The in vitro release of TRH from hypothalamic fragments or purified nerve endings (synaptosomes) has been evaluated after incubation for 10 min in the presence of various concentrations of K+ or neurotransmitters. Release of the hormone from fragments but not from synaptosomes was enhanced in the presence of 56 mM K+ in a Ca++ -dependent manner. Neurotransmitter effects were thus tested on the fragments. Addition of histamine (10 (-7)-10(-5) M) induced a significant increase over the basal release of TRH. A comparable effect was obtained with dimaprit (10(-5) M), a highly specific agonist of histamine H2 receptors; conversely, the response to histamine was blocked by the addition of a H2 (metiamide; 10(-6) M) but not of a H1 (mepyramine; 10(-6) M) antagonist to the incubation medium. Dopamine (10(-7) M) slightly inhibited the release of TRH, but antagonists of dopamine receptors (10(-7)-10(-6) M fluphenazine or 10(-6) M alpha-flupentixol) exhibited an inhibitory effect by themselves, so that specific receptors involved in mediating dopamine actions could not be further characterized. In contrast, noradrenalin, serotonin gamma-aminobutyric acid and acetylcholine (tested at concentration of 10(-7) M) did not alter the basal release of the tripeptide.