The difference in effect of mGlu2/3 and mGlu5 receptor agonists on cognitive impairment induced by MK-801.
The manipulation of glutamate neurotransmission could represent a potential strategy for the pharmacotherapy of schizophrenic symptoms. Preclinical studies suggest that two subtypes of metabotropic glutamate (mGlu) receptors such as mGlu2/3 and mGlu5 receptors have the potential to ameliorate deficits in schizophrenia. In our study we evaluated the role of a non-specific mGlu receptor agonist ((1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid; 1S,3R-ACPD), mGlu5 receptor agonist or positive modulators ((RS)-2-Chloro-5-hydroxyphenylglycine;CHPG; [(3-Fluoro-phenyl)methylene]hydrazone-3-fluorobenzaldehyde; DFB; 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; CDPPB) and a mGlu2/3 receptor agonist (2,2,2-Trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyrdinylmethyl)ethanesulfonamide hydrochloride; LY-487379) on performance in a cognitive task (Active Allothetic Place Avoidance) after sub-chronic administration of 5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclo-hepten-5,10-imine; MK-801 . The Active Allothetic Place Avoidance task is suitable for assessing the executive function and attention of animals and was previously validated for testing the effect of anti-psychotics. Application of the mGlu2/3 receptor agonist had no effect on cognitive impairment induced by MK-801. However, the mGlu5 receptor agonists ameliorated cognitive impairment induced by MK-801 without affecting locomotion. In conclusion, the mGlu5 receptor agonists could be effective in the treatment of cognitive deficits in patients with schizophrenia. However, the pro-cognitive effect of the agonist of mGlu2/3 receptors was not demonstrated in the present study.
Vales
Karel
K
Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, Prague 4, Czech Republic. vales@biomed.cas.cz
Svoboda
Jan
J
Benkovicova
Kristina
K
Bubenikova-Valesova
Vera
V
Stuchlik
Ales
A
D000818:Animals; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy
D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D016291:Dizocilpine Maleate