ABSTRACT
Our previous studies have shown that there is a lower cGMP concentration in the aged brain as well as an alteration in the activity of cGMP-hydrolyzing phosphodiesterases (PDEs) and nitric oxide synthase (NOS). The aim of this study was to investigate the effect of specific inhibitors of selected PDEs on object recognition memory and locomotor activity during aging, and to correlate their action with NOS activity in the following brain regions: hippocampus, striatum, and cerebral cortex. The study was carried out using 3, 12, and 24 month-old rats. Inhibitors of PDE2 and PDE5 (Bayer 60-7550 and zaprinast, respectively) were used. Evaluation of memory and locomotor activity was carried out using an object recognition task and the open field test. NOS activity was determined using a radiochemical method after behavioral analysis in the cytosolic fraction from all brain areas investigated. We have found that the inhibitor of PDE2, Bay60-7550, improves object recognition memory in all age groups investigated and increases basal constitutive NOS activity in the hippocampus and striatum. Moreover, in 3 month-old rats, additional inhibition of PDE5 by zaprinast improves object memory and elevates NOS activity in all brain regions studied. Specific inhibition of nNOS eliminates the effect of Bay60-7550 on memory function and on NOS activity in 24 month-old rats. In summary, our results indicate that inhibition of PDE2 is able to improve cognition and memory function in 3, 12, and 24 month-old rats through the enhancement of nNOS activity in the brain, whereas inhibition of PDE5 is effective only in 3 month-old animals.
Subject(s)
Aging/metabolism , Brain/enzymology , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Nitric Oxide Synthase/metabolism , Animals , Brain/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/enzymology , Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors , Exploratory Behavior/physiology , Hippocampus/drug effects , Hippocampus/enzymology , Male , Motor Activity/physiology , Neostriatum/drug effects , Neostriatum/enzymology , Nootropic Agents/pharmacology , Phosphodiesterase 5 Inhibitors , Phosphodiesterase Inhibitors/pharmacology , Purinones/pharmacology , Rats , Rats, Wistar , Recognition, Psychology/physiologyABSTRACT
Cyclic GMP (cGMP) is synthesized by guanylyl cyclase (GC) in response to nitric oxide (NO) and carbon monoxide (CO) or natiuretic peptides (NPs); atrial, brain and C-type (ANP, BNP and CNP). cGMP is degraded by several cGMP-specific phosphodiesterases (PDEs). Guanylate cyclases (GC) are differentiated into: membrane-bound/particulate (pGC) and cytosolic/soluble (sGC). In recent years evidence has accumulated that NO is the main activator of sGC and NO/cGMP plays important role in glutaminergic, cholinergic and dopaminergic signaling pathways. cGMP in the nervous system is involved in long term potentiation and depression (LTP, LTD) suggesting its participation in learning and memory mechanism. cGMP regulates calcium homeostasis and phototransduction. Its level is regulated by PDEs and their specific inhibitors protect cGMP level in cells and are very important from clinical point of view.
Subject(s)
Brain/metabolism , Cyclic GMP/metabolism , Neurons/metabolism , Second Messenger Systems , 3',5'-Cyclic-GMP Phosphodiesterases/antagonists & inhibitors , 3',5'-Cyclic-GMP Phosphodiesterases/metabolism , Acetylcholine/metabolism , Animals , Brain/drug effects , Brain/enzymology , Calcium/metabolism , Cyclic GMP-Dependent Protein Kinases/metabolism , Guanylate Cyclase/metabolism , Homeostasis , Humans , Isoenzymes/metabolism , Learning , Memory , Neuronal Plasticity , Neurons/drug effects , Neurons/enzymology , Phosphodiesterase Inhibitors/pharmacology , Phosphorylation , Second Messenger Systems/drug effects , Vision, OcularABSTRACT
cGMP synthesis in cholinergic neurons of the basal forebrain, the caudate putamen, and the tegmento-pedunculopontine nucleus of the rat was studied during development after birth at P1, P4, P10, and P21, in the adult, and during aging. NO-mediated cGMP synthesis in these neurons was studied using the approach of in vitro incubation of brain slices in combination with cGMP-immunocytochemistry. The percentage of NO-responsive, cGMP-synthesizing cholinergic cells in the septum and diagonal band of Broca decreased from 75% to 6% in adult animals and to 2% in aged ones. In the caudate putamen, this decrease was from 81% to 21% in adult and 11% in aged animals. Cholinergic cells of the tegmento-pedunculopontine nucleus were unresponsive to NO and never showed cGMP-immunoreactivity. In addition, it was observed that the amount of NO-responsive, cGMP-synthesizing cholinergic fibers in the hippocampus declined in parallel with the maturation of the septal-hippocampal cholinergic pathway, whereas in the caudate putamen, this colocalization became complete 2 weeks after birth. It is concluded that the property of NO-mediated cGMP synthesis in the cholinergic nuclei of the forebrain is developmentally regulated after birth and that NO-cGMP signal transduction has a role in establishing cholinergic neuronal connections in the hippocampus and caudate putamen.