Biochemical and pharmacological studies of amygdaloid kindling in the rat

Abstract

The kindling effect was investigated in the rat amygdala in an attempt to iden¬ tify the biochemical correlates of the long-la-strng-Thanges in neuronal excitability which are characteristic of this phenomenon. The hypothesis that cholinergic mechanisms are facilitatory and catecholaminergic systems are inhibitor}' in amygdaloid kindling was tested. The cholinergic muscarinic antagonist atropine was found to be without effect on kindling and mus¬ carinic receptor sites and sodium-dependent,high affinity choline uptake were not perturbed one month after a kindled convulsion, even though the epileptogenic effect of kindling is known to persist for over 1 year. From these results it was concluded that there was not a signifi¬ cant cholinergic contribution to the development or maintenance of kindling. The involvement of noradrenaline and dopamine in kindling was assessed by measuring the turnover rates of these amines. At the site of stimulus the basal level of noradrenaline was found to be reduced and the rate of depletion of dopamine was increased when compared with the contralateral unstimulated amygdala. Cyclic GMP levels in slices prepared from the amygdala was higher in kindled than in sham-operated animals, whilst an impaired res¬ ponse of cyclic GMP to depolarization or to media containing dopamine or haloperidol was recorded. These findings suggest a role for catecholamines in kindling and support the view that the long-term changes in kindling are associated with dopamine receptor subs ens itivity accompanied by a compensating increase in presynaptic dopamine release. During the course of these experiments it became apparent that the very presence of metal electrodes in the amygdala, for periods of up to 4 weeks, caused enhancement in the rate of kindling. This observation, which has some implications for theories about kindling, was confirmed using both stainless steel and platinum/iridium metal implants. Finally, a comparison of regional metabolic requirements during kindling induced con¬ vulsions, electroshock convulsions and partial kindling were compared and contrasted with regional requirements in sham-operated and unope rated control animals using a deoxyglucose technique for estimating regional glucose utilization. Changes observed in glucose consumption were always bilateral and in no area did rats which had been kindled but not convulsed at the time of the deoxyglucose experiment, differ from sham operated controls. In two regions the hypothalamus and septal nuclei unoperated controls showed a significantly lower uptake than in sham operated rats. Since these groups differed only in the placement of an elec¬ trode into the amygdala the results were taken to imply that the presence of an electrode caused increased neuronal activity in those regions. Kindled induced convulsions were associated with an increase in neuronal activity in the amygdalae, hippocampi, superior colliculi, substantia nigra and septal nuclei. Partial kindling caused increased glucose consumption in the amygdalae hippocampi and superior colliculi. Electro -convulsions led to increased neuronal activity in the amygdalae, hippocampi, hypothalami, substantia nigra, septal nuclei thalamus, striata, cerebellar nuclei, cerebellar hemispheres and reticular formation, Theories about the anatomy of spread of epileptic seizures are discussed.