Anxiolytic-like profiles of histamine H3 receptor agonists in animal models of anxiety: a comparative study with antidepressants and benzodiazepine anxiolytic.
BACKGROUND
Histamine H3 receptor functions as a presynaptic auto- and hetero-receptor on histaminergic and non-histaminergic neurons in the brain regulating the synaptic release of numerous neurotransmitters. Therefore, the ligands for this receptor have been proposed to be of therapeutic interest for the treatment of various neuropsychiatric disorders. At present, however, the psychopharmacological profiles of H3 ligands, particularly H3 agonists, have not been extensively studied.


OBJECTIVE
The present study investigated the anxiolytic-like profiles of H3-selective agonists in a variety of classical (benzodiazepine-sensitive) and atypical (antidepressant-effective) animal models of anxiety. Comparator drugs used were diazepam and both fluvoxamine and desipramine in the former and latter models, respectively.


RESULTS
H3 agonist R-alpha-methylhistamine and immepip were inactive in rat elevated plus maze test and Vogel type conflict test where diazepam (5 mg/kg) produced significant anxiolytic-like effects. Meanwhile, these H3 agonists (10-30 mg/kg) significantly reduced isolation-induced vocalizations in guinea pig pups and isolation-induced aggressive behavior in mouse resident-intruder test. Moreover, in rat conditioned fear stress test, R-alpha-methylhistamine (30 mg/kg) and immepip (10 mg/kg) significantly decreased freezing time, which were completely reversed by concomitant treatment with H3 antagonist, thioperamide (10 mg/kg). In contrast to the limited efficacy obtained with desipramine (30 mg/kg), fluvoxamine (20-60 mg/kg) exhibited anxiolytic-like effects in all the latter three atypical models.


CONCLUSIONS
These data suggest that the H3 agonists may have anxiolytic-like effects similar to those of selective serotonin reuptake inhibitors but not benzodiazepine anxiolytics and represent a novel strategy for the treatment of some anxiety disorders in which selective serotonin reuptake inhibitors are prescribed.
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
Fumikazu
F
Yokoyama
Miki
M
Yamauchi
Masayo
M
Oyama
Kunihiro
K
Okuma
Kaname
K
Onozawa
Takako
T
Nagayama
Rie
R
Shinei
Makoto
M
Ishikawa
Yasuo
Y
Sato
Nobukazu
N
Kakui
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D017442:Histamine Agonists / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014828:Vocalization, Animal / Q000187:drug effects
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D017442:Histamine Agonists; D001569:Benzodiazepines