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Comparative Study
, 171 (3), 799-809

GluN2C/GluN2D Subunit-Selective NMDA Receptor Potentiator CIQ Reverses MK-801-induced Impairment in Prepulse Inhibition and Working Memory in Y-maze Test in Mice

Affiliations
Comparative Study

GluN2C/GluN2D Subunit-Selective NMDA Receptor Potentiator CIQ Reverses MK-801-induced Impairment in Prepulse Inhibition and Working Memory in Y-maze Test in Mice

P S Suryavanshi et al. Br J Pharmacol.

Abstract

Background and purpose: Despite ample evidence supporting the N-methyl-D-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia, progress in the development of effective therapeutics based on this hypothesis has been limited. Facilitation of NMDA receptor function by co-agonists (D-serine or glycine) only partially alleviates the symptoms in schizophrenia; other means to facilitate NMDA receptors are required. NMDA receptor sub-types differ in their subunit composition, with varied GluN2 subunits (GluN2A-GluN2D) imparting different physiological, biochemical and pharmacological properties. CIQ is a positive allosteric modulator that is selective for GluN2C/GluN2D-containing NMDA receptors (Mullasseril et al.).

Experimental approach: The effect of systemic administration of CIQ was tested on impairment in prepulse inhibition (PPI), hyperlocomotion and stereotypy induced by i.p. administration of MK-801 and methamphetamine. The effect of CIQ was also tested on MK-801-induced impairment in working memory in Y-maze spontaneous alternation test.

Key results: We found that systemic administration of CIQ (20 mg·kg⁻¹, i.p.) in mice reversed MK-801 (0.15 mg·kg⁻¹, i.p.)-induced, but not methamphetamine (3 mg·kg⁻¹, i.p.)-induced, deficit in PPI. MK-801 increased the startle amplitude to pulse alone, which was not reversed by CIQ. In contrast, methamphetamine reduced the startle amplitude to pulse alone, which was reversed by CIQ. CIQ also partially attenuated MK-801- and methamphetamine-induced hyperlocomotion and stereotyped behaviours. Additionally, CIQ reversed the MK-801-induced working memory deficit in spontaneous alternation in a Y-maze.

Conclusion and implications: Together, these results suggest that facilitation of GluN2C/GluN2D-containing receptors may serve as an important therapeutic strategy for treating positive and cognitive symptoms in schizophrenia.

Keywords: CIQ; GRIN2C; GRIN2D; GluN2C; GluN2D; NMDA receptor; prepulse inhibition; schizophrenia; working memory in Y-maze.

Figures

Figure 1
Figure 1
CIQ attenuates MK-801-induced impairment in PPI but not the startle response. (A) MK-801 was administered 15 min before the PPI session. MK-801 (0.15 mg·kg−1, i.p.) induced significant impairment in PPI. **P < 0.01, *P < 0.05 compared with Veh-Veh group. CIQ at 20 mg·kg−1 administered 15 min before MK-801 injection significantly attenuated the impairment in PPI by MK-801. ##P < 0.01 compared with Veh-MK-801 0.15 group. (B) MK-801 significantly increased the startle amplitude. *P < 0.05 compared with Veh-Veh group. CIQ (5–20 mg·kg−1, i.p.) had no effect by itself or on the enhanced startle response due to MK-801. n = 6–10 for each group.
Figure 2
Figure 2
CIQ reverses the reduction in startle response by methamphetamine but not the impairment in PPI. (A, B) Methamphetamine was administered 15 min before the PPI session. Methamphetamine (1 mg·kg−1, i.p.) did not induce a significant deficit in PPI or in the startle amplitude. (C) A higher dose of methamphetamine (3 mg·kg−1 i.p.) impaired PPI. **P < 0.01, *P < 0.05 compared with Veh-Veh group. CIQ (20 mg·kg−1, i.p.) administered 15 min before methamphetamine injection was not able to attenuate the PPI impairment. **P < 0.01, *P < 0.05 compared with Veh-Veh group. (D) CIQ (20 mg·kg−1) reversed the reduction in startle amplitude by methamphetamine (3 mg·kg−1). *P < 0.05 compared with Veh-Veh group. ##P < 0.01 compared with Veh-Meth 3 group. n = 5–7 for each group.
Figure 3
Figure 3
Effect of CIQ on MK-801-induced hyperlocomotion and stereotyped behaviours. After 15 min of acclimation, vehicle or CIQ was administered followed by vehicle or MK-801 15 min later. The effect of MK-801 (0.15 mg·kg−1, i.p.) was evaluated in the open-field test, followed by observation for stereotyped behaviours. (A) Raw beam breaks per 10 min. (B) Total beam breaks after MK-801 administration. MK-801 (0.15 mg·kg−1) induced an increase in locomotion in mice. **P < 0.01 compared with Veh-Veh group. Total beam breaks in CIQ (10 mg·kg−1)-MK-801 (0.15 mg·kg−1) was significantly higher than Veh-Veh group (**P < 0.01). Total beam break in CIQ (20 and 30 mg·kg−1)-MK-801 (0.15 mg·kg−1) group was not different from Veh-MK-801 (0.15 mg·kg−1) or Veh-Veh group (P > 0.05). (C) Stereotyped behaviours were measured after the open-field test. MK-801 (0.15 mg·kg−1) significantly increased the stereotyped behaviours in mice. **P < 0.01 compared with Veh-Veh group. CIQ (20 and 30 mg·kg−1) reduced the stereotypies induced by MK-801 (0.15 mg·kg−1). #P < 0.05 compared with Veh-MK-801 0.15 group. n = 5–10 for each group.
Figure 4
Figure 4
CIQ reverses methamphetamine-induced hyperlocomotion and stereotyped behaviours. After 15 min of acclimation, vehicle or CIQ was delivered followed 15 min later by vehicle or methamphetamine. The effect of two doses of methamphetamine (1 and 3 mg·kg−1, i.p.) was evaluated in open-field test and subsequently stereotyped behaviours were measured in home cage. (A) Raw beam breaks per 10 min. (B) Total beam breaks after methamphetamine administration. Methamphetamine (1 and 3 mg·kg−1) with pretreatment with vehicle or CIQ (20 mg·kg−1, i.p.) had higher locomotion compared with Veh-Veh group. **P < 0.01 compared with Veh-Veh group. Total beam break in CIQ 20-Meth 3 group was significantly lower than Veh-Meth 3 group. #P < 0.05. (C) Stereotyped behaviours were measured after the open-field test. Methamphetamine at both doses significantly increased the stereotyped behaviours in mice. **P < 0.01 compared with Veh-Veh group. CIQ (20 mg·kg−1) reduced the stereotypies induced by methamphetamine (1 mg·kg−1). ##P < 0.01 compared with Veh-Meth 1 group. n = 6–8 for each group.
Figure 5
Figure 5
CIQ reverses the MK-801-induced deficit in working memory in the Y-maze spontaneous alternation test. MK-801 was administered 15 min before the Y-maze test. MK-801 (0.15 mg·kg−1, i.p.) induced a significant impairment in % alternation in Y-maze. *P < 0.01 compared with Veh-Veh group. CIQ at 20 mg·kg−1 administered 15 min before MK-801 injection significantly attenuated the impairment in the Y-maze by MK-801. #P < 0.05 compared with Veh-MK-801 0.15 group. n = 7–9 for each group.

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