This study was conducted to determine if the stress-responsive hypothalamic-nucleus accumbens (NAc) regulation is a stressor specific event. Male SD rats were subjected to restraint or cold stress for 2 h, and then mRNA expression of corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) was examined by in situ hybridization and the plasma corticosterone levels by radioimmunoassay. Neuronal activations in the PVN and the NAc were examined by c-Fos immunohistochemistry and the brain GABA contents by HPLC. Both restraint and cold stresses increased c-Fos expression in the PVN and the plasma corticosterone; however, CRH expression in PVN was increased only by restraint, but not by cold, stress. Restraint stress significantly increased the NAc neuronal activation, but cold stress failed to do so. Restraint stress increased the NAc-GABA contents and cold stress did the hypothalamic GABA. Results suggest that the HPA axis regulation responding to restraint stress, but not cold stress, may involve the NAc neuronal activation in relation with GABAergic neurotransmission. Additionally, CRH expression in the PVN may not play a major role in the elevation of plasma corticosterone responding to cold stress.