Nitric Oxide NO and How it Regulates Motor

Nitric Oxide (NO) and How it Regulates Motor Function CONNOR CULLEY, DEREK EMERSON, DOMENICK STUMPO

Point of Paper To analyze the role of Nitric Oxide and the integration of dopaminergic and glutamatergic neurotransmission in the Striatum and what their roles are in Parkinson's Disease

Nitric Oxide (NO) Short lived Soluble Penetrate cell membranes Can be dangerous in high concentrations Neuronal communications Modulation of blood vessel relaxation Immune response Neuro-development within CNS Release and uptake of neuro-transmitters Synaptic plasticity EVOKES RELEASE OF DOPAMINE AND EFFECTS ITS TRANSPORTERS CONTROL OF MENTAL AND MOTOR FUNCTION

NO Synthesis in Brain Synthesized by Nitric Oxide Synthase Requires O 2, NADPH, and L-arginine Cant be stored Synthesized by four enzymes Constitutive Neuronal NOS (Short lasting increase) Endothelial NOS (Short lasting increase) Mitochondrial NOS Inducible (i. NOS) (produce long lasting amounts) n. NOS is the predominant source of NO in neurons

n. NOS Inhibitors Multitude of studies have looked at results of n. NOS inhibitors Conclusions are controversial n. NOS reduces movement in rodents on drugs It can also induce catalepsy in other rodents Shows that NO modulates motor function through Dopaminergic Serotoninergic Cholinergic transmission

NO in Parkinson's Loss of Dopamine producing neurons in substantial nigra pars compacta (SNc) Severe depletion of Dopamine producing neurons in Corpus Striatum NO synthesizing neurons, and expression of n. NOS m. RNA decreases in putamen n. NOS m. RNA is higher in subthalamic nucleus NO in cerebrospinal fluid is very low

Striatum NOS cells only make up 5% of all cells in the Striatum Axons of these cells create a network that allows these cells to influence the whole of the striatum n. NOS is expressed highly in the Striatum Interacts and controls almost 95% of Striatum neurons (MSNs) MSNs interact with dopaminergic and glutamatergic transmission n. NOS controls these through the interactions with MSNs

Glutamate and DA role in the synthesis of NO Dopamine modulates n. NOS activity in the Striatum via both facilitatory and inhibitory signaling Facilitatory is D 1 receptor stimulation Inhibitory is D 2 receptor stimulation In Parkinson Disease the function of the dopaminergic system is decreased NO synthesis is disrupted

The Role of NO-s. GC-c. GNP signaling in the regulation of output pathways in the Striatum The MSNs in the Striatum are the target for dopaminergic innervations These neurons are regulated by two pathways Direct Inhibitory control of substantia nigra D 1 receptors Indirect Increased activity of glutamatergic neurons, excites substantia nigra D 2 receptors

The Role of NO-s. GC-c. GNP signaling in the regulation of output pathways in the Striatum DA release stimulates production of c. AMP Increases n. NOS activity, upregulation of c. GMP production NO acts via c. GMP to regulate ion channels, protein kinases and nucleotide phosphodiesterase's(PDEs) L-dopa affects level of cyclic nucleotides in Striatum differently. Dyskinetic Rats Non-Dyskinetic Rats Severe decreases in in c. AMP and c. GMP levels in the cortex, striatum, and globus pallidus c. AMP increased in cortex and striatum, but decreased in globus pallidus Pretreatment with PDEs inhibitor reduced severity of L-dopa induced dyskinesias, prevented significant drop in cyclic nucleotides Possibly by restoring synaptic plasticity

Summary Further studies are clearly needed Disturbances in nitrergic transmissions can lead to PD Understanding the NO-s. GC-c. GMP pathway during L-dopa therapy can help prevent L-dopa induced dyskinesia These studies may help in finding new treatments for PD