# Neurophysiological Characterization of Novel Neurotensin Receptor Ligands to Define Therapeutic Potential in Combatting Addiction

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2022 · —

## Abstract

PROJECT SUMMARY – ABSTRACT
Drug addiction is an insidious mental health problem that has few effective therapies. This
proposal is a collaborative effort between the PI (Dr. Hnasko) and the Sanford Burnham Prebys
Medical Discovery Institute (SBP). SBP has recently identified ML314 and small molecule
analogs that act at the Neurotensin receptor type 1 (NtsR1) as biased positive allosteric
modulators (PAM). Neurotensin (NT) agonists have long been sought as potential treatments
for drug addiction or other psychiatric illness due to the close association of this peptide with the
midbrain dopamine system. Indeed, dopamine neurons express both the peptide and the
receptor; and NT has been shown to act as an important modulator of dopamine signaling
across multiple systems. A promising ML314 derivative NtsR1 PAM developed by SBP has
shown excellent blood brain barrier penetration and ADME/Pk/Tox properties that support
minimal efficacious doses across multiple models of 10 mg/kg. This compound has also shown
promise in normalizing behaviors in pre-clinical models of schizophrenia and addiction. But
despite substantial molecular pharmacology characterization using cell-based assays in vitro,
and the promising pharmacokinetic and behavioral data described above, very little is
understood about how the NtsR1 PAMs developed by SBP influence physiologically intact
neural circuits. Understanding this is crucial for directing these promising drugs toward
appropriate clinical application/s, developing appropriate biomarkers of clinical efficacy, and
developing further refined analogs. Because dopamine is a central player in the manifestations
of numerous forms of mental illness, particularly drug addiction; we propose to use mouse
models and brain slice preparations to characterize the effects of NtsR1 PAMs on dopamine
neuron excitability and dopamine neuron release properties using electrophysiological,
electrochemical, and optogenetic approaches. We will also assess how NtsR1 PAMs modulate
dopamine neuron plasticity and behavior in animal models of drug addiction/dependence.
These experiments are thus aimed directly at accelerating the path of an already highly
developed and very promising ligand forward toward the clinical treatment of mental illness, with
an emphasis on drug addiction.

## Key facts

- **NIH application ID:** 10427135
- **Project number:** 5I01BX003759-05
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Thomas Hnasko
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427135

## Citation

> US National Institutes of Health, RePORTER application 10427135, Neurophysiological Characterization of Novel Neurotensin Receptor Ligands to Define Therapeutic Potential in Combatting Addiction (5I01BX003759-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10427135. Licensed CC0.

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