Long-term depression of cortico-striatal synaptic transmission by DHPG depends on endocannabinoid release and nitric oxide synthesis.
In models of early stage Parkinson's disease (PD), motor deficits are accompanied by excessive activation of striatal glutamate receptors. Metabotropic glutamate group I receptors (mGluR I) play an important but not well-understood role in PD progression. In mouse brain slices, bath application of the mGluR I agonist (RS)-DHPG (3,5-dihydroxyphenylglycine, 100 microm for 20 min) caused a long-term depression of corticostriatal transmission (LTD(DHPG)), which was reversed by three mGluR I antagonists: LY 367385, CPCCOEt and MPEP. LTD(DHPG) required nitric oxide (NO) synthesis as it was blocked by the broad-spectrum NO synthase (NOS) inhibitor Nomega-nitro-l-arginine (NL-Arg) and impaired under blockade of neuronal NOS and in endothelial NOS-deficient mice. Release of endocannabinoids (eCB) was critically involved in this form of striatal plasticity givem that the CB1 receptor antagonist AM251 prevented LTD(DHPG), while the CB1 agonist ACEA elicited LTD. The NO synthesis necessary for LTD(DHPG) induction occurred downstream of CB1 activation as ACEA-evoked LTD was also abolished by NL-Arg. These findings are relevant for the pathophysiology of PD, as they link the overactivation of group I mGluRs and striatal NO production.
Sergeeva
O A
OA
Department of Neurophysiology, Heinrich-Heine-University, D-40001, Dusseldorf, Germany. olga.sergeeva@uni-duesseldorf.de
Doreulee
N
N
Chepkova
A N
AN
Kazmierczak
T
T
Haas
H L
HL
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology*; D003342:Corpus Striatum / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000528:radiation effects; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency; D019335:Nitroarginine / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D019335:Nitroarginine; D009569:Nitric Oxide; D008734:Methoxyhydroxyphenylglycol; D052250:Nitric Oxide Synthase Type III; C010117:3,4-dihydroxyphenylglycol