Abstract: There are two major inhibitory mechanisms that constrain the activity of the hypothalamo-pituitary-adrenocortical axis: the hormonal negative feedback and the neural inhibition including that posed by the GABAergic neurons. This chapter summarizes our recent morphologic and functional findings on the role of γ-aminobutyric acid (GABA) in the transcriptional regulation of hypophyseotropic neuropeptide genes in the parvocellular neurosecretory cells of the hypothalamic paraventricular nucleus (PVH). We used organotypic hypothalamic slice cultures and in vivo microinjection protocols in combination with in situ histologic and ultrastructural procedures to address the role of local interneurons in the regulation of hypothalamic effector neurons. Under basal conditions, an intrinsic GABAergic mechanism in the PVH microenvironment was revealed that by itself, without limbic contribution, impinged a tonic inhibitory influence on the parvocellular corticotropin-releasing hormone (CRH) neurons in vitro. In vivo, remote inputs were superimposed on the local circuit, allowing differential transcriptional regulation of CRH and arginine vasopressin (AVP) genes in the hypophyseotropic neurons. During stress, GABAergic cells that are known to project to the PVH become activated and are involved in restraining the cellular, transcriptional, and hormonal responses to stress.