Histamine H₃ receptor activation increases the firing of striatal medium spiny neurons in slices from infantile rats

Striatal medium spiny neurons (MSN) form two subpopulations (MSN-D₁ and MSN-D₂) according to the expression of dopamine D₁ or D₂ receptors and their target regions. The activation of postsynaptic histamine H₁ and H₂ receptors increases MSN-D₁ and MSN-D₂ excitability. Since MSN also express H₃ receptors (H₃Rs), in this work we explored the effect of their activation on MSN firing. Electrophysiological recordings (whole-cell patch-clamp, current-clamp mode) were conducted on forebrain slices from infantile rats (12-16 postnatal days). In both MSN-D₁ and MSN-D₂ perfusion with the H₃R agonist immepip (1 µmol/L) increased neuronal firing evoked by current injection, an effect reproduced by R-α-methylhistamine (1 µmol/L) and prevented by the antagonist clobenpropit (10 µmol/L). Blockade of N- or P/Q-type voltage-activated calcium channels by ω-conotoxin-GVIA (1 µmol/L) or ω-agatoxin-TK (400 nmol/L) increased MSN firing but did not preclude the immepip effect. The potassium channel blockers 4-aminopyridine (1 mmol/L) and tetraethylammonium (300 µmol/L) increased neuronal firing and prevented the immepip action. Likewise, the K_V7 channel blocker XE-991 (10 µmol/L) and the muscarinic receptor agonist carbachol (10 µmol/L) increased MSN firing frequency and occluded the immepip effect. These data indicate that the activation of postsynaptic H₃Rs facilitates MSN-D₁ and MSN-D₂ firing by inhibiting K_V7 potassium channels.