The hippocampus appears to be involved in tonic regulation of the hypothalamo-pituitary-adrenocortical axis via interactions with corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP)-containing neurons of the hypothalamic paraventricular nucleus (PVN). To further investigate the anatomical basis of such interactions, lesions were made to forebrain fiber tracts in position to communicate inhibitory information from the hippocampus to the PVN. Total fimbria-fornix transections (TFF) and lateral fimbria-fornix lesions (LFF) both significantly increased CRH mRNA levels in the medial parvocellular PVN, as assayed by semi-quantitative in situ hybridization histochemistry. Medial fimbria-fornix lesions or section of the medial corticohypothalamic tracts (MCHT) did not influence CRH mRNA levels. The LFF group showed increases in both AVP mRNA and ACTH secretion, whereas no other lesion was effective in this regard. The results suggest: (1) hippocampal efferents conferring tonic inhibition of the HPA axis probably originate in regions contributing to the lateral extent of the fornix, representing structures in the ventral subiculum and ventral extent of CA1; (2) projections from the hippocampus to the medial basal hypothalamus (travelling in the MCHT) are unlikely to affect HPA function; (3) hippocampus may influence the PVN CRH/AVP neuron at multiple levels, in that LFF and TFF lesions have differential effects on PVN AVP mRNA levels and ACTH secretion.