Extensive studies exploring the regulation of hypothalamic somatostatin GHRIH release have been reported, but the factors regulating GHRIH release in the cerebral cortex have not been well defined. We have studied the effects of central neurotransmitters on GHRIH secretion by cultured fetal rat cerebral cortical cells and on intracellular GHRIH levels. Cells maintained in vitro for 15-20 days were incubated with dopamine (DA), acetylcholine (ACh), gamma-aminobutyric acid (GABA), norepinephrine (NE), serotonin (SE) or histamine (His) (10(-11) M to 10(3) M) for 30 minutes. Following incubation, immunoreactive GHRIH was measured by RIA in cell extracts and incubation media. DA increased intracellular GHRIH content but have no effect on GHRIH in the media. Both media and intracellular GHRIH content were significantly reduced by GABA and SE. The effect of NE was stimulatory at low (10(-9) M) and inhibitory at high (10(-5) M to 10(-3) M) concentrations. ACh was found to increase media GHRIH and to decrease intracellular GHRIH content; 30 min exposure to His did not significantly modify either media or intracellular GHRH. Our findings with fetal rat cerebral cortical cells in culture demonstrate that endogenous neurotransmitters do have the capacity to directly influence GHRIH regulation.