation of stress and cocaine comorbidity in rats

摘要/文摘

SUMMARY/ABSTRACT Generally, post traumatic stress disorder (PTSD) and substance use disorder (SUD) are examined seperately in preclinical studies, although they can occur simultaneously in patients. Therefore, it is necessary to observe these two disorders closely together to better understand the mechanisms that underlie this comorbidity and the effects on the neurophysiology. One of the main problems in addiction is the high relapse rate when the patient is exposed to environmental cues or other factors that can trigger memories associated with addiction. Presently, one of the factors associated with a high relapse state is stress. Exposure to a stressful or traumatic events can lead to the development of PTSD. Moreover, PTSD patients exhibit higher rates of SUD. Two important brain structures involved in the development of these disorders are the basolateral amygdala (BLA) and the nucleus accumbens ( NAc). The BLA concerns the development of fear memories and PTSD, while the NAc is part of the reward circuitry and plays an important role in the progression of SUD. This NAc is sub-divided in two main regions: the core and the shell. Studies have shown that the core drives cocaine-seeking behavior while the shell modulates extinction, decreasing cocaine-seeking behavior. Importantly, the inhibition of BLA-NAc synapses leads to a decrease in overall drug seeking behavior, but the effects of chronic stress on these synapses are still unknown. The objective is to dissect the mechanism by which BLA modulates the NAc in a combined animal model of PTSD and SUD. This will help to better understand how one disorder influences the other. The central hypothesis is that chronic stress will induce neurophysiological changes to the BLA-NAc core and shell synapses, which will correlate with increased cocaine-seeking behaviors. To address this, the team proposed the following aims: Aim 1: Determine the effects of chronic stress on the neurophysiology of synapses of the basolateral amygdala and nucleus accumbens prior to cocaine exposure. Aim 2: Determine the effects of optical activation of BLA-NAc shell and core synapses independently on cocaine-seeking behavior in rats with chronic stress prior to cocaine exposure. The overall goal is to understand how the chronic stress induced neurophysiological changes in a rodent correlate with cocaine seeking-behavior changes prior to cocaine exposure. The long-term goal is to understand the mechanisms and adaptations of the brain caused by a traumatic event that leads to the development of PTSD and the susceptibility of acquiring SUD.