Mechanisms of Action and Targets of Nitric Oxide in the Oculomotor System

Abstract

Nitric oxide (NO) production by neurons in the prepositus hypoglossi (PH) nucleus is necessary for the normal performance of eye movements in alert animals. In this study, the mechanism(s) of action of NO in the oculomotor system has been investigated. Spontaneous and vestibularly induced eye movements were recorded in alert cats before and after microinjections in the PH nucleus of drugs affecting the NO-cGMP pathway. The cellular sources and targets of NO were also studied by immunohistochemical detection of neuronal NO synthase (NOS) and NO-sensitive guanylyl cyclase, respectively. Injections of NOS inhibitors produced alterations of eye velocity, but not of eye position, for both spontaneous and vestibularly induced eye movements, suggesting that NO produced by PH neurons is involved in the processing of velocity signals but not in the eye position generation. The effect of neuronal NO is probably exerted on a rich cGMP-producing neuropil dorsal to the nitrergic somas in the PH nucleus. On the other hand, local injections of NO donors or 8-Br-cGMP produced alterations of eye velocity during both spontaneous eye movements and vestibulo-ocular reflex (VOR), as well as changes in eye position generation exclusively during spontaneous eye movements. The target of this additional effect of exogenous NO is probably a well defined group of NO-sensitive cGMP-producing neurons located between the PH and the medial vestibular nuclei. These cells could be involved in the generation of eye position signals during spontaneous eye movements but not during the VOR.

Morphological identification of nitric oxide sources and targets in the cat oculomotor system

“…Unilateral injections of NOS inhibitors within this nucleus produced velocity imbalances in a direction contralateral to the injected side, resulting in a dramatic and long-lasting nystagmus, which was more accentuated in darkness. Furthermore, local injections of NO donors produced a nystagmus in a direction opposite to that of NOS inhibitors, together with an alteration in eye position generation (Moreno-López et al, 1998). These functional data indicate that NO is tonically produced in the PH nucleus in normal conditions and suggest that NO acts by a retrograde action on nerve terminals from medial vestibular neurons projecting to the PH nucleus.…”

“…Functional experiments have identified neurons within this area that fire with eye position (McFarland and Fuchs, 1992), and therefore the primate marginal zone has been proposed as part of the integrator controlling eye movements (Kaneko, 1997). We have recently reported that this NO-responsive region may also have a role in the generation of the eye position after saccadic eye movements in the cat, based on the alterations in eye position observed when NO donors were injected in the proximity of these neurons (Moreno-López et al, 1998). However, the physiological significance of these results is not clear, because the marginal zone is devoid of nitrergic neurons, and the closest source of NO, the nitrergic PH neurons, is relatively distant for NO to reach the marginal zone cell bodies at adequate concentration.…”

“…The actions of NO in the PH nucleus are most probably due to cGMP synthesis, because local administration of the permeant cGMP analog 8-Br-cGMP in this nucleus produced an effect identical to that of NO donors (Moreno-López et al, 1996, 1998. Identification in the oculomotor structures of neuronal cell bodies, nerve fibers, or terminals able to increase their cGMP concentration in response to NO might provide valuable information about the possible targets of NO in the control of eye movements.…”

Anatomical and pharmacological relationship between acetylcholine and nitric oxide in the prepositus hypoglossi nucleus of the cat: Functional implications for eye‐movement control

“…During spontaneous eye movements in darkness, the alterations induced by drug injections in the PH nucleus consisted of nystagmic eye movements with straight or curved slow phases separated by quick resetting eye movements. Linear and curved slow phases are indicative of two different alterations: velocity imbalance and eye-position generation failure, respectively (Cannon and Robinson, 1987;Godaux et al, 1993;Mettens et al, 1994a,b;Moreno-López et al, 1998). Slow phases with duration greater than 0.5 seconds were fitted separately, by the least-squares method, to linear and exponential equations, and were considered to be linear or exponential when more than 80% of the analyzed phases had a correlation coefficient Ͼ0.99 or Ͼ0.90, respectively.…”

“…In neurons, NO targets mainly guanylyl cyclase, increasing cyclic guanosine monophosphate (cGMP), which in turn may exert a variety of effects via cGMP-dependent kinases and phosphodiesterases and cyclic nucleotide-gated ion channels (Lucas et al, 2000), depending on the neural type, cerebral region, and physiological state. In the PH nucleus, although there is a high number of nitrergic neurons, there are no nitroceptive neuronal bodies (Moreno-López et al, 1998, 2001, indicating that NO must be acting on the afferents that constitute part of the rich neuropil that is sensitive to NO within the nucleus. Retrograde tracer studies, in combination with immunocytochemistry using antibodies against cGMP and GABA, show that GABAergic terminals from the ipsilateral medial vestibular nucleus are targets for the NO released in the PH nucleus (MorenoLópez et al, 2001).…”