Fig. 4: Novel HCN inhibitors MS7710 and MS7712 reverse CSDS-induced hyperdopaminergia in male CSDS-susceptible mice. | Molecular Psychiatry

Fig. 4: Novel HCN inhibitors MS7710 and MS7712 reverse CSDS-induced hyperdopaminergia in male CSDS-susceptible mice.

From: Design and validation of novel brain-penetrant HCN channel inhibitors to ameliorate social stress-induced susceptible phenotype

Fig. 4: Novel HCN inhibitors MS7710 and MS7712 reverse CSDS-induced hyperdopaminergia in male CSDS-susceptible mice.

a Experimental timeline for CSDS and in vivo electrophysiology. b SI ratios of the male CSDS mice before in vivo electrophysiological recordings (n = 6,8,9; p = 0.36). c Example in vivo electrophysiology trace of firing rate in VTA DA neurons in CSDS-susceptible mice. d Examples of tonic activity (yellow box labeled i) and phasic (bursting) activity (red box labeled ii). e Classical waveform of a VTA DA neuron, averaged over 50 spikes (scale bar 20 mV vs. 1 ms). f Sample traces of baseline firing rate and firing rate following a 20 mg/kg IP injection of Cilobradine (scale bars 0.05 mV vs. 1 s). Summary and inset cumulative distribution (dotted horizontal line represents 100%) of: g firing rate in VTA DA neurons during baseline conditions (0 mg/kg Cilobradine; n = 57/17) or post-IP injection of 20 mg/kg Cilobradine (n = 44/11; * p = 0.0184), and h bursting activity in VTA DA neurons during baseline conditions (0 mg/kg Cilobradine; n = 57/17) or post-IP injection of 20 mg/kg Cilobradine (n = 44/11; *** p = 0.0001). i Sample traces of baseline firing rate and firing rate following an IP injection of 1 mg/kg and 10 mg/kg MS7712. Summary and inset cumulative distribution of: j firing rate in VTA DA neurons during baseline conditions (0 mg/kg MS7712; n = 17/6) or post-IP injection of 1 mg/kg (n = 21/3) or 10 mg/kg (n = 22/3) MS7712 (H3/60 = 23.42, p < 0.0001; 10 mg/kg MS7712 vs. baseline, *** p < 0.0001), and k bursting activity in VTA DA neurons during baseline conditions (0 mg/kg MS7712; n = 17/6) or post-IP injection of 1 mg/kg (n = 21/3) or 10 mg/kg (n = 22/3) MS7712 (H3/60 = 11.38, p = 0.0034; 10 mg/kg MS7712 vs. baseline, **p = 0.0023). l Sample traces of firing rate following an IP injection of 1 and 10 mg/kg MS7710. Summary and inset cumulative distribution of m firing rate in VTA DA neurons during baseline conditions (0 mg/kg MS7710; n = 27/8) or post-IP injection of 1 mg/kg (n = 15/3) or 10 mg/kg (n = 18/3) MS7710 (H3/59 = 14.97, p = 0.0006; 1 mg/kg MS7710 vs. baseline, * p = 0.0150; 10 mg/kg MS7710 vs. baseline, *** p = 0.0007) and n bursting activity in VTA DA neurons during baseline conditions (0 mg/kg MS7710; n = 27/8) or post-IP injection of 1 mg/kg (n = 15/3) or 10 mg/kg (n = 18/3) MS7710 (H3/59 = 7.752, * p = 0.0207; 1 mg/kg MS7710 vs. baseline, * p = 0.0494; 10 mg/kg MS7710 vs. baseline, * p = 0.0364). All sample trace scale bars 0.1 mV vs. 1 s unless otherwise noted. Notation of n = ntotal cells/ntotal mice. Data are presented as median ± quartiles ± min and max, analyzed by the Mann-Whitney test for two groups or the Kruskal-Wallis test for three groups, followed by Dunn’s test for multiple comparisons. * p < 0.05, ** p < 0.01, *** p < 0.001.

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