Trace amine-associated receptor 1 agonists differentially regulate dopamine transporter function.

Area of Science:

• Neuroscience
• Pharmacology

Background:

• Trace amine-associated receptor 1 (TAAR1) agonists, including ulotaront, have been investigated for neuropsychiatric disorders.
• Ulotaront's clinical antipsychotic efficacy was similar to placebo in Phase III trials, raising questions about TAAR1 agonist mechanisms.

Purpose of the Study:

• To investigate the pharmacology of TAAR1 agonists RO5166017, RO5256390, and ulotaront at the dopamine transporter (DAT).
• To test the hypothesis that different TAAR1 agonists have distinct effects on DAT function and dopamine homeostasis.

Main Methods:

• Evaluated direct binding and inhibition of dopamine uptake at DAT for RO5166017, RO5256390, and ulotaront.
• Assessed TAAR1-dependent effects on dopamine uptake and amphetamine-induced dopamine efflux in cultured cells and rodent synaptosomes.
• Utilized surface biotinylation to measure changes in cell-surface DAT levels.

Main Results:

• RO5166017 and RO5256390 directly inhibited dopamine uptake via DAT, while ulotaront did not.
• RO5166017 increased dopamine uptake, whereas ulotaront and RO5256390 reduced it, in a TAAR1-dependent manner.
• RO5166017 increased cell-surface DAT and amphetamine-induced dopamine efflux, effects dependent on TAAR1 activation.

Conclusions:

• Clinically relevant differences exist in the direct and TAAR1-mediated effects of TAAR1 agonists on DAT.
• Each agonist (RO5166017, RO5256390, ulotaront) displayed a unique pharmacological profile at DAT.
• These distinct mechanisms should be considered in the therapeutic design and clinical application of TAAR1 agonists.