Effects of histamine H(3) receptor ligands GT-2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup.
Histamine H(3) receptor antagonists have been proposed as potentially useful therapeutic agents for the treatment of several disorders including attention deficit, schizophrenia, depression, and Alzheimer's disease. We have developed a repeated acquisition version of an inhibitory avoidance task using spontaneously hypertensive rat (SHR) pups that we believe provides a reproducible measure of the cognitive and attention deficits often characteristic of these disease states, and evaluated two H(3) receptor antagonists. Male SHR, Wistar (WI) and Wistar Kyoto (WKY) rat pups (20--24 days old) were trained to avoid a mild footshock (0.1 mA, 1 s duration), delivered when the pup had transferred from a brightly lit to a darkened compartment. After the first trial, the pup was removed and returned to its home cage. One minute later, the same pup was replaced in the brightly-lit compartment and the training process repeated. A total of five trials were recorded. SHR pups performed significantly more poorly than WI or WKY pups using this training schedule, and SHR pups were used for all subsequent studies. Methylphenidate and ABT-418, both clinically active in attention deficit hyperactivity disorder (ADHD), were tested to validate the model. Methylphenidate (1 and 3 mg/kg s.c.) and ABT-418 (0.03 mg/kg s.c.) significantly improved SHR pup performance. The H(3) receptor antagonists GT-2331 (1 mg/kg s.c.) and ciproxifan (3 mg/kg s.c.), also significantly, and in a dose-related manner, enhanced performance of the SHR pups. (R)-alpha-methylhistamine (3 mg/kg s.c.) blocked the pro-cognitive effects of ciproxifan, suggesting an H(3) receptor site of action for this compound. This model is useful for evaluating the cognition/attention-enhancing potential of H(3) receptor antagonists.
Fox
Gerard B
GB
CNS Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, AP9A D4N5, Abbott Park, IL 60064, USA. gerard.b.fox@abbott.com
Pan
Jia Bao
JB
Esbenshade
Timothy A
TA
Bennani
Youssef L
YL
Black
Lawrence A
LA
Faghih
Ramin
R
Hancock
Arthur A
AA
Decker
Michael W
MW
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001143:Arousal / Q000187:drug effects; D001289:Attention Deficit Disorder with Hyperactivity / Q000523:psychology; D001362:Avoidance Learning / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003072:Cognition Disorders / Q000523:psychology; D004195:Disease Models, Animal; D006633:Histamine Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007175:Impulsive Behavior / Q000523:psychology; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018100:Receptors, Histamine H3 / Q000187:drug effects*
C114969:4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole; D014151:Anti-Anxiety Agents; D000697:Central Nervous System Stimulants; D006633:Histamine Antagonists; D007093:Imidazoles; D007555:Isoxazoles; D008024:Ligands; D018722:Nicotinic Agonists; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D008774:Methylphenidate; C115705:ciproxifan