In vivo electrophysiology of dopamine-denervated striatum: focus on the nitric oxide/cGMP signaling pathway.
Within the striatum, the gaseous neurotransmitter nitric oxide (NO) is produced by a subclass of interneurons containing the neuronal NO synthase (nNOS). NO promotes the second messenger cGMP through the activation of the soluble guanyl cyclase (sGC) and plays a crucial role in the integration of glutamate (GLU) and DA transmission. The aim of this study was to characterize the impact of 6-hydroxyDA (6-OHDA) lesion of the rat nigrostriatal pathway on NO/cGMP system. In vivo extracellular single units recordings were performed under urethane anesthesia to avoid any potentially misleading contributions of cortically-driven changes on endogenous NO. Hence, no electrical extrastriatal stimulation was performed and great attention was paid to the effects of 3-morpholinosydnonimine (SIN-1, a NO donor), N(G)-nitro-L-arginine methyl ester (L-NAME, a nonselective NOS inhibitor) and Zaprinast (a PDE inhibitor) delivered by iontophoresis upon the main striatal phenotypes. The latter were operationally distinguished in silent medium spiny-like neurons (MSN), with negligible spontaneous activity but displaying glutamate-induced firing discharge at rest and spontaneously active neurons (SAN), representing to a large extent nonprojecting interneurons. SANs were excited by SIN-1 and Zaprinast while MSNs showed a clear inhibition during local iontophoretic application of SIN-1 and Zaprinast. In 6-OHDA animals, SIN-1-induced excitation in SANs was significantly increased (on the contrary, the inhibitory effect of L-NAME was less effective). Interestingly, in DA-denervated animals, a subclass of MSNs (40%) displayed a peculiar excitatory response to SIN-1. These findings support the notion of an inhibitory modulatory role exerted by endogenous NO on control striatal projection cells. In addition, these findings suggest a functional cross-talk between NO, spontaneously active interneurons, and projection neurons that becomes critical in the parkinsonian state.
Galati
Salvatore
S
Division of Neurology, Department of Neuroscience, University of Rome Tor Vergata, Rome, Italy.
D'angelo
Vincenza
V
Scarnati
Eugenio
E
Stanzione
Paolo
P
Martorana
Alessandro
A
Procopio
Teresa
T
Sancesario
Giuseppe
G
Stefani
Alessandro
A
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000293:injuries / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism*; D003714:Denervation / Q000379:methods*; D004298:Dopamine / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009569:Nitric Oxide / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013565:Sympatholytics / Q000633:toxicity
D004791:Enzyme Inhibitors; D013565:Sympatholytics; D009569:Nitric Oxide; C002385:linsidomine; D016627:Oxidopamine; D008981:Molsidomine; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester; D004298:Dopamine