The present study investigated the hormonal and neural responses to stress in a perimenopause animal model induced by 4-vinylcyclohexene diepoxide (VCD), which induces progressive follicular depletion in rodents, allowing studies on the transition to ovarian failure. Female rats, aged 28days old, were s.c. injected for 15 consecutive days with corn oil or VCD. At 85±5days after the onset of treatment, the jugular vein was cannulated in the afternoon of metoestrus and in next morning (dioestrus) at 10.00am, rats were subjected to 30minutes of restraint stress. Blood samples were withdrawn before (-5minutes), during (2, 5, 15 and 30minutes) and after (45, 60 and 90minutes) stress and plasma prolactin, progesterone and corticosterone levels were measured. Animals were perfused, brains processed for c-Fos/tyrosine hydroxylase (TH) in the locus coeruleus (LC) and c-Fos/corticotrophin-releasing factor (CRF) in the paraventricular nucleus (PVN). In unstressed rats the density of β-endorphin fibres was assessed in LC and PVN. In VCD-treated rats, stress-induced prolactin peak was higher, basal and peak progesterone levels were lower, and both levels of corticosterone were similar to controls. However, the recovery period was longer for both adrenal hormones. In VCD-treated rats the number of c-Fos/TH and c-Fos/CRF-immunoreactive neurones was higher whereas the density of β-endorphin fibres was lower in LC and PVN. We surmise that the hyperactivity of the LC and PVN neurones in VCD-treated rats may be a result of the lower progesterone levels that resulted in the decrease of β-endorphin content in both nuclei, thus impairing the negative-feedback mechanism in the recovery period.