Endogenous GABA modulates histamine release from the anterior hypothalamus of the rat

Using a microdialysis method, we investigated the effects of the nipecotic acid-induced increase in content of endogenous GABA on in vivo release of histamine from the anterior hypothalamus (AHy) of urethane-anesthetized rats. Nipecotic acid (0.5 mM), an inhibitor of GABA uptake, decreased histamine release to ~60% of the basal level. This effect was partially antagonized by picrotoxin (0.1 mM), an antagonist of GABA(A) receptors, or phaclofen (0.1 mM), an antagonist of GABA(B) receptors. These results suggest that histamine release is modulated by endogenous GABA through both GABA(A) and GABA(B) receptors. When the tuberomammillary nucleus, where the cell bodies of the histaminergic neurons are localized, was stimulated electrically, the evoked release of histamine from the nerve terminals in the AHy was significantly enhanced by phaclofen, suggesting that GABA(B) receptors may be located on the histaminergic nerve terminals and modulate histamine release presynaptically. On the other hand, picrotoxin caused an increase in histamine release to ~170% of the basal level, and this increase was diminished by coinfusion with D(-)-2-amino-5-phosphonopentanoic acid (0.1 mM), an antagonist of NMDA receptors. Previously, we demonstrated tonic control of histamine release by glutamate mediated through NMDA receptors located on the histaminergic terminals in the AHy. These results suggest the possible localization of GABA(A) receptors on glutamatergic nerve terminals and that the receptors may regulate the basal release of histamine indirectly.