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Neurotoxic Effects of Kainic Acid on Substantia Nigra Neurons in Rat Brain Slices

Excitatory amino acids (EAAs) have been implicated as mediators of cell death in neurodegenerative diseases involving catecholamine neurons. Few studies, however, have examined the toxic effects of EAAs on identified catecholamine neurons in vitro. We have investigated the neurotoxic effects of kainic acid in a rat brain substantia nigra (SN) slice preparation. Rats (60-80 g) were anesthetised with halothane and killed by cervical dislocation. SN slices, 300 microm thick, were incubated at 35 degrees C in a modified Krebs solution in the presence or absence of kainic acid and then fixed and processed for either immunohistochemistry (IHC) or electron microscopy (EM). In IHC experiments, SN neurons were labeled using antibody to tyrosine hydroxylase (TH) coupled to diaminobenzidine. In control slices, the antibody labeled not only the cell body but also the prolific dendritic arbor of SN neurons. Treatment with 50 microM kainic acid for 15 min or 2 h resulted in loss of TH staining and apparent fragmentation of the dendrites. EM provided ultrastructural evidence for kainic acid-induced degeneration of the dendritic arbor of SN neurons. Typically, the dendritic membrane was broken, or diffuse and collapsed. Ultrastructural damage, including clumping and marginalization of chromatin and vacuolation of the cytoplasm, was also observed in cell bodies. Damage to the dendritic arbor may occur early in the neurotoxic events leading to cell death, preceding the loss of the cell body. Our observations are consistent with the postulated role of EAAs as mediators of catecholamine neuron death.