Histaminergic modulation of GABAergic transmission in rat ventromedial hypothalamic neurones

1. The ventromedial nucleus of the hypothalamus (VMH) is a key nucleus in the homeostatic regulation of neuroendocrine and behavioural functions. In mechanically dissociated rat VMH neurones with attached native presynaptic nerve endings, GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded using the nystatin perforated patch recording mode under voltage-clamp conditions. 2. Histamine reversibly inhibited the sIPSC frequency in a concentration-dependent manner without affecting the mean current amplitude. The selective histamine receptor type 3 (H₃) agonist imetit (100 nM) mimicked this effect and it was completely abolished by the selective H₃ receptor antagonists clobenpropit (3 μM) and thioperamide (10 μM). 3. The GTP-binding protein inhibitor N-ethylmaleimide (10 μM) removed the histaminergic inhibition of GABAergic sIPSCs. 4. Elimination of external Ca²⁺ reduced the GABAergic sIPSC frequency without affecting the distribution of current amplitudes. In this condition, the inhibitory effect of imetit on the sIPSC frequency completely disappeared, suggesting that the histaminergic inhibition requires extracellular Ca²⁺. 5. The P/Q-type Ca²⁺ channel blocker ω-agatoxin IVA (300 nM) attenuated the histaminergic inhibition of the GABAergic sIPSC frequency, but neither the N-type Ca²⁺ channel blocker ω-conotoxin GVIA (3 μM) nor the L-type Ca²⁺ channel blocker nicardipine (3 μM) was effective. 6. Activation of adenylyl cyclase with forskolin (10 μM) had no effect on histaminergic inhibition of the sIPSCs. 7. In conclusion, histamine inhibits spontaneous GABA release from presynaptic nerve terminals projecting to VMH neurones by inhibiting presynaptic P/Q-type Ca²⁺ channels via a G-protein coupled to H₃ receptors and this may modulate the excitability of VMH neurones.