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[Preprint]. 2024 Nov 21:2024.11.20.624209. [Version 2] doi: 10.1101/2024.11.20.624209

Figure 6. SBI-593 does not produce a complete block of NTSR1 agonist-induced, Gq-mediated hypothermia in mice.

Figure 6.

(A-B) Systemic PD142948A induces an NTSR1-dependent hypothermia in mice. (A) Experimental timeline. (B) Effect of PD149163 (0.1–1.0 mg/kg, i.p.) on core body temperature in WT and NTSR1−/− mice. (C-D) SBI-593 partially antagonizes PD149163-induced Gq activation by the NTSR1. (C) Effect of SBI-553 and SBI-593 on PD149163-induced Gq activation by the (C) human and (D) mouse NTSR1. In HEK293T cells transiently expressing NTSR1, the NT-induced association between NTSR1 and miniGq was assessed by BRET. (E-G) Systemic SBI-593 administration does not attenuate PD149163-induced hypothermia. (E) Experimental timeline. (F) Effect of SBI-553 (12 mg/kg, i.p.) vs. Vehicle (5% HP-β-cyclodextrin) pretreatment on PD149163 (15 mg/kg,i.p.)-induced hypothermia. (G) Effect of SBI-593 (12 mg/kg, i.p.) vs. Vehicle (20% DMSO, 5% Tween 80) pretreatment on PD149163 (0.15 mg/kg, ,i.p.)-induced hypothermia. (H) Overview of bilateral intracranial cannula placement in mice. Cannulas targeted the nucleus accumbens (NAc). (I-K) Intra-NAc PD142948A induces an NTSR1-dependent hypothermia in mice. (I) Experimental timeline. (J) Ink-verified cannula placements for mice in panel K. Numbers denote mm in front of bregma. AP, anterior-posterior. (K) Effect of microinjection of PD149163 (93 ng, bilateral) into the NAc on core body temperature in WT and NTSR1−/− mice. (L-P) Intra-NAc SBI-593 administration partially but does not fully attenuate PD149163-induced hypothermia. (L) Experimental timeline. (M) Ink-verified cannula placements for mice in panel N. Numbers denote mm in front of bregma. AP, anterior-posterior. (N) Effect of intra-NAc SBI-553 (100 µg, bilateral) and SBI-593 (100 µg, bilateral) on PD149163 (9.3 ng, bilateral, intra-NAc)-induced hypothermia. (O) Area of the curve for data in panel N. Baseline set at 37⁰C. (P) Proportion of mice exhibiting complete vs. incomplete blockade of PD149163-induce hypothermia by treatment group. For information on N, statistical comparisons, and curve parameters, see Table S6.