Intrahippocampal bethanechol in rats: behavioural, electroencephalographic and neuropathological correlates

Unilateral microinjections of bethanechol chloride into the CA3 subfield of the dorsal hippocampus in unrestrained rats produced a seizure-related type behavioural and disseminated brain damage syndrome. Injection of bethanechol in the dose of 50 micrograms resulted in locomotor activation, mouth movements, teeth chattering, chewing, wet dog shakes and mild limbic seizures. Shortly after intrahippocampal injection the electroencephalogram (EEG) showed an increase in the frequency of the theta rhythm in both hippocampi. Then EEG showed spiking activity of high frequency in the injected hippocampus, with rapid propagation to the lateral septum, amygdala, neocortex and contralateral hippocampus. The periods of spiking activity of high frequency were followed by depression in the background EEG rhythm with some interspersed spike and wave complexes of very low frequency. Histological examination of frontal forebrain sections revealed disseminated, apparently seizure-mediated pattern of brain damage. The patterning of distant damage after intrahippocampal injections of bethanechol involved the piriform cortex, entorhinal cortex, olfactory tubercle, anterior olfactory nucleus, subiculum, amygdaloid complex, temporoparietal cortex and hypothalamic nuclei. Neuropathological alterations were occasionally observed in the lateral septum and thalamus. These results seem to establish a causative relationship between excessive stimulation of cholinergic muscarinic receptors in the hippocampal formation and epileptic brain damage.