Activation of Cerebellar Climbing Fibers Increases Cerebellar Blood Flow

Abstract

Background —The mechanisms regulating the cerebellar microcirculation during neural activity are poorly understood. One of the major neural inputs to the cerebellar cortex is the climbing fiber (CF), a pathway that uses excitatory amino acids, including glutamate, as a transmitter. We studied whether CF activation increases cerebellar blood flow (BFcrb) and, if so, we investigated the role of glutamate receptors, nitric oxide (NO) and cGMP, in the response. Methods —The CF were activated by harmaline administration (40 mg/kg, IP) in halothane-anesthetized rats with a cranial window placed over the cerebellar vermis. BFcrb was monitored by a laser-Doppler probe, and arterial pressure and blood gases were controlled. Results —With Ringer superfusion, harmaline produced sustained increases in BFcrb that peaked 20 minutes after administration (+115±13%; n=6; P <.05). The increases in BFcrb were substantially reduced by superfusion with tetrodotoxin (10 μmol/L; −91±5%; n=5; P <.05 from Ringer). The response was also attenuated by the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor inhibitor 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)-quinoxaline (100 μmol/L; −70±6%; P <.05; n=5), but not by the N -methyl- d -aspartate receptor blocker 2-amino-5-phosphonopentanoic acid (500 μmol/L; P >.05; n=5). The response was attenuated by the nonselective NO synthase (NOS) inhibitor nitro- l -arginine (1 mmol/L; −73±5%; n=6) or by 7-NI (50 mg, IP; −71±5%; n=5), a relatively selective neuronal NOS inhibitor. The soluble guanylyl cyclase inhibitor 1H- 1,2,4 oxadiazolo[4,3-a]quinoxalin-1-one (100 μmol/L) attenuated the response to harmaline (−73±5; P <.05; n=6) but not to superfusion with adenosine ( P >.05; n=5) or 8-bromo–cGMP ( P >.05; n=5). Conclusions —Activation of the CF system increases BFcrb. The response depends on activation of glutamate receptors and is in large part mediated by NO via stimulation of soluble guanylyl cyclase. Glutamate receptors NO and cGMP are important factors in the mechanisms of functional hyperemia in cerebellar cortex.