title: H3 agonist immepip markedly reduces cortical histamine release, but only weakly promotes sleep in the rat.
abstract: Presynaptic H3 receptors exert negative control on brain histamine synthesis and release and may thereby play a key role in the control of the sleep/wake cycle. This suggests that pharmacological stimulation by H3 receptor agonists may potentially decrease wakefulness and induce sleep. This study reports the effect of a potent and selective H3 agonist, immepip, on EEG assessed sleep/wake phases in Sprague-Dawley rats at doses that significantly modulate brain histamine release. Immepip injected intraperitoneally (i.p.) at 5 or 10 mg kg(-1) induced a sustained decrease in cortical histamine efflux as measured by in vivo microdialysis. In a separate experiment, rats were prepared for EEG/EMG recording and evaluated during the dark phase of their light/dark cycle. The results showed that the same i.p. doses of 5 and 10 mg kg(-1) of immepip was devoid of any significant impact on the sleep/wake phases (active awake, drowsiness and slow wave sleep), except for a slight, albeit significant, decrease in sleep onset latency. These results reveal that a marked H3 receptor agonist-mediated reduction in cortical histamine release is not corroborated by a significant sleep promoting effect and therefore question the hypnotic potential of H3 agonists.
authors.affiliation: UCB Pharma, Preclinical CNS Research, Chemin du Foriest, B-1420, Braine-l'Alleud, Belgium. yves.lamberty@ucb-group.com
authors.forename: Yves
authors.initials: Y
authors.lastname: Lamberty
authors.forename: Doru Georg
authors.initials: DG
authors.lastname: Margineanu
authors.forename: Donald
authors.initials: D
authors.lastname: Dassesse
authors.forename: Henrik
authors.initials: H
authors.lastname: Klitgaard
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004569:Electroencephalography; D004576:Electromyography; D005479:Flurazepam / Q000494:pharmacology; D017442:Histamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007263:Infusions, Parenteral; D008297:Male; D017551:Microdialysis; D023421:Models, Animal; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D012890:Sleep / Q000187:drug effects*
chemical_list: D017442:Histamine Agonists; D007093:Imidazoles; D010880:Piperidines; D018100:Receptors, Histamine H3; C085755:4-(1H-imidazol-4-ylmethyl)piperidine; D005479:Flurazepam