Fig. 6.

TAAR1 activity modulates D2 receptor desensitization rate and agonist potency in DA neurons of the VTA. (A and B) Representative traces of quinpirole-induced currents in the presence and absence of EPPTB. (Scale bar, 5 min/20 pA.) Bar graphs represent the desensitization rate, which is expressed as the residual current after continuous quinpirole application for 15 min [I(t)], normalized to the initial maximal current (Imax). (A) Preincubation of WT slices with EPPTB (10 nM) prevents the D2 receptor desensitization seen in control slices (control, I(t)/Imax = 0.31 ± 0.04; EPPTB, I(t)/Imax = 1.08 ± 0.05; n = 9, ***, P < 0.001). (B) Taar1^−/− slices exhibit non-desensitizing D2-mediated currents in the absence and presence of EPPTB (control, I(t)/Imax = 1.03 ± 0.14; EPPTB, I(t)/Imax = 1.09 ± 0.08; n = 6). Following application of the D2 antagonist sulpiride, the holding current was reduced below baseline (dotted line) in WT slices preincubated with EPPTB, similar as in Taar1^−/− slices. (C) Dose-response relationships of the quinpirole-induced current in WT slices, WT slices preincubated with EPPTB (10 nM), WT slices preincubated with p-tyr (40 nM) and Taar1^−/− slices. Current amplitudes were normalized to the maximal current obtained with a saturating concentration of quinpirole (10 μM). EC₅₀ values: WT, 109.5 ± 3.8 nM, n = 9; WT + EPPTB, 27.2 ± 0.4 nM, n = 9; WT + p-tyr, 754.4 ± 6.6 nM, n = 4; Taar1^−/−, 23.3 ± 0.4 nM, n = 9.