2. Academic Validation
  3. Neurotensin receptor 1-biased ligand attenuates neurotensin-mediated excitation of ventral tegmental area dopamine neurons and dopamine release in the nucleus accumbens

Neurotensin receptor 1-biased ligand attenuates neurotensin-mediated excitation of ventral tegmental area dopamine neurons and dopamine release in the nucleus accumbens

  • Neuropharmacology. 2023 Aug 15:234:109544. doi: 10.1016/j.neuropharm.2023.109544.
Sarthak M Singhal 1,  Vivien Zell 1,  Lauren Faget 1,  Lauren M Slosky 2,  Lawrence S Barak 3,  Marc G Caron 4,  Anthony B Pinkerton 5,  Thomas S Hnasko 6
Affiliations

Affiliations

  • 1 Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • 2 Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
  • 3 Department of Cell Biology, Duke University, Durham, NC, USA.
  • 4 Departments of Cell Biology, Neurobiology and Medicine, Duke University, Durham, NC, USA.
  • 5 Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 6 Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Research Service, VA San Diego Healthcare System, San Diego, CA, USA. Electronic address: [email protected].
PMID: 37055008 DOI: 10.1016/j.neuropharm.2023.109544
Abstract

Strong expression of the G protein-coupled receptor (GPCR) Neurotensin Receptor 1 (NTR1) in ventral tegmental area (VTA) dopamine (DA) neurons and terminals makes it an attractive target to modulate DA neuron activity and normalize DA-related pathologies. Recent studies have identified a novel class of NTR1 ligand that shows promising effects in preclinical models of addiction. A lead molecule, SBI-0654553 (SBI-553), can act as a positive allosteric modulator of NTR1 β-arrestin recruitment while simultaneously antagonizing NTR1 Gq protein signaling. Using cell-attached recordings from mouse VTA DA neurons we discovered that, unlike neurotensin (NT), SBI-553 did not independently increase spontaneous firing. Instead, SBI-553 blocked the NT-mediated increase in firing. SBI-553 also antagonized the effects of NT on dopamine D2 auto-receptor signaling, potentially through its inhibitory effects on G-protein signaling. We also measured DA release directly, using fast-scan cyclic voltammetry in the nucleus accumbens and observed antagonist effects of SBI-553 on an NT-induced increase in DA release. Further, in vivo administration of SBI-553 did not notably change basal or cocaine-evoked DA release measured in NAc using fiber photometry. Overall, these results indicate that SBI-553 blunts NT's effects on spontaneous DA neuron firing, D2 auto-receptor function, and DA release, without independently affecting these measures. In the presence of NT, SBI-553 has an inhibitory effect on mesolimbic DA activity, which could contribute to its efficacy in animal models of psychostimulant use.

Keywords

D2 autoreceptor; Dopamine; Neurotensin; Neurotensin receptor-1; Nucleus accumbens; Ventral tegmental area.

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