By using double in situ hybridization performed with proen-kephalin and H 3-receptor riboprobes on the same sections from rat brain, we show that histamine H 3 receptors are expressed within striatopallidal neurons of the indirect movement pathway. The majority (70%) of striatal enkephalin neurons express H 3-receptor mRNAs. This important degree of coexpression of proenkephalin and H 3-receptor mRNAs prompted us to explore the effect of H 3-receptor ligands on the regulation of enkephalin mRNA expression in the striatum. Acute administration of ciproxifan, a H 3-receptor antagonist/inverse agonist, did not modify the expression of the neuropeptide by itself but strongly increased the upregulation of its expression induced by haloperidol. This potentiation (1) was suppressed by the administration of (R)-methylhistamine, a H 3-receptor agonist, (2) occurred both in the caudate–putamen and nucleus accumbens, and (3) was also observed with a similar pattern on c-fos and neurotensin mRNA expression. Similarly, whereas it was devoid of any motor effect when used alone, ciproxifan strongly potentiated haloperidol-induced locomotor hypoactivity and catalepsy, two behaviors in which striatal neurons are involved. The strong H 3-receptor mRNA expression in enkephalin neurons suggests that the synergistic neurochemical and motor effects of ciproxifan and haloperidol result from direct H 3 /D 2-receptor interactions, leading to an enhanced activation of striatopallidal neurons of the indirect movement pathway. The potentiation of the effects of haloper-idol by ciproxifan strengthens the potential interest of H 3-receptor antagonists/inverse agonists to improve the symptomatic treatment of schizophrenia.