Effects of the H3 receptor inverse agonist thioperamide on cocaine-induced locomotion in mice: role of the histaminergic system and potential pharmacokinetic interactions.
BACKGROUND
Previous studies have shown that intraperitoneal injections of thioperamide, an imidazole-based H3 receptor inverse agonist that enhances histamine release in the brain, potentiate cocaine-induced hyperlocomotion. The present study examined the involvement of the histaminergic system in these effects of thioperamide in mice.


METHODS
We investigated whether immepip, a selective H3 agonist, could reverse the potentiating effects of thioperamide. Moreover, the non-imidazole H3 inverse agonist A-331440 was tested on the locomotor effects of cocaine. Using high-performance liquid chromatography with ultraviolet detection, cocaine plasma concentrations were measured to study potential drug-drug interactions between thioperamide and cocaine. Finally, thioperamide was tested on the locomotor effects of cocaine in histamine-deficient knockout mice in order to determine the contribution of histamine to the modulating effects of thioperamide.


RESULTS
Thioperamide potentiated cocaine-induced hyperlocomotion in normal mice, and to a higher extent, in histamine-deficient knockout mice. A-331440 only slightly affected the locomotor effects of cocaine. Immepip did not alter cocaine-induced hyperactivity but significantly reduced the potentiating actions of thioperamide on cocaine's effects. Finally, plasma cocaine concentrations were more elevated in mice treated with thioperamide than in mice that received cocaine alone.


CONCLUSIONS
The present results indicate that histamine released by thioperamide through the blockade of H3 autoreceptors is not involved in the ability of this compound to potentiate cocaine induced-hyperactivity. Our data suggest that thioperamide, at least at 10 mg/kg, increases cocaine-induced locomotion through the combination of pharmacokinetic effects and the blockade of H3 receptors located on non-histaminergic neurons.
Centre de Neurosciences Cognitives et Comportementales (CNCC), Université de Liège, Boulevard du Rectorat 5/B-32, 4000 Liège, Belgium.
Christian
C
Brabant
Livia
L
Alleva
Thierry
T
Grisar
Etienne
E
Quertemont
Bernard
B
Lakaye
Hiroshi
H
Ohtsu
Jian-Sheng
JS
Lin
Peter
P
Jatlow
Marina R
MR
Picciotto
Ezio
E
Tirelli
D000818:Animals; D019540:Area Under Curve; D001713:Biphenyl Compounds / Q000494:pharmacology; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006632:Histamine / Q000502:physiology*; D017442:Histamine Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000235:genetics / Q000502:physiology
C493218:4'-(3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy)-biphenyl-4-carbonitrile; D001713:Biphenyl Compounds; D017442:Histamine Agonists; D007093:Imidazoles; D009570:Nitriles; D010880:Piperidines; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; C085755:4-(1H-imidazol-4-ylmethyl)piperidine; D006632:Histamine; D003042:Cocaine; C052075:thioperamide