Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, modulates the effects of methamphetamine on neuropeptide mRNA expression in rat striatum.
We have explored the effect of histamine H3-receptor ligands on the regulation of neuropeptide mRNA expression in the striatum by using in situ hybridization performed with proenkephalin, prodynorphin, substance P and proneurotensin riboprobes. Acute administration of ciproxifan, an H3-receptor antagonist/inverse agonist, or (R)-alpha-methylhistamine, an H3-receptor agonist, did not modify the striatal expression of the neuropeptides by itself. However, ciproxifan strongly and differentially modulated the effect of a single administration of 3 mg/kg methamphetamine on neuropeptide mRNA expression. This modulation was suppressed by the administration of (R)-alpha-methylhistamine and occurred in both the caudate-putamen and nucleus accumbens. Ciproxifan strongly potentiated the decrease of proenkephalin mRNA expression induced by methamphetamine. In contrast, it suppressed the increase in prodynorphin and substance P mRNA expression induced by methamphetamine. Methamphetamine alone or with ciproxifan did not modify proneurotensin mRNA expression. These neurochemical findings indicate that ciproxifan differentially regulates the effect of methamphetamine on the neuropeptides contained in striatonigral and striatopallidal neurons. They suggest that endogenous histamine and dopamine cooperate to modulate the activity of striatal projection neurons and strengthen the interest of H3-receptors as new targets for the treatment of psychotic disorders and drug abuse.
Pillot
Catherine
C
Laboratoire de Physiologie, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France.
Héron
Anne
A
Schwartz
Jean-Charles
JC
Arrang
Jean-Michel
JM
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004357:Drug Synergism; D004745:Enkephalins / Q000096:biosynthesis / Q000187:drug effects; D006633:Histamine Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D017403:In Situ Hybridization; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D008761:Methylhistamines / Q000494:pharmacology; D009479:Neuropeptides / Q000096:biosynthesis* / Q000187:drug effects; D009496:Neurotensin / Q000096:biosynthesis / Q000187:drug effects; D011498:Protein Precursors / Q000096:biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000378:metabolism*; D013373:Substance P / Q000096:biosynthesis / Q000187:drug effects
D000697:Central Nervous System Stimulants; D004745:Enkephalins; D006633:Histamine Antagonists; D007093:Imidazoles; D008761:Methylhistamines; D009479:Neuropeptides; D011498:Protein Precursors; D012333:RNA, Messenger; D018100:Receptors, Histamine H3; C029992:proenkephalin; C411471:proneurotensin; D013373:Substance P; D009496:Neurotensin; D008694:Methamphetamine; C115705:ciproxifan; C033660:preproenkephalin