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1. Nitric oxide (NO) production in the nervous system has been implicated in cellular mechanisms of learning and memory. Our study investigates an in vivo sensorimotor model of learning. It demonstrates that a localized vestibulocerebellar injection of the NO synthase inhibitor, L-NG-monomethyl-arginine (L-NMMA), which specifically blocks NO production, inhibited the acquisition of adaptive vestibulo-ocular reflex (VOR) gain increases but not gain decreases in the goldfish. 2. Restoration of NO production by concomitant administration of L-arginine (the substrate for NO synthase) and L-NMMA suppressed the inhibitory effect of L-NMMA on adaptive gain increases. 3. This effect of L-NMMA was stereospecific because injection of D-NMMA did not suppress adaptive VOR gain increases. 4. Injection of L-NMMA after VOR adaptation had no effect on retention, failing to alter the postadaptive recovery after a VOR gain increase. 5. In conclusion, acquisition of adaptive VOR gain increases are affected by cerebellar NO inhibition. However, because gain decreases are not, they may involve either non-NO cerebellar or extracerebellar mechanisms. In addition, different processes for acquisition and retention of gain increases may be operating, because inhibition of cerebellar NO affects the acquisition but not the retention phase.

Vestibuloocular reflex performance and adaptation were examined during vestibulocerebellar inactivation by localized lidocaine microdialysis or injection in goldfish. In the light, eye velocity perfectly compensated for head velocity (Vis-VOR) during sinusoidal yaw rotation (1/8 Hz +/- 20 degrees). In the dark, the reflex (VOR) gain was slightly reduced (gain approximately 0.8-0.9). In neither Vis-VOR nor VOR, was gain altered after 1 h of lidocaine microdialysis in the vestibulocerebellum. Before adaptation of reflex gain, the initial suppression or augmentation of Vis-VOR reflex gain produced by in-phase or out-of-phase visual-vestibular stimulation was also unaffected by cerebellar inactivation. Subsequently, 3 h of adaptive reflex training in either the in-phase or out-of-phase paradigm (acquisition phase) respectively decreased (0.30 +/- 0.09) or increased (1.60 +/- 0.08) VOR gain during artificial cerebral spinal fluid (CSF) microdialysis. However, microdialysis of lidocaine completely blocked adaptive gain changes during a 3-4 h period of continuous application. This effect was reversible because VOR gain changes were produced 1 h after lidocaine was replaced with CSF as the dialysate. After adaptive training, bilateral CSF injections (0.25 microl/side) into the vestibulocerebellum did not alter the normal retention or decay of adapted gain changes during a 3 h period in the dark (retention phase). However, injection of lidocaine into the vestibulocerebellum completely blocked retention of the adapted VOR gain returning the gain to values recorded before adaptation. In contrast to either acute or chronic surgical removal, lidocaine inactivation of the cerebellum by microdialysis did not alter either Vis-VOR and VOR behavior or interactive Vis-VOR performance over a wide range of gain extending from 0.3 to 1.4. Thus short-term VOR motor learning is a dynamic process requiring either continuous operation of brain stem cerebellar loops or, alternatively, modifiable sites within or directly influenced by the cerebellum. Our data supports the latter hypothesis, because the direct brain stem VOR pathways appear to be unaltered after cerebellar inactivation, and, hence, independent of the VOR-adapted state.

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