Effects of sustained seizures produced by intrahippocampal injection of kainic acid on noradrenergic neurons: evidence for local control of norepinephrine release
Nelson, M.F.; Zaczek, R.; Coyle, J.T.
Journal of Pharmacology and Experimental Therapeutics 214(3): 694-702
1980
ISSN/ISBN: 0022-3565 PMID: 7400971 Document Number: 159507
Stereotoxic injection of 2.3 nmol kainic acid, a potent neuroexcitant, into the dentate gyrus of the hippocampus of rats anesthetized briefly with ether caused a seizure disorder lasting several hours as manifested by behavioral and EEG abnormalities. Within 3 h, the levels of norepinephrine decreased significantly in the hippocampus, lateral cortex, frontal cortex and cerebellum ipsilateral and contralateral to the side of injection but were unaffected in the hypothalamus and medulla pons. GABA, serotonin and dopamine levels were not reduced in these regions. Norepinephrine depletion was associated with 2-fold increases in 3-methoxy-4-hydroxyphenylglycol sulfate. Injections of kainate in the thalamus and amygdala produced seizures and acute, widespread depletions of norepinephrine, but intracortical injection affected norepinephrine only in the ipsilateral cortex without causing generalized seizures. Acute transection of the dorsal noradrenergic bundle did not prevent cortical norepinephrine depletion after hippocampal kainate injection; the release of norepinephrine occurred independent of impulse flow from the locus coeruleus. To determine possible direct action of kainic acid on noradrenergic terminals, the effects of the agent on L-[3H]norepinephrine release from perfused prelabeled slices were examined. Kainic acid caused release of [3H]norepinephrine from the slices with half-maximal effects at 0.3 mM; the release was Ca-dependent and blocked by tetrodotoxin. Kainic acid was .gtoreq. 15-fold more potent than L-glutamate but 20-fold less effective than 40 mM K+. The presynaptic effects of kainic acid were not robust. Maintenance of anesthesia with chloral-hydrate-pentobarbital or pretreatment with phenobarbital (100 mg/kg) protected against cortical seizures activity and prevented the depletion of norepinephrine in the cortex and hippocampus. Paroxysmal activity of neurons in the terminal field of the locus coeruleus noradrenergic projection can locally stimulate norepinephrine release independent of impulse flow from the locus.