Abstract
Histamine H3 receptors are located on presynaptic terminals in key brain areas important for learning and memory. Blockade of the histamine H3 receptor via an antagonist leads to enhanced histamine release as well as enhanced neurotransmitter release of acetylcholine, dopamine and noradrenaline. Such neurochemical actions are implicated in cognitive processes and thus, histamine H3 antagonists may represent a novel drug class with therapeutic potential against neurodegenerative diseases like Alzheimer's disease, schizophrenia and attentional deficit hyperactive disorder. The present study assessed the possible procognitive effects associated with the histamine H3 antagonist thioperamide (1–10 mg/kg, ip; 30 min) on episodic and spatial reference memories in young and aged rodents. In an object recognition model of episodic memory, young Sprague–Dawley rats showed a significant and dose–dependent improvement in object recognition memory at the 48hr test delay interval. In the rat Morris water–maze model of spatial reference memory, aged Fischer 344 rats are screened and classified as either aged cognitively–impaired or aged cognitively–unimpaired based upon their water–maze performance to that of young Fischer 344 rats, Approximately 40% of the aged rats are considered performance impaired (>2 STDs from young rat performance) whereas 25% of the aged rats are not significantly different from young controls. Following classification, aged–impaired rats were given thioperamide during 3 additional days of water–maze performance assessment. Thioperamide significantly reversed the aged–related spatial reference memory deficit. Both latency to platform and probe trial (e.g., % time in quadrant, entry to first annulus–40 and time in annulus–40) performance were significantly enhanced by the H3 receptor antagonist compared to aged–impaired controls. These results suggest that histamine H3 receptor antagonists may be a viable therapeutic drug target for the treatment of Alzheimer's disease and other neurodegenerative disorders.
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