TAAR1-Dependent and -Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition

Trace Amine-Associated Receptor 1 Contributes to Diverse Functional Actions of O-Phenyl-Iodotyramine in Mice but Not to the Effects of Monoamine-Based Antidepressants

“…Consistent with this possibility, several studies have shown that trace amines exert a positive influence on affect, and that a reduction in their levels may be related to depressed states in patients [16,28,29]. Furthermore, it has been conjectured that a component of the antidepressant actions of Monoamine Oxidase inhibitors reflects their protection of trace amines from degradation [16,28,30]. That is, their antidepressant properties might at least partially depend upon increases in levels of trace amines and ipso facto activation of TAAR1 receptors-or another subclass of TAAR [31].…”

“…In parallel with other TAAR1 agonists, preclinical studies have shown that SEP-363856 displays antidepressant actions in rodents [24], and beneficial effects of SEP-363856 in depressed patients may be revealed by future clinical trials. Consistent with this possibility, several studies have shown that trace amines exert a positive influence on affect, and that a reduction in their levels may be related to depressed states in patients [16,28,29]. Furthermore, it has been conjectured that a component of the antidepressant actions of Monoamine Oxidase inhibitors reflects their protection of trace amines from degradation [16,28,30].…”

“…In particular, TAAR1 is expressed in monoaminergic cell groups such as cortical and striatal projecting dopamine (DA) neurons, as well as corticolimbic projecting 5-HT neurons. Moreover, TAAR1 is found in the prefrontal cortex, entorhinal cortex, bed nucleus of stria terminalis, amygdala, hypothalamus and lateral parabrachial nucleus [14][15][16]. TAAR1 is coupled to Gs and G13 and responds to conventional, endogenous trace amines and amphetamine, methamphetamine and MDMA [10,[17][18][19].…”

“…Due to its distinctive relationship with DA releasing agents, much TAAR1-related research has focused on the DAergic system. Mice lacking TAAR1 display higher VTA neuron firing rates [15,20,21] and heightened behavioural sensitivity to psychostimulants [15,16,18,22], suggesting that pharmacological TAAR1 activation might be beneficial for tackling schizophrenia. Indeed, TAAR1 agonists exhibit antipsychoticlike activity in certain animal models [23,24].…”

“…That is, their antidepressant properties might at least partially depend upon increases in levels of trace amines and ipso facto activation of TAAR1 receptors-or another subclass of TAAR [31]. Alternatively, TAAR1 may act as a negative feedback regulator of trace amine levels, and TAAR1 antagonists might facilitate the antidepressant actions of monoamine oxidase inhibitor [16]. This remains, however, to be directly examined, and the putative role of TAAR1 in the actions of other classes of antidepressant agent has not as yet been evaluated [14,25].…”