Fig. 1: Short- and long-term ethanol intake is controlled by 5-HT1A autoreceptors.
From: Neural serotonergic circuits for controlling long-term voluntary alcohol consumption in mice
A–C Short-term ethanol intake (6 weeks) is reduced by 5-HT1A receptor stimulation, with the highest dose of the unbiased agonist NLX-112 (A, repeated-measure one-way ANOVA, n = 8, F (1.760, 12.32) = 9.049, p = 0.0047, with Bonferroni multiple comparison: *: p = 0.0114 vs vehicle). This effect is likely mediated by the activation of 5-HT1A autoreceptors as ethanol intake is dose-dependently reduced by the autoreceptor agonist F13714 (B, repeated-measure one-way ANOVA, n = 8, F(1.585, 11.10) = 20.17, p = 0.0003, with Bonferroni multiple comparison: ***: p = 0.0006 (0.16 mg/kg) and p = 0.0003 (0.64 mg/kg) vs vehicle), but not by the heteroreceptor agonist NLX-101 (C, repeated-measure one-way ANOVA, n = 8, F(2.046, 14.32) = 2.446, p = 0.1211). D-I. Long-term ethanol intake (12 weeks) is reduced by 5-HT1A receptor stimulation, with a dose-dependent effect of the unbiased agonist NLX-112 (D, repeated-measure one-way ANOVA, n = 8, F(1.945, 13.61) = 12.03, p = 0.001, with Bonferroni multiple comparison: **p = 0.0028 (0.16 mg/kg) and p = 0.0038 (0.64 mg/kg) vs vehicle). Again, this effect is likely mediated by the activation of 5-HT1A autoreceptors as ethanol intake is dose-dependently reduced by the autoreceptor agonist F13714 (E, repeated-measure one-way ANOVA, n = 7, F(2.134, 12.80) = 24.27, p < 0.0001, with Bonferroni multiple comparison: *p = 0.044, **p = 0.0051, ***p = 0.0007), but not the heteroreceptor agonist NLX-101 (F, repeated-measure one-way ANOVA, n = 8 F(1.643, 11.50) = 2.252, p = 0.15). The specific involvement of 5-HT1A receptors has been confirmed by the blockade of the effects of the highest dose of NLX-112 (G, one-way ANOVA, n = 8, F(3, 28) = 9.622, p = 0.0002, with Bonferroni multiple comparison: ****p < 0.0001 vs veh/veh control), or F13714 (H, one-way ANOVA, n = 7, F(3, 24) = 18.33, p < 0.0001, with Bonferroni multiple comparison: ****p < 0.0001 vs veh/veh control) by the selective 5-HT1A receptor antagonist WAY100635 (0.64 mg/kg). The lack of efficacy of the highest dose of NLX-101 on ethanol intake showed also no effect of the WAY100635 (n = 8, I). J–L Effects of NLX-112, F13714 and NLX-101 on locomotor activity was assessed in ethanol-naïve mice, for 2.5 h after injection, or 2 h min into the drinking session, showing no effect on locomotor activity of NLX-112 (J, t test on the area-under-curve (AUC), n = 6, p = 0.1523), F13714 (K, t test on the area-under-curve, n = 6, p = 0.0877) or NLX-101 (L, t test on the area-under-curve, n = 6, p = 0.6107).
