Prolonged (for two weeks), but not acute, intensive treatment with tricyclic antidepressant drugs (amitriptyline, AMI; doxepine, DOX; imipramine, IMI) and H1-antihistaminics (chloropyramine, CPYR; diphenhydramine, DPHA; promethazine, PMZ; tripelenamine, TPA) decreased histamine (HI) level in rat brain, especially in the cerebral cortex. These drugs did not modify L-histidine decarboxylase activity in any analyzed brain structure, except chronically given AMI and IMI which significantly increased the enzyme activity. None of the tested compounds, administered both acutely or chronically, affected the activity of HI-methyltransferase, as well as HI level in the heart. Under in vitro conditions, all antidepressants, PMZ and CPYR, but not DPHA or TPA, only at high concentrations (10(-3) or 3 X 10(-3M) released HI from both pleural and PMZ did not modulate the pleural mast cells HI-releasing profile of both DOX or DPHA. Chronic treatment with the antidepressants and the H1-antihistaminics decreased slightly but not significantly HI contents in the brains of L-histidine-treated rats. It is suggested that the decrease in the brain HI levels induced by chronic administration of both tricyclic antidepressants and H1-antihistaminics is, most probably, a consequence of HI release from central histaminergic nerve terminals; this release could result from the drug-produced persistent blockade of central H1- and/or H3- (i.e. HI auto-receptors)receptors.