Some G-protein-coupled receptors display ‘constitutive activity’, that is, spontaneous activity in the absence of agonist^,,,. This means that a proportion of the receptor population spontaneously undergoes an allosteric transition, leading to a conformation that can bind G proteins. The process has been shown to occur with recombinant receptors expressed at high density, and/or mutated, but also non-mutated recombinant receptors expressed at physiological concentrations^,,. Transgenic mice that express a constitutively active mutant of the β ₂-adrenergic receptor display cardiac anomalies; and spontaneous receptor mutations leading to constitutive activity are at the origin of some human diseases^,. Nevertheless, this process has not previously been found to occur in animals expressing normal levels of receptor^,. Here we show that two isoforms of the recombinant rat H₃ receptor^, display high constitutive activity. Using drugs that abrogate this activity (‘inverse agonists’) and a drug that opposes both agonists and inverse agonists (‘neutral antagonist’), we show that constitutive activity of native H₃ receptors is present in rodent brain and that it controls histaminergic neuron activity in vivo . Inverse agonists may therefore find therapeutic applications, even in the case of diseases involving non-mutated receptors expressed at normal levels.