Histaminergic neurons in the tuberomammillary nucleus (TMN) promote arousal. Many of these neurons also contain GABA, but its function in arousal is unclear. In mice, short interfering RNA-mediated knockdown of the expression of the vesicular GABA transporter (VGAT) in TMN histaminergic neurons led to hyperactivity and increased wakefulness. In brain slices from naive mice, optogenetic activation of histaminergic TMN neuron terminals in the neocortex and caudate putamen induced extrasynaptic GABA type A receptor-mediated currents. These findings suggest that GABA acts in a paracrine manner to negatively modulate the effects of histamine on arousal.