Allosteric Modulation of the Sigma-1 Receptor Elicits Antipsychotic-like Effects

Abstract

Allosteric modulation represents an important approach in drug discovery because of its advantages in safety and selectivity. SOMCL-668 is the first selective and potent sigma-1 receptor allosteric modulator, discovered in our laboratory. The present work investigates the potential therapeutic effects of SOMCL-668 on phencyclidine (PCP)-induced schizophrenia-related behavior in mice and further elucidates underlying mechanisms for its antipsychotic-like effects. SOMCL-668 not only attenuated acute PCP-induced hyperactivity and PPI disruption, but also ameliorated social deficits and cognitive impairment induced by chronic PCP treatment. Pretreatment with the selective sigma-1 receptor antagonist BD1047 blocked the effects of SOMCL-668, indicating sigma-1 receptor-mediated responses. This was confirmed using sigma-1 receptor knockout mice, in which SOMCL-668 failed to ameliorate PPI disruption and hyperactivity induced by acute PCP and social deficits and cognitive impairment induced by chronic PCP treatment. Additionally, in vitro SOMCL-668 exerted positive modulation of sigma-1 receptor agonist-induced intrinsic plasticity in brain slices recorded by patch-clamp. Furthermore, in vivo lower dose of SOMCL-668 exerted positive modulation of improvement in social deficits and cognitive impairment induced by the selective sigma-1 agonist PRE084. Also, SOMCL-668 reversed chronic PCP-induced down-regulation in expression of frontal cortical p-AKT/AKT, p-CREB/CREB and BDNF in wide-type but not sigma-1 knockout mice. Moreover, administration of the PI3K/AKT inhibitor LY294002 abolished amelioration by SOMCL-668 of chronic PCP-induced schizophrenia-related behaviors by inhibition of BDNF expression. The present data provide initial, proof-of-concept evidence that allosteric modulation of the sigma-1 receptor may be a novel approach for the treatment of psychotic illness.

Keywords: AKT–CREB–BDNF pathway; SOMCL-668; allosteric modulator; chaperone protein; schizophrenia.

Fig. 1.

Effects of SOMCL-668 on acute and chronic phencyclidine-induced schizophrenia-related behaviors. (A) Experimental outline of acute studies. (B) PPI (%) was assessed using a startle stimulus intensity of 120 dB and prepulse intensities of 76, 83 and 87 dB. (C) Representative specimen traces of locomotor activity and summary bar graph of distance traveled. (D) Experimental outline of chronic studies. Social interaction (E) is presented as interaction time (s) and novel object recognition is presented as exploration time (s) for the familiar and novel objects (F) and as discrimination index (G). Data are shown as mean ± SEM; n = 10–12 mice per group. Statistical analysis was by one-way ANOVA (C, E and G) and two-way ANOVA (B and F); * P < .05, ** P < .01, *** P < .001.

Fig. 2.

SOMCL-668 fails to improve phencyclidine-induced schizophrenia-related behaviors in sigma-1 receptor knockout mice. (A) PPI (%) was assessed using a startle stimulus intensity of 120 dB and prepulse intensities of 76, 83 and 87 dB. (B) Representative specimen traces of locomotor activity and summary bar graph of distance traveled. Social interaction (C) is presented as interaction time (s) and novel object recognition is presented as exploration time (s) for the familiar and novel objects (D) and as discrimination index (E). Data are shown as mean ± SEM; n = 10–12 mice per group. Statistical analysis was by two-way ANOVA; * P < .05, ** P < .01, *** P < .001.

Fig. 3.

SOMCL-668 positively modulates the effect of PRE084 both in vitro and in vivo. (A) Representative traces of intrinsic excitability and spike frequency adaption. (B) Spike frequencies elicited at 140 pA and 360 pA, with or without bath application of PRE084. (C) Complete plot of spike frequency against step current (pA) with or without bath application of PRE084. (D) Representative traces of intrinsic excitability and spike frequency adaption for action potentials. (E) Spike frequencies elicited at 220 pA and 360 pA, with or without bath application of SOMCL-668. (F) Complete plot of spike frequency against step current (pA) with or without bath application of SOMCL-668. (G) Representative traces of intrinsic excitability and spike frequency adaption for action potentials. (H) Spike frequencies elicited at 180 pA and 360 pA, with or without bath application of PRE084 + SOMCL-668. (I) Complete plot of spike frequency against step current (pA) with or without bath application of PRE084 + SOMCL-668. (J) Experimental outline of behavioral study. Social interaction (K) is presented as interaction time (s) and novel object recognition is presented as exploration time (s) for the familiar and novel objects (L) and as discrimination index (M). Data are shown as mean ± SEM; n = 16–18 cells from 3–4 mice in electrophysiological tests and n = 10–12 mice in behavioral tests. Statistical analysis was by two-way ANOVA (C, F, I and L), one-way ANOVA (K and M) and Student’s paired t-test (B, E and H); * P < .05, ** P < .01, *** P < .001.

Fig. 4.

Effects of SOMCL-668 on AKT–CREB–BDNF pathway in chronic PCP-treated mice. (A) Expression of BDNF in WT treated with Veh, PCP and SOMCL-668 + PCP. (B–E) Representative immunoblots (B) and ratios of p-AKT/AKT (C), p-CREB/CREB (D) and BDNF (E) in WT and S1R^-/- mice treated with PCP, SOMCL-668 and SOMCL-668 + PCP. (F) Experimental outline of chronic studies. Social interaction (G) is presented as interaction time (s) and novel object recognition is presented as exploration time (s) for the familiar and novel objects (H) and as discrimination index (I). (J, K) Representative immunoblots (J) and quantitation (K) of BDNF levels from prefrontal cortex after the behavioral studies in (I). Data are shown as mean ± SEM; n = 6 mice per group (A–E), n = 14–16 mice per group (G–I) and n = 4 mice in each group (J, K). Statistical analysis was by two-way ANOVA; * P < .05, ** P < .01, *** P < .001.