EPPTB

Although it is well documented that the striatal GABAergic projection neurons receive excitatory and inhibitory dopaminergic innervation via D1 and D2 receptors, the trace amine-associated receptor 1 (TAAR1)-mediated regulation of this neural connection is much less studied. The presence of TAAR1 was originally detected in brain aminergic neurons, with recent evidence indicating its presence in striatal GABAergic neurons as well. The objective of the present study was to demonstrate the role of TAAR1 and signaling in dopaminergic-GABAergic interaction in the neural circuitry of the striatum. Besides trace amines, which are considered natural ligands for TAAR1, series of different exogenous drugs were identified to act on this receptor. Using the dopaminergic activity enhancer compound (-)BPAP ((-)-1-(benzofuran-2-yl)-2-propylaminopentane HCl), a potential agonist for TAAR1, we have found that it increased the electrical stimulation-induced [3H]dopamine release in rat striatal slices. This effect of (-)BPAP occurred parallel with increases of [3H]GABA release in striatum when used in 10–13–10–11 mol/L concentrations. The effects of (-)BPAP on the release of both neurotransmitters were bell-shaped. We speculated that the rising phase of the concentration-effect curves was evoked by an agonist effect of (-)BPAP on TAAR1 whereas the declining phase was a result of heterodimerization of TAAR1 with pre- and postsynaptic dopamine D2 receptors. The bell-shaped curves suggest that the (-)BPAP-induced heterodimerization of TAAR1 with dopamine D2 receptors may switch off TAAR1 signaling and switch on transduction coupled to D2 receptors. We also suggest that (-)BPAP increases synaptic strength in a hypothetical quadrilateral neuronal organization consisting of dopaminergic nerve ending, GABAergic neurons, trace amine-producing D cells, and supportive glial cell processes.

Substantial evidence indicates trace amines can induce vasoconstriction independently of noradrenaline release. However, the mechanism underlying noradrenaline-independent vasoconstrictor responses to trace amines has not yet been established. This study evaluates the role of trace amine-associated receptor 1 (TAAR1) and other biogenic amine receptors in mediating β-phenylethylamine and the TAAR-1 selective agonist RO5256390-induced vasoconstriction.

Vasoconstrictor responses to β-PEA and the TAAR1-selective agonist, RO5256390 were assessed in vitro in endothelium-denuded aortic rings and third-order mesenteric arteries of male Sprague Dawley rats.

β-PEA and RO5256390 induced concentration-dependent vasoconstriction of aortic rings but not third-order mesenteric arteries. Vasoconstrictor responses in aortic rings were insensitive to antagonists of 5-HT. The murine-selective TAAR1 antagonist, EPPTB, had no effect on either β-PEA or RO5256390-induced vasoconstriction. The α₁-adrenoceptor antagonist, prazosin, and the α₂-adrenoceptor antagonist, yohimbine, induced a shift of the β-PEA concentration response curve too small to be ascribed to antagonism of α₁-or α₂-adrenoceptors, respectively. The α₂-adrenoceptor antagonist atipamezole had no effect on β-PEA or RO5256390-induced vasoconstriction.

Vasoconstrictor responses to trace amines are not mediated by classical biogenic amine neurotransmitter receptors. Insensitivity of β-PEA vasoconstrictor responses to EPPTB, may be explained by its low affinity for rat rather than murine TAAR1. Therefore, TAAR1 remains the most likely candidate receptor mediating vasoconstrictor responses to trace amines and that prazosin and yohimbine have low affinity for TAAR1.