Role of Nitric Oxide on Motor Behavior

Abstract

The present review paper describes results indicating the influence of nitric oxide (NO) on motor control. Our last studies showed that systemic injections of low doses of inhibitors of NO synthase (NOS), the enzyme responsible for NO formation, induce anxiolytic effects in the elevated plus maze whereas higher doses decrease maze exploration. Also, NOS inhibitors decrease locomotion and rearing in an open field arena. These results may involve motor effects of this compounds, since inhibitors of NOS, NG-nitro-L-arginine (L-NOARG), N(G)-nitro-L-arginine methylester (L-NAME), N(G)-monomethyl-L-arginine (L-NMMA), and 7-Nitroindazole (7-NIO), induced catalepsy in mice. This effect was also found in rats after systemic, intracebroventricular or intrastriatal administration. Acute administration of L-NOARG has an additive cataleptic effect with haloperidol, a dopamine D2 antagonist. The catalepsy is also potentiated by WAY 100135 (5-HT1a receptor antagonist), ketanserin (5HT2a and alfal adrenergic receptor antagonist), and ritanserin (5-HT2a and 5HT2c receptor antagonist). Atropine sulfate and biperiden, antimuscarinic drugs, block L-NOARG-induced catalepsy in mice. L-NOARG subchronic administration in mice induces rapid tolerance (3 days) to its cataleptic effects. It also produces cross-tolerance to haloperidol-induced catalepsy. After subchronic L-NOARG treatment there is an increase in the density NADPH-d positive neurons in the dorsal part of nucleus caudate-putamen, nucleus accumbens, and tegmental pedunculupontinus nucleus. In contrast, this treatment decreases NADPH-d neuronal number in the substantia nigra compacta. Considering these results we suggest that (i) NO may modulate motor behavior, probably by interfering with dopaminergic, serotonergic, and cholinergic neurotransmission in the striatum; (ii) Subchronic NO synthesis inhibition induces plastic changes in NO-producing neurons in brain areas related to motor control and causes cross-tolerance to the cataleptic effect of haloperidol, raising the possibility that such treatments could decrease motor side effects associated with antipsychotic medications. Finally, recent studies using experimental Parkinson's disease models suggest an interaction between NO system and neurodegenerative processes in the nigrostriatal pathway. It provides evidence of a protective role of NO. Together, our results indicate that NO may be a key participant on physiological and pathophysiological processes in the nigrostriatal system.

Nitric Oxide Modulation of the Basal Ganglia Circuitry: Therapeutic Implication for Parkinson's Disease and Other Motor Disorders

“…Nevertheless, sub-chronic 7-NI treatment induced an even stronger regularization of temporal structure of nigral spiking activity reducing burst firing of about 60% when compared with the control group. These findings are in line with the evidence that NOS inhibitors induce catalepsy in rodents [62,63] and decrease exploratory behaviour in rats [64] while both effects disappear after only 4 days of NOS inhibition [36,[64][65][66][67]. Therefore, the increase in DA neurotransmission after 7-NI sub-chronic treatment showed by Di Matteo et al [47] might be the mechanism involved in the rapid tolerance development after chronic NOS inhibition.…”

“…It has been proposed that NO modulates motor behaviour [43,66,165] and considerable data indicate a direct NO-DA interaction either in normal BG function (as explained above) or in BG related movement disorders such as PD. For instance the DA agonists, cocaine, morphine, substance P or methamphetamine-induced hyperlocomotion could be impeded by NOS inhibitors in mice and rats [166][167][168].…”

“…For instance the DA agonists, cocaine, morphine, substance P or methamphetamine-induced hyperlocomotion could be impeded by NOS inhibitors in mice and rats [166][167][168]. Yet, inhibition of NOS also induces catalepsy after systemic or intrastriatal injection [65,66], in agreement with the finding that striatal NOS activity is depressed in parkinsonian animal models [136,137] and in human PD [24,169]. NO synthesis seems to be under the control of the phasic/synaptic striatal DA transmission [70,71] and extracellular increase of NO tone within the GPi, motor putamen and SNr are correlated with transient clinical transition in PD patients [122,170,171].…”

Endothelial Nitric Oxide Synthase (eNOS) Knockout Mice Have Defective Mitochondrial β-Oxidation

“…The underlying mechanism for the increased locomotion in eNOS Ϫ/Ϫ mice needs further study but could represent an adaptive response to decreased energy consumption or be related to a central neural effect of eNOS deletion (21). In line with this latter concept, chronic NO inhibition increases locomotion activity in rats (22). Energy expenditure, normalized for ambulatory activity, was Ͼ30% lower in eNOS Ϫ/Ϫ mice than in control mice, suggesting decreased FFA oxidation in skeletal muscle of eNOS Ϫ/Ϫ mice.…”

Nitric Oxide Potentiation of Locomotor Activity in the Spinal Cord of the Lamprey

“…NO has recently been implicated in the regulation of motor behavior including locomotory and respiratory activity Del Bel et al, 2005;Hedrick et al, 2005). NO modulates locomotor activity via actions at multiple levels along the neuroaxis from the cortex (Del Bel et al, 2005), to the brainstem and the spinal cord Sillar, 2002, 2004).…”