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.
OBJECTIVE
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.).


METHODS
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.


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.


CONCLUSIONS
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.
Department of Pharmacology, Creighton University, Omaha, NE, USA.
P S
PS
Suryavanshi
R R
RR
Ugale
D
D
Yilmazer-Hanke
D J
DJ
Stairs
S M
SM
Dravid
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate; D006948:Hyperkinesis / Q000209:etiology / Q000517:prevention & control; D007546:Isoquinolines / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018697:Nootropic Agents / Q000627:therapeutic use*; D021122:Protein Subunits / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D011804:Quinolines / Q000627:therapeutic use*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology
C000592157:(3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone; D007546:Isoquinolines; C432823:NR2C NMDA receptor; C464436:NR2D NMDA receptor; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D021122:Protein Subunits; D011804:Quinolines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate
CIQ; GRIN2C; GRIN2D; GluN2C; GluN2D; NMDA receptor; prepulse inhibition; schizophrenia; working memory in Y-maze