Host regulation of noradrenaline release from grafts of seizure-suppressant locus coeruleus neurons

Abstract

Intrahippocampal implants of noradrenaline-rich neural tissue from the fetal locus coeruleus region suppress development of seizures induced by hippocampal kindling stimulation in hyperexcitable, noradrenaline-depleted rats. In the present study the intracerebral microdialysis technique has been used to monitor seizure-induced release of noradrenaline from such grafts. The steady-state output of noradrenaline in the hippocampus of grafted animals (previously treated with intraventricular 6-hydroxydopamine) was similar to the baseline level in normal rats. A generalized seizure gave rise to a threefold increase of hippocampal noradrenaline levels as compared to baseline (15-min samples) in both normal and grafted animals. The maximal increase of extracellular noradrenaline levels occurred within 2–4 min after the onset of seizure activity and the levels then tapered off, reaching baseline after another 6–8 min. In 6-hydroxydopamine-treated animals without grafts baseline noradrenaline levels were markedly reduced compared to those of normal rats and only minor changes were observed in response to seizures. This supports the theory that the high extracellular noradrenaline concentrations measured in conjunction with seizures originate from the grafts. A knife cut transecting the ascending bundle from the locus coeruleus led to a marked attenuation of the seizure-induced increase of noradrenaline release in normal animals. In the intact brain, and probably also in the grafts, this response thus seems to be dependent on impulse flow in locus coeruleus neurons and only to a minor extent on local regulatory mechanisms in the hippocampus. In conclusion, the present study demonstrates that grafted locus coeruleus neurons are able to restore both basal and seizure-induced extracellular noradrenaline levels in the hippocampus. A pathological state affecting the host can thus activate grafted seizure-suppressant neurons, which, despite their ectopic location, are functionally integrated with the recipient's brain.