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The Journal of Neuroscience, August 15, 2002, 22(16):7272-7280

Ciproxifan, a Histamine H₃-Receptor Antagonist/Inverse Agonist, Potentiates Neurochemical and Behavioral Effects of Haloperidol in the Rat

Catherine Pillot¹, Jordi Ortiz¹, Anne Héron¹, Sophie Ridray¹, Jean-Charles Schwartz², and Jean-Michel Arrang²

¹ Laboratoire de Physiologie, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France, and ² Unité de Neurobiologie et Pharmacologie Moléculaire de l'Institut National de la Santé et de la Recherche Médicale, Centre Paul Broca, 75014 Paris, France

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 (~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)--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.

Key words: histamine; H₃ receptor; ciproxifan; antagonist/inverse agonist; D₂ receptor; haloperidol; enkephalin; neurotensin; c-fos; in situ hybridization; catalepsy; locomotor activity

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22167272-09$05.00/0

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				H. L. Haas, O. A. Sergeeva, and O. Selbach Histamine in the Nervous System Physiol Rev, July 1, 2008; 88(3): 1183 - 1241. [Abstract] [Full Text] [PDF]

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