Role of GABA and Glutamate Circuitry in Hypothalamo-Pituitary-Adrenocortical Stress Integration


Address for correspondence: James P. Herman, Ph.D., Department of Psychiatry, University of Cincinnati, Psychiatry North, Bldg. 43, UC E, 2nd Fl., 2170 East Galbraith Road, Reading, OH 45237-0506, USA. Voice: 513-558-4813; fax: 513-558-9104. e-mail:


Abstract: GABA and glutamate play a major role in central integration of hypothalamo-pituitary-adrenocortical (HPA) stress responses. Recent work in our group has focused on mechanisms whereby GABAergic and glutamatergic circuits interact with parvocellular paraventricular nucleus (PVN) neurons controlling the HPA axis. GABAergic neurons in the bed nucleus of the stria terminalis, preoptic area, and hypothalamus can directly inhibit PVN outflow and thereby reduce ACTH secretion. In contrast, glutamate activates the HPA axis, presumably by way of hypothalamic and brainstem projections to the PVN. These inhibitory and excitatory PVN-projecting neurons are controlled by descending information from limbic forebrain structures, including glutamatergic neurons of the ventral subiculum, prefrontal cortex, and GABAergic cells from the amygdala and perhaps septum. Lesion studies indicate that the ventral subiculum and prefrontal cortex are involved in inhibition of HPA axis responses to psychogenic stimuli, whereas the amygdala is positioned to enhance hormone secretion by way of GABA-GABA disinhibitory connections. Thus, it seems the psychogenic responses to stress are gated by discrete sets of GABAergic neurons in the basal forebrain and hypothalamus. As such, these neurons are positioned to summate limbic inputs into net inhibitory tone on the PVN and may thus play a major role in HPA dysfunction seen in affective disease states and aging.