PMID- 37055008
OWN - NLM
STAT- MEDLINE
DCOM- 20230517
LR  - 20231114
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Print)
IS  - 0028-3908 (Linking)
VI  - 234
DP  - 2023 Aug 15
TI  - Neurotensin receptor 1-biased ligand attenuates neurotensin-mediated excitation 
      of ventral tegmental area dopamine neurons and dopamine release in the nucleus 
      accumbens.
PG  - 109544
LID - S0028-3908(23)00134-X [pii]
LID - 10.1016/j.neuropharm.2023.109544 [doi]
AB  - 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 
      beta-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.
CI  - Published by Elsevier Ltd.
FAU - Singhal, Sarthak M
AU  - Singhal SM
AD  - Department of Neurosciences, University of California San Diego, La Jolla, CA, 
      USA.
FAU - Zell, Vivien
AU  - Zell V
AD  - Department of Neurosciences, University of California San Diego, La Jolla, CA, 
      USA.
FAU - Faget, Lauren
AU  - Faget L
AD  - Department of Neurosciences, University of California San Diego, La Jolla, CA, 
      USA.
FAU - Slosky, Lauren M
AU  - Slosky LM
AD  - Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA.
FAU - Barak, Lawrence S
AU  - Barak LS
AD  - Department of Cell Biology, Duke University, Durham, NC, USA.
FAU - Caron, Marc G
AU  - Caron MG
AD  - Departments of Cell Biology, Neurobiology and Medicine, Duke University, Durham, 
      NC, USA.
FAU - Pinkerton, Anthony B
AU  - Pinkerton AB
AD  - Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical 
      Discovery Institute, La Jolla, CA, USA.
FAU - Hnasko, Thomas S
AU  - Hnasko TS
AD  - 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: thnasko@health.ucsd.edu.
LA  - eng
GR  - I01 BX005782/BX/BLRD VA/United States
GR  - R00 DA048970/DA/NIDA NIH HHS/United States
GR  - R01 DA036612/DA/NIDA NIH HHS/United States
GR  - I01 BX003759/BX/BLRD VA/United States
GR  - R33 DA038019/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20230411
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - VTD58H1Z2X (Dopamine)
RN  - 0 (neurotensin type 1 receptor)
RN  - 0 (Receptors, Neurotensin)
RN  - 39379-15-2 (Neurotensin)
RN  - 0 (Ligands)
RN  - 0 (Dopamine D2 Receptor Antagonists)
SB  - IM
MH  - *Ventral Tegmental Area/metabolism/physiology
MH  - *Dopaminergic Neurons/drug effects/metabolism/physiology
MH  - *Nucleus Accumbens/metabolism
MH  - *Dopamine/metabolism
MH  - Male
MH  - Female
MH  - Animals
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Presynaptic Terminals/metabolism/physiology
MH  - Action Potentials/drug effects
MH  - *Receptors, Neurotensin/antagonists & inhibitors/metabolism
MH  - *Neurotensin/metabolism/pharmacology
MH  - Ligands
MH  - *Dopamine D2 Receptor Antagonists/metabolism/pharmacology
PMC - PMC10192038
MID - NIHMS1893083
OTO - NOTNLM
OT  - D2 autoreceptor
OT  - Dopamine
OT  - Neurotensin
OT  - Neurotensin receptor-1
OT  - Nucleus accumbens
OT  - Ventral tegmental area
COIS- Declaration of competing interest US patents 9 868 707 and 10 118 902 relating to 
      the chemistry of SBI-553 and its derivatives have been issued to the Sanford 
      Burnham Prebys Medical Research Institute (A.B.P.) and Duke University (M.G.C., 
      L.S.B.).
EDAT- 2023/04/14 06:00
MHDA- 2023/05/17 06:42
PMCR- 2024/08/15
CRDT- 2023/04/13 19:27
PHST- 2022/12/02 00:00 [received]
PHST- 2023/03/29 00:00 [revised]
PHST- 2023/04/10 00:00 [accepted]
PHST- 2024/08/15 00:00 [pmc-release]
PHST- 2023/05/17 06:42 [medline]
PHST- 2023/04/14 06:00 [pubmed]
PHST- 2023/04/13 19:27 [entrez]
AID - S0028-3908(23)00134-X [pii]
AID - 10.1016/j.neuropharm.2023.109544 [doi]
PST - ppublish
SO  - Neuropharmacology. 2023 Aug 15;234:109544. doi: 10.1016/j.neuropharm.2023.109544. 
      Epub 2023 Apr 11.