Neuroscience Vol. 23, No. 3, pp. 95S968, 1987 Printedin Great Britain 0306-4522/87 $3.00 + 0.00 Pergamon Journals Ltd 0 1987 IBRO THE FUNCTIONAL ANATOMY AND PAThOLOGY OF LITHIUM-PILOCARPINE AND HIGH-DOSE PILOCARPINE SEIZURES D. B. CLIFFORD,*$ J. W. OLNEY,~A. MANIOTIS, R. C. COLLINS* and C. F. ZORUMSKI~~ *Department of Neurology and Neurological Surgery (Neurology), tDepartment of Psychiatry, SMcDonnell Center for Studies of Higher Brain Function, Washington University School of Medicine, St Louis, U.S.A. Abstract-Subcutaneous treatment of rats with low doses of lithium and pilocarpine or a high dose of pilocarpine results in a severe seizurebrain damage syndrome. Bats thus treated were studied with multipledepth electrodes, quantitative [14CJ2-deoxyghtcose autoradiography, and light and electron microscopy. Bats receiving lithium-pilocarpine did not differ from high-dose pilocarpine rats in behavioral, electrographic, metabolic or histopathological findings, but lithium-pilocarpine reproduced the syndrome more reliably and with a lower acute mortality rate. Organized electrographic seizure activity developed just prior to the onset of behavioral forelimb clonus and appeared to originate from ventral forebrain in the vicinity of the ventral pallidum and/or nucleus accumbens. From these sites activity spread rapidly to involve other regions. Once initiated, electrographic seizures persisted for hours. Increased glucose utilixation was found in most brain regions during the period of continuous seizure activity. The greatest increases were found in the ventral pallidum, globus pallidus, hippocampus, entorhinal cortex, amygdala, lateral septum, substantia nigra, ventrobasal and mediodorsal tbalamus and frontal motor cortex. Animals sustaining seizures displayed a disseminated pattern of neural degeneration not involving globus pallidus or ventral pallidum but otherwise coinciding with the above pattern of enhanced glucose utilization. No consistent correlation was observed between the pattern of brain damage and known regions of high muscarinic cholinergic receptor density. Ultrastructurally, the cytopathological changes, like those associated with various other sustained seizure syndromes, resemble the excitotoxic type of damage glutamate is known to cause. This seizure-brain damage syndrome and that induced by systemic kainic acid appear to be similar in behavioral but not in electrophysiological or metabolic manifestations. During kainic acid seizures, electrographic changes are first recorded in the hippocampus while they are first detected in the ventral forebrain repjon in pilocarpine seizures. Pilocarpine also induced metabolic activation of ventral forebrain sites not activated by kainic acid. The cytopathology associated with the two syndromes is identical in type but not in pattern, the cholinergic model being characterized by much greater neocortical and slightly less hippocampal damage. Further study of these choline@ models may provide new insights into the roles of the major excitatory neurotransmitter systems (cholinergic and glutamergic) in limbic epilepsy. It is postulated that choline@ mechanisms play an important role in the onset and propagation of limbic seizures. This belief is supported by early studiesioJ9 and by the more recent finding24 that focal, intra- mygdaloid injections of cholinomimetics produce prolonged, recurring seizures and brain damage. In addition, rats administered repeated subconvulsive amygdaloid injections of carbamylcholine develop a progressive behavioral seizure syndrome similar to that seen with electrical kindling.” Evidence support- ing a role for the choline+ system in the propaga- tion of limbic seizure activity is provided by studies demonstrating that lesions of the cholinergic cell bodies in the substantia innominata inhibt the gener- alization of electrically kindled amygdaloid seizures.i5 Furthermore, atropine, a muscarinic antagonist, sup- *Address for correspondence: Dr David B. Clifford, Washington University School of Medicine, Box 8111, Department of Neurology, 660 South Euclid Avenue, St Louis, Missouri 63110, U.S.A. Abbreviations: 2-DG, 2-deoxyglucose; EEG, electro- encephalogram; MlP, myo-inositol-l-phosphate. presses the spread of amygdaloid kindled seizures,3 while focal injections of cholinomimetic enhance hippocampal kindled discharges.’ These findings may be a result of the muscarinic action of acetylcholine, which produces long lasting neuronal depolarization by blockade of a specific potassium conductance.’ Recently Honchar et uf.‘* described a model of limbic seizures produced by systemic injection of pilocarpine (30 mg/kg) in rats pretreated with lithium chloride (3 mEq/kg). Behaviorally, these seizures re- semble other models of limbic seizures beginning with facial automatisms and’ head nodding and progressing to forelimb clonus with rearing and falling. When seizures continued for several hours, animals developed brain damage. A similar syndrome of seizures and brain damage has been described by Turski et aL3* in rats administered much higher systemic doses of pilocarpine alone (4OOmg/kg). These pilocarpine seizure models provide an oppor- tunity to study the involvement of the central cholinergic system in the onset, propagation and pathological consequences of limbic seizures. In this 953