Regulation by Trace Amine-Associated Receptor 1 (TAAR1) of Dopaminergic-GABAergic Interaction in the Striatum: Effects of the Enhancer Drug (-)BPAP

Abstract

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.

Keywords: (-)BPAP; Dopaminergic activity enhancer effect; Rat striatum; Trace amines / Trace amine-associated receptor 1; [3H]Dopamine and [3H]GABA release.

Fig. 1

The chemical structures of the trace amines (phenylethylamine, tyramine, tryptamine) and catecholamine activity enhancer aryl-2-propylaminopentane drugs (-)PPAP, (-)BPAP, (-)IPAP) [20]

Fig. 2

Concentration-dependent effects of (-)BPAP on resting and electrical stimulation-induced [³H]dopamine release from rat striatum. The resting and electrical stimulation-induced [³H]dopamine release was determined as a fractional rate. (-)BPAP was added to the superfusion buffer from fraction 8 in a concentration range from 10^–15 to 10^–5 mol/L. A: Resting [³H]dopamine release was determined in fractions 3 (basal outflow in the absence of drug, B1) and 17 (basal outflow in the presence of drug, B2) and the B2/B1 ratio was calculated. The B2/B1 value was 0.95 ± 0.05 (n = 8) in control c experiments. (-)BPAP added in these concentrations was without effect on resting [³H]dopamine release. One-way ANOVA followed by the Dunnett’s test, F(11,40) = 0.464, p = 0.914, mean ± S.E.M., n = 3–8. B: The effect of (-)BPAP on electrical stimulation-induced [³H]dopamine release. Electrical stimulation (40 V, 10 Hz, 2-ms for 3 min) was applied in the 1st (absence of drug, S1) and 2nd (presence of drug, S2), stimulations carried out in fractions 4 and 18 and the release was expressed as S2/S1 ratio. The S2/S1 value was 0.77 ± 0.05 (n = 8) in control experiments. Note: (-)BPAP exerted a dual-effect: it increased electrical stimulation-induced [³H]dopamine release in 10^–12, 10^–11 and 10^–6, 10^–5 mol/L concentrations. One-way ANOVA followed by the Dunnett’s test, F(11,40) = 7.743, p = 0.0001, *p < 0.05, mean ± S.E.M., n = 3–8

Fig. 3

The effect of (-)BPAP on resting and electrical stimulation-induced [³H]GABA release from rat striatum. The resting and the electrical stimulation-induced [³H]GABA release was determined as a fractional rate. (-)BPAP was added in a concentration range from 10^–15 to 10^–5 mol/L to the superfusion buffer from fraction 8 and maintained through the experiment. A: The B2/B1 ratio indicates the effect of (-)BPAP on resting [³H]GABA release determined in fractions 4 (absence of drug, B1) and 14 (presence of drug, B2). The B2/B1 value was 0.87 ± 0.04 (n = 10) in control experiments (c). One-way ANOVA followed by the Dunnett’s test, F(11,58) = 2.136, p = 0.031, the Dunnett’s test did not indicate significant changes, mean ± S.E.M., n = 4–10. B: The effect of (-)BPAP on electrical stimulation-induced [³H]GABA release. The stimulation (40 V, 20 Hz, 2-ms for 6 min) was applied in the presence and absence of the drug in collected fractions 15 and 16. Control (c) [³H]GABA release was 2.02 ± 0.34 per cent of content released (n = 10). Note: (-)BPAP exerted a dual-effect: it increased electrical stimulation-induced [³H]GABA release in 10^–13 and 10^–12 and 10^–9 to 10^–7 mol/L concentrations. Data in Fig. 3B were subjected to logarithmic transformation and one-way ANOVA followed by the Dunnett’s test, F(11,58) = 2.825, p = 0.0051, *p < 0.05, mean ± S.E.M., n = 4–10

Fig. 4

Comparison of the effects of (-)BPAP on resting and electrical stimulation-induced [³H]dopamine and [³H]GABA release from rat striatum. (-)BPAP was added to the tissue in a concentration range of 10^–15 to10⁻⁵ mol/L. Data were collected from Figs. 2 and 3 and plotted repeatedly here for comparison. A: The B2/B1 ratios indicate no effects of (-)BPAP on resting [³H]dopamine and [³H]GABA outflow. B: Effects of (-)BPAP on the electrical stimulation-induced [³H]dopamine and [³H]GABA release. Effect on [³H]dopamine release was expressed by the S2/S1 ratios, that on [³H]GABA release was expressed as per cent of content released in response to electrical stimulation. For details of determinations and statistical analyses see Figs. 2 and 3, one-way ANOVA followed by the Dunnett’s test, *p < 0.05 indicates significant increases in release when compared to control (c), mean ± S.E.M

Fig. 5

Hypothetical model for the regulation of TAAR1 and signaling. This regulation is based upon a quadripartite model with cross-talk between trace amine-producing D cells, TAAR1-expressing dopaminergic nerve endings, GABAergic neurons, and astroglial processes [22, 53]. Astroglial influences to dopaminergic axon terminals by gliotransmitters have been discussed in the striatum in details by Adermark and coworkers [54]. In our model, TAAR1 activation switches on, whereas the heterodimer form of TAAR1 with dopamine D2 receptor switches off action potential-mediated dopamine release [55]. Dopamine released into the extrasynaptic space up- or downregulates AADC activity in D cells and trace amine synthesis, which then will influence TAAR1 activity in positive or negative direction. Supporting this, recent experiments in our laboratory indicated that the trace amine phenylethylamine evokes [³H]dopamine release from rat striatum [17]. We also postulate here a receptor resembling to TAAR1 function in the regulation of GABA release. Abbreviations: AA, amino acid; TA, trace amine; DA, dopamine; AADC, aromatic amino acid decarboxylase; TAAR1, trace amine-associated receptor 1