Pharmacological evidence for an anticonvulsant relay in the rat ventromedial medulla

Abstract

Local disinhibition of several interconnected regions in the brainstem of rats, including the dorsal midbrain, the mesencephalic locomotor region and the ventrolateral pontine reticular formation, has anticonvulsant properties in the maximal electroshock model of epilepsy. A recent anatomical study [Shehab, S., McGonigle, D., Hughes, D., Todd, A. & Redgrave, P. (2005) Eur. J. Neurosci., 22, 1431-1444.] revealed significant anatomical connections between an anticonvulsant relay region in the ventrolateral pons and reticulospinal projection neurons in the ventromedial medullary reticular formation. This pathway was shown to have both glutamatergic and GABAergic components. The purpose of the present study was to test whether local excitation or inhibition directed to the target zone of this projection in the ventral medulla would also have anticonvulsant properties. Neural excitation induced by local bilateral injections of the GABA(A) antagonist bicuculline into the ventromedial medulla caused a reliable dose-related suppression of hindlimb extension in the maximal electroshock test. The anticonvulsant effect of bicuculline was significantly greater in the terminal zone of the afferent projection from the ventral pons than that observed in adjacent tissue. Neither direct excitation following injections of N-methyl-D-aspartate nor direct inhibition by injections of the GABA agonist muscimol into the same region had reliable anticonvulsant effects. A statistically reliable association was observed between the anticonvulsant and locomotor activation effects of injections of bicuculline into the ventral medulla. No such relationship was found with bicuculline-induced disturbances of muscle tone, as reflected by the presence of postural dysfunction. Together these data establish the final functional link connecting brainstem anticonvulsant circuitry with reticulospinal systems controlling hindlimb musculature.

Segregated Anatomical Input to Sub-Regions of the Rodent Superior Colliculus Associated with Approach and Defense

“…Both efferent projections connect the SC with pre-motor and pre-cerebellar nuclei in the brainstem and upper spinal cord (King et al, 1996; Shehab et al, 2007). The SC receives input from several of these efferent relays through which the SC exercises control over the eyes, head, and body.…”

Role of the superior colliculus in the expression of acute and kindled audiogenic seizures in Wistar audiogenic rats

“…Particularly, in audiogenic seizures it has been shown in GEPR‐9s that the propagation of seizure activity from the IC involves activation of motor neurons in the nucleus reticularis pontis oralis (RPO, Browning, 1986) and that SC is important for the spreading of seizures activity between the IC and RPO. It is interesting to know also if the SC‐reticular‐spinal cord pathways in genetically developed audiogenic strains such as WARs or GEPRs are similar to those described, for example, for electroshock‐induced seizures (Shehab et al., 2005, 2007).…”

“…Other explanations could be related to the disruption of normal activity of efferent projections from dorsal midbrain, which has been associated with defensive behaviors (Ribeiro et al., 2005; Castellan‐Baldan et al., 2006). It is intriguing to note that Shehab et al. (2007) show a powerful anticonvulsant action often associated with locomotor activation.…”

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

“…Accordingly, disinhibition of the deep layers of the SC exerts an anticonvulsant action, as was proved by the observation that bilateral, but not unilateral, application of bicuculline to the SC attenuates limbic motor seizures induced by unilateral bicuculline injection into the anterior piriform cortex in rats [174]. The mechanism by which disinhibition of the deep/intermediate layers of the SC exerts anticonvulsant actions are not yet understood, although a contribution of connections with lower brain stem regions including areas in pons and medulla has been suggested (e.g., [246,247].…”