H3 agonist immepip markedly reduces cortical histamine release, but only weakly promotes sleep in the rat.
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.
Lamberty
Yves
Y
UCB Pharma, Preclinical CNS Research, Chemin du Foriest, B-1420, Braine-l'Alleud, Belgium. yves.lamberty@ucb-group.com
Margineanu
Doru Georg
DG
Dassesse
Donald
D
Klitgaard
Henrik
H
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*
D017442:Histamine Agonists; D007093:Imidazoles; D010880:Piperidines; D018100:Receptors, Histamine H3; C085755:4-(1H-imidazol-4-ylmethyl)piperidine; D005479:Flurazepam