BACKGROUND: In addition to the hippocampus, the dorsolateral caudate nucleus (CN) and the pars reticularis of the substantia nigra (SNr) are among the most vulnerable brain areas to ischemia. A possible association of the neuronal injury in these two subcortical nuclei has been proposed, the primary damage affecting the CN GABAergic neurons innervating the SNr, and secondarily the SNr neurons as a result of an imbalance of GABAergic and glutamatergic input to the SNr. Progesterone (P(4)) exerts a GABAergic action on the central nervous system (CNS) and is known to protect neurons in the cat hippocampus from the damaging effect of acute global cerebral ischemia (AGCI). The effects of AGCI on the neuronal populations of the CN and SNr, in addition to the possible neuroprotective effects of P(4), were assessed in cats in the present study. METHODS: Ovariectomized adult cats were treated subcutaneously (s.c.) with either P(4) (10 mg/kg/day) or corn oil during the 7 days before and 7 days after being subjected to a period of AGCI by 15 min of cardiorespiratory arrest followed by 4 min of reanimation. After 14 days of survival, animals were sacrificed and their brains perfused in situ with phosphate-buffered 10% formaldehyde for histologic examination. RESULTS: ACGI resulted in an intense glial reaction in the CN and a significant loss (43%) of medium-sized neurons of the CN, but no difference was found in the densities of SNr neurons between controls and ischemic oil- and P(4)-treated cats. Progesterone treatment completely prevented CN neuronal loss. CONCLUSIONS: The overall results point to the higher vulnerability of CN neurons to ischemia as compared to neurons in the SNr and show the protective effects of P(4) upon CN neuronal damage after ischemia.