Modulating Endogenous Opiate Signaling to Reverse Stress-Induced Deficits in Reward Processing

Project Abstract Millions of Americans suffer from deficits in reward processing, in the context of psychiatric disorders including major depressive disorder and schizophrenia. Disrupted reward processing leads to worse outcomes, yet current treatments poorly treat this symptom and new treatments are urgently needed. Recent evidence that

mu opioid antagonists function as antidepressants suggest the opioid system as a promising line for developing novel treatments. We hypothesize that increasing endogenous enkephalins by using molecules (DENKIs) that inhibit the degradation of this endogenous class of opioid peptides will reverse reward seeking

deficits without raising the liability for substance use disorders. To test this hypothesis and extend our preliminary data, we will administer a DENKI to chronically stressed mice and record in vivo neural activity in the reward circuitry (ventral tegmental area (VTA) and nucleus accumbens (NAc)) as the freely moving mice

engage in a reward task that assesses different aspects of reward processing. Using KO mice and receptor- specific antagonists, in Aim 1, we will determine if these effects are mediated by MOR and in Aim 2, test whether they are mediated by delta opioid receptor (DOR). We will also confirm that DENKI administration is

not inherently rewarding. Successful completion of these aims will yield novel insights into how the opioid system influence reward circuity activity during behavior and establish the basis for more detailed study of endogenous enkephalin modulators as treatments for the anhedonia commonly seen in psychiatric disorders.