Harmaline-induced tremor and impairment of learning are both blocked by dizocilpine in the rabbit

Harmaline is known to produce tremors and retard acquisition of the rabbit's nictitating membrane response. These actions have been demonstrated to depend on the ability of harmaline to activate the inferior olive which gives rise to climbing fibers that project directly onto Purkinje cells in cerebellar cortex. However, the precise receptor systems involved in harmaline's actions remains unknown. This study examined the role of the NMDA receptor in harmaline's actions. Harmaline (10 mg/kg, s.c.) produced intense tremors and impaired the acquisition of conditioned responses. Both of these effects of harmaline were significantly blocked by the prior administration of the noncompetitive NMDA channel blocker, dizocilpine (0.01 mg/kg, s.c. given 20 min prior to the administration of harmaline). This dose od dizocilpine had no effect on acquisition of conditioned responses when given alone. A higher dose of dizocilpine (0.1 mg/kg s.c.) completely blocked the tremorogenic effects of harmaline (10 mg/kg, s.c.). Dizocilpine had no effect on motor behavior when given alone. It was suggested that the blockade of harmaline's actions by dizocilpine may be occurring at NMDA channels within the inferior olive. Regardless of the site of action, these data demonstrate that harmaline's ability to activate the interior olivary nucleus depends on the normal activity of the NMDA receptor.