PMID- 35033729
OWN - NLM
STAT- MEDLINE
DCOM- 20220310
LR  - 20220531
IS  - 1879-0046 (Electronic)
IS  - 0376-8716 (Linking)
VI  - 231
DP  - 2022 Feb 1
TI  - Ulotaront, a novel TAAR1 agonist with 5-HT1A agonist activity, lacks abuse 
      liability and attenuates cocaine cue-induced relapse in rats.
PG  - 109261
LID - S0376-8716(21)00756-0 [pii]
LID - 10.1016/j.drugalcdep.2021.109261 [doi]
AB  - BACKGROUND: Ulotaront (SEP-363856) is a trace amine-associated receptor 1 (TAAR1) 
      agonist with 5-hydroxytryptamine type 1A (5-HT1A) agonist activity that is 
      currently in Phase 3 clinical development for the treatment of schizophrenia. 
      Unlike available antipsychotics, the efficacy of ulotaront is not mediated by 
      blockade of dopamine D2 or serotonin 5-HT2A receptors. In a short-term randomized 
      clinical trial, ulotaront has demonstrated significant efficacy in the treatment 
      of adults with an acute exacerbation of schizophrenia. Given ulotaront's novel 
      mechanism of action a series of preclinical studies were performed to evaluate 
      its potential abuse liability. METHODS: A battery of studies were conducted in 
      male and female rats to evaluate whether ulotaront produces behavioral changes 
      suggestive of human abuse potential. In addition, studies were undertaken to 
      probe the potential for ulotaront to block reinstatement of cocaine-seeking 
      behavior in male rats. RESULTS: Ulotaront was not self-administered by rats 
      trained to self-administer amphetamine, cocaine, or heroin. The subjective 
      qualities of ulotaront were distinct from those produced by amphetamine in a drug 
      discrimination procedure. Ulotaront, and buspirone, a non-scheduled anxiolytic 
      with 5-HT1A agonism, partially generalized to the interoceptive cue elicited by 
      3, 4-methylenedioxymethamphetamine (MDMA). In addition, ulotaront demonstrated a 
      trend to reduce cocaine-primed induced reinstatement, and dose-dependently 
      reduced cue-reinstated responding. CONCLUSION: The current results suggest that 
      the TAAR1/5-HT1A agonist ulotaront is not likely to pose a risk for recreational 
      abuse in humans and may have potential therapeutic utility as a treatment of 
      substance use disorders.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Synan, Colleen
AU  - Synan C
AD  - Sunovion Pharmaceuticals, Inc., Marlborough, MA, USA.
FAU - Bowen, Carrie
AU  - Bowen C
AD  - Sunovion Pharmaceuticals, Inc., Marlborough, MA, USA.
FAU - Heal, David J
AU  - Heal DJ
AD  - DevelRx Ltd, BioCity, Nottingham, United Kingdom.
FAU - Froger-Colleaux, Christelle
AU  - Froger-Colleaux C
AD  - Porsolt, Le Genest-Saint-Isle, France.
FAU - Beardsley, Patrick M
AU  - Beardsley PM
AD  - Department of Pharmacology and Toxicology, Virginia Commonwealth University, 
      Richmond, VA, USA.
FAU - Dedic, Nina
AU  - Dedic N
AD  - Sunovion Pharmaceuticals, Inc., Marlborough, MA, USA.
FAU - Hopkins, Seth C
AU  - Hopkins SC
AD  - Sunovion Pharmaceuticals, Inc., Marlborough, MA, USA.
FAU - Campbell, Una
AU  - Campbell U
AD  - Sunovion Pharmaceuticals, Inc., Marlborough, MA, USA.
FAU - Koblan, Kenneth S
AU  - Koblan KS
AD  - Sunovion Pharmaceuticals, Inc., Marlborough, MA, USA. Electronic address: 
      kenneth.koblan@sunovion.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211231
PL  - Ireland
TA  - Drug Alcohol Depend
JT  - Drug and alcohol dependence
JID - 7513587
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Serotonin 5-HT1 Receptor Agonists)
RN  - I5Y540LHVR (Cocaine)
RN  - XMC8VP6RI2 (Trace amine-associated receptor 1)
SB  - IM
MH  - Animals
MH  - *Cocaine
MH  - Cues
MH  - Dose-Response Relationship, Drug
MH  - Extinction, Psychological
MH  - Female
MH  - Male
MH  - Rats
MH  - Receptors, G-Protein-Coupled
MH  - Recurrence
MH  - Self Administration
MH  - Serotonin 5-HT1 Receptor Agonists/pharmacology
OTO - NOTNLM
OT  - Amphetamine
OT  - Cocaine
OT  - Heroin
OT  - Recreational abuse
OT  - Schizophrenia
OT  - Ulotaront
EDAT- 2022/01/17 06:00
MHDA- 2022/03/11 06:00
CRDT- 2022/01/16 20:51
PHST- 2021/10/19 00:00 [received]
PHST- 2021/11/16 00:00 [revised]
PHST- 2021/11/29 00:00 [accepted]
PHST- 2022/01/17 06:00 [pubmed]
PHST- 2022/03/11 06:00 [medline]
PHST- 2022/01/16 20:51 [entrez]
AID - S0376-8716(21)00756-0 [pii]
AID - 10.1016/j.drugalcdep.2021.109261 [doi]
PST - ppublish
SO  - Drug Alcohol Depend. 2022 Feb 1;231:109261. doi: 
      10.1016/j.drugalcdep.2021.109261. Epub 2021 Dec 31.