Differential Effect of Histamine 3 Receptor-Active Agents on

The activation of presynaptic histamine 3 (H3) receptors inhibits the release of histamine and other neurotransmitters from cen-tral nervous system neurons. Rat brain mast cells (MCs) release histamine and 5-hydroxytryptamine (5-HT) in response to neu-ropeptides and neurotransmitters secreted from adjacent neu-rons. Dura MCs also degranulate in response to antidromic trigeminal nerve stimulation and with acute psychological stress. Such findings have implicated brain MCs in certain neuroinflammatory disorders, such as migraines. We investi-gated the ultrastructural appearance of control and stimulated thalamic/hypothalamic (brain) MCs before and after treatment with the H3 receptor agonist N a-methylhistamine (Na-mH) and the H3 receptor antagonist thioperamide (Th). Ultrastructural investigation of brain MCs stimulated with compound 48/80 revealed extensive intragranular changes that paralleled 5-HT secretion but without degranulation by exocytosis typical of connective tissue MCs. Na-mH significantly reduced these morphological changes, as well as 5-HT release from brain MCs and neurons stimulated with KCl; conversely, Th aug-mented both histamine and 5-HT release from brain neurons and MCs. Neither Na-mH nor Th had any effect on peritoneal MCs. Simultaneous addition of both drugs largely antagonized each other’s effects on brain MC activation and 5-HT secretion. Ultrastructural observations and lack of lactic dehydrogenase release in the perfusate excluded any cytotoxic effect. The ability of H3 agonists to inhibit brain MC activation, as well as secretion of 5-HT from both brain MCs and neurons, may be useful in the management of migraines. Presynaptic H3 receptors are present perivascularly in the central nervous system (CNS; Ishikawa and Sperelakis, 1987; Hill, 1990). Their activation leads to autoinhibition o