Studies reported recently have shown that tumor necrosis factor-alpha (TNF-alpha) a cytokine released by macrophages and monocytes plays a key role in inflammatory processes and immune and neuro-endocrine regulation. TNF-alpha is also produced in the central nervous system (CNS). However, the role of this cytokine in the CNS is largely unknown, although evidence indicates that it is involved in various neurobehavioral manifestations. Using transgenic mice expressing high amounts of murine TNF-alpha transgene in the neurons of the CNS, we investigated the stereotyped, exploratory, and displacement activities in the hole-board and black/white box. Transgenic mice and their normal control littermates were hybrids of the CBA x C57BL/6 genetic backgrounds and were obtained by backcrossing the CBA x C57BL/6 founder female and her progeny with F1 hybrid mates. Transgenic mice did not show changes in the stereotyped behavior on the hole-board, but they displayed several alterations in the exploratory activities both in the hole-board and black/white box. Transgenic mice also exhibited an increase in grooming when exposed to a highly unfamiliar environmental stimuli in the black/white box. The study suggests that supranormal endogenous TNF-alpha in the brain affects the behavioral responses to stressful conditions.