TY - JOUR

T1 - Behavioral effects of a potential novel TAAR1 antagonist

AU - Lam, Vincent M.

AU - Mielnik, Catharine A.

AU - Baimel, Corey

AU - Beerepoot, Pieter

AU - Espinoza, Stefano

AU - Sukhanov, Ilya

AU - Horsfall, Wendy

AU - Gainetdinov, Raul R.

AU - Borgland, Stephanie L.

AU - Ramsey, Amy J.

AU - Salahpour, Ali

PY - 2018/9/4

Y1 - 2018/9/4

N2 - The trace amine associated receptor 1 (TAAR1) is a G-protein coupled receptor expressed in the monoaminergic regions of the brain, and represents a potential novel therapeutic target for the treatment of neurological disorders. While selective agonists for TAAR1 have been successfully identified, only one high affinity TAAR1 antagonist has been described thus far. We previously identified four potential low potency TAAR1 antagonists through an in silico screen on a TAAR1 homology model. One of the identified antagonists (compound 22) was predicted to have favorable physicochemical properties, which would allow the drug to cross the blood brain barrier. In vivo studies were therefore carried out and showed that compound 22 potentiates amphetamine- and cocaine-mediated locomotor activity. Furthermore, electrophysiology experiments demonstrated that compound 22 increased firing of dopamine neurons similar to EPPTB, the only known TAAR1 antagonist. In order to assess whether the effects of compound 22 were mediated through TAAR1, experiments were carried out on TAAR1-KO mice. The results showed that compound 22 is able to enhance amphetamine- and cocaine-mediated locomotor activity, even in TAAR1-KO mice, suggesting that the in vivo effects of this compound are not mediated by TAAR1. In collaboration with Psychoactive Drug Screening Program, we attempted to determine the targets for compound 22. Psychoactive Drug Screening Program (PDSP) results suggested several potential targets for compound 22 including, the dopamine, norepinephrine and serotonin transporters; as well as sigma 1 and 2 receptors. Our follow-up studies using heterologous cell systems showed that the dopamine transporter is not a target of compound 22. Therefore, the biological target of compound 22 mediating its psychoactive effects still remains unknown.

AB - The trace amine associated receptor 1 (TAAR1) is a G-protein coupled receptor expressed in the monoaminergic regions of the brain, and represents a potential novel therapeutic target for the treatment of neurological disorders. While selective agonists for TAAR1 have been successfully identified, only one high affinity TAAR1 antagonist has been described thus far. We previously identified four potential low potency TAAR1 antagonists through an in silico screen on a TAAR1 homology model. One of the identified antagonists (compound 22) was predicted to have favorable physicochemical properties, which would allow the drug to cross the blood brain barrier. In vivo studies were therefore carried out and showed that compound 22 potentiates amphetamine- and cocaine-mediated locomotor activity. Furthermore, electrophysiology experiments demonstrated that compound 22 increased firing of dopamine neurons similar to EPPTB, the only known TAAR1 antagonist. In order to assess whether the effects of compound 22 were mediated through TAAR1, experiments were carried out on TAAR1-KO mice. The results showed that compound 22 is able to enhance amphetamine- and cocaine-mediated locomotor activity, even in TAAR1-KO mice, suggesting that the in vivo effects of this compound are not mediated by TAAR1. In collaboration with Psychoactive Drug Screening Program, we attempted to determine the targets for compound 22. Psychoactive Drug Screening Program (PDSP) results suggested several potential targets for compound 22 including, the dopamine, norepinephrine and serotonin transporters; as well as sigma 1 and 2 receptors. Our follow-up studies using heterologous cell systems showed that the dopamine transporter is not a target of compound 22. Therefore, the biological target of compound 22 mediating its psychoactive effects still remains unknown.

KW - Amphetamine

KW - Cocaine

KW - Dopamine transporter (DAT)

KW - Electrophysiology

KW - Locomotor activity

KW - TAAR1

KW - MESOLIMBIC SYSTEM

KW - cocaine

KW - dopamine transporter (DAT)

KW - BASAL GANGLIA

KW - amphetamine

KW - AMINE-ASSOCIATED RECEPTOR

KW - COCAINE

KW - DOPAMINE TRANSPORTER

KW - AGONISTS

KW - electrophysiology

KW - ADENOSINE A(2A) RECEPTORS

KW - IN-VIVO

KW - ANIMAL-MODELS

KW - locomotor activity

KW - SIGMA-1 RECEPTOR

UR - http://www.scopus.com/inward/record.url?scp=85053169049&partnerID=8YFLogxK

U2 - 10.3389/fphar.2018.00953

DO - 10.3389/fphar.2018.00953

M3 - Article

AN - SCOPUS:85053169049

VL - 9

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

IS - SEP

M1 - 953

ER -