Excessive glutamate signaling through N-methyl-D-aspartate receptors (NMDARs) is implicated in altered forms of neuronal plasticity associated with opioid reward and dependence. The present Cutting Edge Basic Research Award proposes to functionally decouple signaling complexes downstream of NMDAR activation to eliminate aberrant NMDAR-dependent nitric oxide signaling and circumvent the development of opioid reward. In the United States, unintentional deaths due to prescription drug overdoses have more than tripled since 1990, more than deaths attributed to cocaine and heroin combined. The increase in unintentional drug overdose death rates has mainly been driven by increased use of opioid analgesics. Inadequate treatment for pain, exacerbated by incomplete analgesic efficacy and narcotic abuse liability, contributes to escalating drug use, resulting in socioeconomic costs estimated at $600 billion annually. Improving the safety, efficacy, side effect profile and abuse liability of opioid analgesics thus remains an urgent medical need. Excessive NMDAR stimulation triggers a signaling cascade involving activation of the enzyme neuronal nitric oxide synthase (nNOS), which catalyzes formation of the signaling molecule nitric oxide (NO), which promotes addiction- related behaviors. Inhibition of aberrant glutamatergic hyperexcitability and inhibition of nNOS reduces addiction-related behaviors in preclinical studies. However, the therapeutic potential of NMDA receptor antagonists and NOS inhibitors are limited by severe side effects. We propose to functionally decouple NMDARs from nNOS signaling to circumvent opioid reward without unwanted side effects of global NMDAR antagonists or nonselective NOS catalytic inhibitors. We propose to accomplish this objective by selectively disrupting the protein-protein interface between nNOS and postsynaptic density 95kDA, a scaffolding protein which tethers nNOS to NMDARs.
Aim 1 will test the hypothesis that disruption of PSD95-nNOS protein-protein interactions will suppress morphine-induced reward using conditioned place preference and drug self- administration approaches.
Aim 2 will test the hypothesis that disruption of PSD95-nNOS interactions will attenuate opioid-induced dopamine dynamics in the nucleus accumbens shell, a key component of the reward circuit. Disruption of protein-protein interactions was once considered an impossible target for drug development. Completion of these high risk, high impact studies will establish the feasibility of disrupting the PSD95-nNOS interface to eliminate opioid reward, while retaining therapeutic efficacy, bypassing unwanted side effects of both NMDAR antagonists and NOS catalytic inhibitors. Validation of our hypotheses will provide a strong rationale for undertaking lead optimization of PSD95-nNOS inhibitors for advancement toward clinical studies in opioid addiction, filling a major gap in an area of unmet therapeutic need.

Public Health Relevance

Opioids have been used for centuries for chronic pain treatment, but their utilities are limited by potential for abuse. This proposal seeks to validate a novel strategy for blocking opioid reward: the functional decoupling of NMDA receptor signaling from formation of the signaling molecule nitric oxide. Our studies will assess the efficacy of disrupting protein-protein interactions in this key signaling pathway to decrease opioid abuse liability using preclinical models of opioid-induced reward (conditioned place preference, drug self-administration) and in vivo measurements of opioid-induced dopamine dynamics in the nucleus accumbens.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA042584-01
Application #
9197559
Study Section
Special Emphasis Panel (ZDA1-SXM-M (13)S)
Program Officer
Rapaka, Rao
Project Start
2016-08-15
Project End
2018-07-31
Budget Start
2016-08-15
Budget End
2017-07-31
Support Year
1
Fiscal Year
2016
Total Cost
$195,156
Indirect Cost
$70,156
Name
Indiana University Bloomington
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401