The Effects Of Metabotropic Glutamate Receptorson Glutamatergic Neuronal Functionsin Brain Of Freely Moving Rats

Glutamate receptors including metabotropic(m Glu Rs) and ionotropic(i Glu Rs) glutamate receptors are the most developed area in neuroscience over past twenty years. Especially the crucial roles of the glutamate receptors played in psychiatric disorders such as depression, anxiety, cognition,schizophrenia and neuroprotection, glutamate receptors have therefore received most attentions from neuroscientists globally.In the present studies, we investigated the effects of m Glu R ligands on glycine and glutamate release in the rat striatum using intercerebral microdialysis, in order to unveil the characteristics of various m Glu Rs on glutamatergic neurotransmission. The work covered by the present studies including:1. The first, the methodology of intercerebral microdialysis technique has been established and fully validated using tetrodotoxin, high concentration of K+, and Ca2+ free perfusate, in order to demonstrate the origin of neurotransmitter from dialysates.2. Local administration of group I m Glu R agonist(S)-3,5-DHPG maximally enhanced glutamate and glycine levels in the striatum of freely moving rats, the maximal effects were reached 40 min after drug administration, and went back to normal levels when normal artificial CSF was restored. Such effects showed a concentration dependent manner.3. Local administration of group I m Glu R antagonist CPCCOEt alone had no effect on glutamate and glycine levels. When(S)-3,5-DHPG was co-administered with CPCCOEt simultaneously, both glutamate and glycine levels showed no significant changes, indicating the(S)-3,5-DHPG induced enhancement of levels of glutamate and glycine were completely prevented by the group I m Glu R antagonist.4. MTPG, a group II m Glu R antagonist, or CPPG, a group III m Glu R antagonist alone administered locally had no effect on both glutamate and glycine levels in the rat brain. When(S)-3,5-DHPG was co-administered with MTPG simultaneously, the DHPG-induced enhancement of glutamate and glycine levels were significantly reduced, the maximal effects were approximately 50 and 30 % above the basal levels. When DHPG was co-administered with CPPG simultaneously, the DHPG-induced enhancement of glutamate and glycine levels were also significantly reduced, the maximal effects were approximately 70 and 70 % above the basal levels respectively.5. DCG-IV, a group II m Glu R agonist, L-SOP, L-AP4 and L-CCG-1, group III m Glu R agonists, to different content, significantly reduced glutamate levels, when normal a CSF restored, the glutamate levels went back to normal only in L-AP4 treated group, the glutamate levels stayed in reduced levels in DCG-IV, L-SOP or L-CCG-1 treated group. DCG-IV, L-SOP and L-AP4 had no significant effects on glycine levels, except L-CCG-1 showed significant enhancement in glycine levels.6. Local administration of 1S,3S-ACPD, a group II m Glu R agonist, significantly decreased glutamate levels, while the glycine levels was significantly enhanced, both glutamate and glycine levels went back to normal when normal a CSF restored.7. Co-administration of CPCCOEt, a group I mGluR antagonist, MTPG, a group II m Glu R antagonist or CPPG, a group III m Glu R antagonist, with 1S,3S-ACPD, had no significant effect on 1S,3S-ACPD induced reduction of glutamate levels,when normal a CSF restored, the glutamate stayed in reduced levels. Co-administration of CPCCOEt with 1S,3S-ACPD completely prevented 1S,3S-ACPD induced enhancement of glycine levels, whereas MTPG or CPPG significantly, but not completely, reduced 1S,3S-ACPD induced responses in glycine levels.In conclusion, the present studies investigated the effects of different group I, II and III m Glu R agonists and antagonists on glutamate and glycine release in the striatum of freely moving rats, using intercerebral microdialysis technique, therefore to unveil the characteristics of effects on different subtypes of glutamate receptors on glutamatergic neuronal transmissions.