Neonatal administration of N-omega-nitro-L-arginine induces permanent decrease in NO levels and hyperresponsiveness to locomotor activity by D-amphetamine in postpubertal rats.
Nitric oxide (NO) is associated with dopamine (DA) release. Previously, we demonstrated that rats treated with a non-selective nitric oxide synthase inhibitor, N-omega-nitro-L-arginine (L-NNA) at postnatal days 4-6 (PD4-6) show increased locomotion and disrupt neuronal cytoarchitecture after puberty (PD60). Here, we investigate whether the modulation of NO production in rats at PD4-6 causes long term changes of NO system, its impact on DA innervation, and schizophrenia-like behaviors. NO levels were measured in seven brain areas at PD35, PD60, PD90, and PD120. Autoradiographic studies explored the effect of l-NNA on the expression of D1 and D2 receptors in the caudate-putamen (CPu) and nucleus accumbens (NAcc) at PD60. Locomotor activity was assessed at PD60 using the non-selective DA agonists, amphetamine and apomorphine, and the selective DA receptor agonist [D2, quinpirole; D3, 7-hydroxy-N,N-di-n-propylaminotetralin ((+/-)-7-OH-DPAT)]. L-NNA treatment produced decreases in NO levels in the frontal cortex, striatum, brainstem and cerebellum, while in the occipital cortex changes were observed at PD120. Hippocampus and temporoparietal cortex showed differential levels of NO. Receptor autoradiography revealed increases in D1 receptor levels in the NAcc (shell), while decreases in D2 receptor binding were observed in the CPu and NAcc (core). Amphetamine and quinpirole treatments resulted in increases in locomotion. In contrast, treatment with 7-OH-DPAT produced hypolocomotion at low doses, while increased locomotion was seen at the highest dose. These results show that modulation of NO levels early postnatally (PD4-6) produces long term alteration in NO levels, with possible consequences on DA transmission, and related behaviors relevant to schizophrenia.
Morales-Medina
Julio César
JC
Laboratorio de Neuropsiquiatría, Instituto de Fisiología, Universidad Autónoma de Puebla, 14 Sur 6301, Col. San Manuel, CP 72570 Puebla, Mexico.
Mejorada
Alejandro
A
Romero-Curiel
Alejandra
A
Aguilar-Alonso
Patricia
P
León-Chávez
Bertha Alicia
BA
Gamboa
Citlalli
C
Quirion
Remi
R
Flores
Gonzalo
G
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001345:Autoradiography; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003913:Dextroamphetamine / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D009043:Motor Activity / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013997:Time Factors
D000697:Central Nervous System Stimulants; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D019335:Nitroarginine; D009569:Nitric Oxide; D003913:Dextroamphetamine