Down-regulation of nitrergic transmission in the rat striatum after chronic nigrostriatal deafferentation.
Dopamine and NO are physiological stimulators of synthesis of cAMP and cGMP, respectively, and NO synthase-containing interneurons in the striatum are physiologically activated by dopamine-containing neurons in the substantia nigra. This study investigated whether lesioning dopamine neurons has multiple consequences in the striatum consistent with the reported sensitization of cAMP synthesis, including alteration of the NO-cGMP pathway and phosphodiesterase-dependent metabolism of cyclic nucleotides. The substantia nigra of adult Sprague-Dawley rats was unilaterally lesioned with 6-hydroxydopamine. Two months later, we determined expression of NO synthase and evaluated cGMP and cAMP levels of intact and deafferented striatum. Moreover, we evaluated cAMP- and cGMP-phosphodiesterase activities in basal conditions and after Ca2+-calmodulin stimulation and determined the expression of the phosphodiesterase-1B isoform and the levels of phosphodiesterase-1B mRNA. Using immunocytochemistry we characterized the distribution of NO synthase and phosphodiesterase-1B within striatal neurons. In the dopamine-deafferented striatum, NO synthase levels were decreased by 42% while NO synthase-immunopositive intrastriatal fibres but not NO synthase neuronal bodies were reduced in number. In the deafferented striatum basal cGMP levels were reduced, and cAMP levels were increased, but cGMP-phosphodiesterase and cAMP-phosphodiesterase activities were both increased in basal and Ca2+-calmodulin-stimulated conditions. Accordingly, phosphodiesterase-1B expression and phosphodiesterase-1B mRNA were upregulated while a large population of medium-sized striatal neurons showed increased phosphodiesterase-1B immunoreactivity. Dopamine deafferentation led to a complex down-regulation of the NO-cGMP pathway in the striatum and to an up-regulation of phosphodiesterase-1B-dependent cyclic nucleotide metabolism, showing new aspects of neuronal plasticity in experimental hemiparkinsonism.
Department of Neuroscience, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. sancesario@med.uniroma2.it
Giuseppe
G
Sancesario
Mauro
M
Giorgi
Vincenza
V
D'Angelo
Anna
A
Modica
Alessandro
A
Martorana
Maria
M
Morello
C Peter
CP
Bengtson
Giorgio
G
Bernardi
D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000201:enzymology*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D015536:Down-Regulation / Q000502:physiology*; D008297:Male; D026602:Nitrergic Neurons / Q000166:cytology / Q000201:enzymology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052248:Nitric Oxide Synthase Type I; D016627:Oxidopamine / Q000633:toxicity; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology / Q000201:enzymology*; D009435:Synaptic Transmission / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis
D009569:Nitric Oxide; D016627:Oxidopamine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D014446:Tyrosine 3-Monooxygenase; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1