Modulation of prepulse inhibition and stereotypies in rodents: no evidence for antipsychotic-like properties of histamine H3-receptor inverse agonists.
BACKGROUND
H(3)-receptor inverse agonists raise a great interest as innovative therapeutics in several central disorders. Whereas their procognitive properties are well established, their antipsychotic-like properties are still debated.


OBJECTIVE
We further explored the effect of maximal doses (3-10 mg/kg) of ciproxifan, BF2.649, and ABT-239, three selective H(3)-receptor inverse agonists, on deficits of prepulse inhibition (PPI) induced by apomorphine, MK-801, and phencyclidine (PCP). Their effect was also investigated on stereotypies induced by apomorphine and methamphetamine.


RESULTS
Ciproxifan, BF2.649, and ABT-239 did not reverse the PPI impairment produced by apomorphine (0.5 mg/kg, subcutaneous) in rats. Ciproxifan and BF2.649 did not reverse the impairment induced in mice by MK-801 (0.3 mg/kg). Ciproxifan and BF2.649 also failed to reverse the disruption induced in mice by PCP (5-10 mg/kg). Low to moderate doses of haloperidol (0.1-0.4 mg/kg, intraperitoneal), alone or co-administered with BF2.649, did not reverse MK-801-induced PPI disruption. A high dose (1 mg/kg) of haloperidol partially reversed the MK-801-induced deficit and BF2.649 tended to increase this effect, although nonsignificantly. Whereas stereotypies induced in mice by apomorphine and methamphetamine were totally suppressed by haloperidol, the decrease induced by ciproxifan was partial against apomorphine and very low, if any, against methamphetamine.


CONCLUSIONS
Their total absence of effect in several validated animal models of the disease does not support antipsychotic properties of H(3)-receptor inverse agonists. However, their positive effects previously reported in behavioral tasks addressing learning, attention, and memory maintain the interest of H(3)-receptor inverse agonists for the treatment of cognitive symptoms of schizophrenia as adjunctive medications.
Burban
Aude
A
Laboratoire de Neurobiologie et Pharmacologie Moléculaire, INSERM/Université Paris Descartes, 2 ter rue d'Alésia, 75014, Paris, France.
Sadakhom
Chit
C
Dumoulin
Dominique
D
Rose
Christiane
C
Le Pen
Gwenaëlle
G
Frances
Henriette
H
Arrang
Jean-Michel
JM
D000818:Animals; D014150:Antipsychotic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001058:Apomorphine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001572:Benzofurans / Q000037:antagonists & inhibitors; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D054314:Drug Inverse Agonism; D006220:Haloperidol / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology; D007093:Imidazoles / Q000037:antagonists & inhibitors; D007266:Inhibition, Psychological; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D010622:Phencyclidine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010880:Piperidines / Q000037:antagonists & inhibitors; D011759:Pyrrolidines / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects*
D014150:Antipsychotic Agents; D001572:Benzofurans; D006633:Histamine Antagonists; D007093:Imidazoles; D010880:Piperidines; D011759:Pyrrolidines; D008694:Methamphetamine; C516975:pitolisant; C115705:ciproxifan; D016291:Dizocilpine Maleate; C496397:benzonitrile, 4-(2-(2-((2r)-2-methyl-1-pyrrolidinyl)ethyl)-5-benzofuranyl)-; D010622:Phencyclidine; D006220:Haloperidol; D001058:Apomorphine