What are the brain mechanisms engaged during conflict processing? How are they disregulated by opioid drugs like fentanyl?

Human decision making in Opioid Use Disorder (OUD) is complex, with the motivation for drugs, avoiding negative consequences, and seeking non-drug alternatives all converging to organize behavior. Nearly 80% of OUD patients relapse to daily use within a month of abstaining, despite the conflicting negative consequences or positive alternatives that may have led to abstinence. To develop new strategies that reduce drug use and prevent relapse we must first better understand the brain circuitry underlying conflict processing.  Our recent work shows that the amygdala-insular circuits coordinate natural reward seeking in the face of conflict. In our ongoing collaborative work, we combine translationally relevant models with cutting edge neuroscience tools to determine the precise conditions that recruit insluar-amygdala circuitry to drive opioid consumption, motivation and relapse in the face of positive and negative conflict. 

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​What are the brain mechanisms psychedelics engage to promote lasting brain and behavioral change?

The most compelling treatment effects of psychedelics are observed after only one or two acute treatments and have lasting positive impacts on mental health that persist for many months. The Calu Lab studies the acute and lasting impacts of psychedelics like psilocybin on neuroplasticity in the nucleus accumbens (NAc) - a critical hub driving learning and motivational processes that are dysregulated in OUD. In our recent work, we focus on a fundamental brain plasticity signal, the reward prediction error (RPE), which drives new learning and is predictive of therapeutic efficacy in humans. We find that acute psychedelics restore NAc dopamine (DA) RPE signaling and decrease opioid motivation, both of which are dependent on serotonin 5HT2A receptor activation. Our ongoing, collaborative pre-clinical studies will establish a multi-target mechanistic understanding of how psychedelics alter the neural substrates of opioid motivation, to promote lasting behavioral changes, which will aid in developing psychedelic and RPE-guided treatments for opioid-induced symptoms.

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How can neuromodulation be harnessed to treat OUD? What specific aspects of motivated behavior change when reward circuitry is activated or inhibited?

Focused Ultrasound Neuromodulation (FUn), has growing safety and efficacy data for various mental health indications, including OUD. What specific areas are most promising targets of FUn? Which specific aspects of motivated behavior change when we modulate specific brain targets? In our ongoing collabortive work, we combine FUn with behavioral economic approaches to understand how FUn of specific brain targets impacts motivation for opioid and food rewards. We use our prior systems neuroscience work to inform ongoing research to develop neuromodulation strategies to treat OUD.  

Also, Dopamine is cool. Most people agree. If you like Dopamine, too... check out our work.
Psychedelics and Dopamine
Endocanabinoids and Dopamine
Dopamine in the extended amygdala

 

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