Glycine and D: -serine, but not D: -cycloserine, attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801.
BACKGROUND
Several agents that stimulate the glycine site of N-methyl-D: -aspartate (NMDA) receptors have been reported to moderately improve both negative symptoms and cognitive dysfunctions in patients with schizophrenia. However, differences in efficacy have also been reported, and further comparative pharmacological studies are still needed.


OBJECTIVE
We aimed to explore the effects of two glycine site agonists of the NMDA receptor, glycine and D: -serine, and a partial agonist, D: -cycloserine, on prepulse inhibition (PPI) deficits induced by a NMDA receptor antagonist, MK-801, in mice. Furthermore, we performed in vivo microdialysis and additional PPI measurements using a selective glycine site antagonist to verify if the beneficial effects observed after the systemic administration of glycine were due to glycine itself via its activity at the glycine site.


RESULTS
High doses of glycine (1.6 g/kg) and D: -serine (1.8 and 2.7 g/kg) significantly attenuated MK-801-induced PPI deficits. In contrast, D: -cycloserine did not show any amelioration of MK-801-induced PPI deficits at doses ranging from 7.5 mg/kg to 60 mg/kg. The selective glycine site antagonist, L-701,324 (10 mg/kg), antagonized the effect of glycine on MK-801-induced PPI deficits. Furthermore, in vivo microdialysis demonstrated that intraperitoneal injection of glycine significantly increased glycine and L: -serine levels, but decreased D: -serine levels in the prefrontal cortex.


CONCLUSIONS
The findings of the present study suggest that glycine and D: -serine but not D: -cycloserine could attenuate PPI deficits associated with NMDA receptor hypofunction via NMDA glycine sites in the brain.
Kanahara
Nobuhisa
N
Department of Psychiatry, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan.
Shimizu
Eiji
E
Ohgake
Shintaro
S
Fujita
Yuko
Y
Kohno
Mami
M
Hashimoto
Tasuku
T
Matsuzawa
Daisuke
D
Shirayama
Yukihiko
Y
Hashimoto
Kenji
K
Iyo
Masaomi
M
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003523:Cycloserine / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005998:Glycine / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D017551:Microdialysis; D015363:Quinolones / Q000494:pharmacology; D013216:Reflex, Startle / Q000187:drug effects*; D012694:Serine / Q000494:pharmacology*
D000963:Antimetabolites; D018691:Excitatory Amino Acid Antagonists; D015363:Quinolones; D012694:Serine; D016291:Dizocilpine Maleate; D003523:Cycloserine; C094635:L 701324; D005998:Glycine