Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat.
By using double in situ hybridization performed with proenkephalin and H3-receptor riboprobes on the same sections from rat brain, we show that histamine H3 receptors are expressed within striatopallidal neurons of the indirect movement pathway. The majority ( approximately 70%) of striatal enkephalin neurons express H3-receptor mRNAs. This important degree of coexpression of proenkephalin and H3-receptor mRNAs prompted us to explore the effect of H3-receptor ligands on the regulation of enkephalin mRNA expression in the striatum. Acute administration of ciproxifan, a H3-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)-alpha-methylhistamine, a H3-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 H3-receptor mRNA expression in enkephalin neurons suggests that the synergistic neurochemical and motor effects of ciproxifan and haloperidol result from direct H3/D2-receptor interactions, leading to an enhanced activation of striatopallidal neurons of the indirect movement pathway. The potentiation of the effects of haloperidol by ciproxifan strengthens the potential interest of H3-receptor antagonists/inverse agonists to improve the symptomatic treatment of schizophrenia.
Pillot
Catherine
C
Laboratoire de Physiologie, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France.
Ortiz
Jordi
J
Héron
Anne
A
Ridray
Sophie
S
Schwartz
Jean-Charles
JC
Arrang
Jean-Michel
JM
D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D017403:In Situ Hybridization; D008024:Ligands; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009496:Neurotensin / Q000032:analysis / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D004745:Enkephalins; D006633:Histamine Antagonists; D007093:Imidazoles; D008024:Ligands; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018100:Receptors, Histamine H3; C029992:proenkephalin; D009496:Neurotensin; D005680:gamma-Aminobutyric Acid; C115705:ciproxifan; D006220:Haloperidol