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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
Author(s) -
Suryavanshi P S,
Ugale R R,
YilmazerHanke D,
Stairs D J,
Dravid S M
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12518
Subject(s) - potentiator , prepulse inhibition , chemistry , nmda receptor , receptor , pharmacology , biochemistry , biology , medicine , schizophrenia (object oriented programming) , psychiatry
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 receptor s ( M ullasseril 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.