Evidence for tolerance following repeated dosing in rats with ciproxifan, but not with A-304121.
Blockade of presynaptic histamine H(3) receptors with potent and selective ligands improves cognitive function in rodents and there is significant interest in developing such drugs for long-term symptomatic treatment of CNS disorders such as attention deficit hyperactivity disorder (ADHD). Unfortunately, little is known about the effects of repeated exposure to H(3) receptor antagonists/inverse agonists. We therefore investigated the effects of acute and repeated daily administration of two potent, brain penetrating H(3) receptor antagonists/inverse agonists, ciproxifan and A-304121, on rat body weight, food and water intake, core temperature and locomotor activity, as well as H(3) receptor density and gene expression levels. Methylphenidate, used clinically for the treatment of ADHD, was included as an additional comparator. Ciproxifan, an imidazole-based compound, decreased food intake over the first 10 days and locomotor activity acutely, but these effects were lost after further repeated administration. The ex vivo binding studies revealed increased H(3) receptor density in rats following repeated administration of ciproxifan for 10 or 15 days; however, H(3) receptor gene expression was not changed. In contrast, rats treated with the non-imidazole, A-304121, did not differ from controls on any measure during the observation period, while rats treated with methylphenidate exhibited hyperthermia and hyperactivity. The implications for potential long-term treatment with H(3) receptor antagonists in CNS disorders such as ADHD are discussed.
Pan
Jia Bao
JB
Neuroscience Research, Abbott Laboratories, 100 Abbott Road, Abbott Park, IL 60064-6125, USA. jia.bao.pan@abbott.com
Yao
Betty B
BB
Miller
Thomas R
TR
Kroeger
Paul E
PE
Bennani
Youssef L
YL
Komater
Victoria A
VA
Esbenshade
Timothy A
TA
Hancock
Arthur A
AA
Decker
Michael W
MW
Fox
Gerard B
GB
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004326:Drinking / Q000187:drug effects; D004361:Drug Tolerance; D004435:Eating / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D017442:Histamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics
C475225:4-((3-(4-(2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone; D000697:Central Nervous System Stimulants; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D010879:Piperazines; D018100:Receptors, Histamine H3; D008774:Methylphenidate; C115705:ciproxifan