The question of whether neurons versus fibers of passage in the medial prefrontal cortex (MPC) are essential in maintaining self-stimulation of this same area of the brain was examined. Rats were prepared with electrode-guide cannulae implanted stereotaxically to rest within MPC. A micro-injection of (KA), 10 nmol/1.0 microliter, into the right MPC produced a clear degeneration of neuronal cell bodies characterized by picnocytosis and glial invasion of the tissue surrounding the tip of the electrode. These histopathological changes were correlated with a permanent abolition of self-stimulation of the right MPC. In contrast, self-stimulation of the contralateral side of the MPC, micro-injected with 0.9% NaCl vehicle as a control, was unaffected. These results suggest that neurons of the MPC are part of the neural substrate underlying self-stimulation behavior in this cortical area of the rat.