Extensive literature suggests that the brain histaminergic system can modulate learning and reinforcement. However, many details are lacking, and some findings seem contradictory. For example, several workers have found that microinjections of HA into certain brain areas facilitate cognitive performance and task recall, and pharmacological depletion of brain HA has the opposite effect (Kamei et al. 1993; Leurs et al. 1998). Furthermore, both H1 receptor agonists, and an inhibitor of brain HA metabolism reversed scopolamine amnesia in a passive avoidance test (Malmberg-Aiello et al. 2000). In contrast, H1 antagonists have been found to reduce some kinds of cognitive performance and to impair recall (Kamei and Tasaka 1991). However, a number of studies have also shown that tuberomammillary lesions (which were thought to deplete neuronal HA) actually improve performance on several kinds of learning tasks (Klapdor et al. 1994; Frisch et al. 1998). Moreover, in some studies H1 antagonists have been shown to produce reinforcing and memory-promoting effects (Frisch etal. 1997). Thus, HA, H1 antagonists, and tuberomammillary lesions have all been reported to enhance memory. While this paradox has not yet been resolved, all of the key findings have recently been observed by the same laboratory and discussed (Hasenohrl etal. 2001). The 'direction' of cognitive modulation by brain H3 receptors seems somewhat more clear. Thus, H3 antagonists reverse scopolamine amnesia in several tests; this effect is antagonized and enhanced, respectively, by blockers of H1 and H2 receptors, respectively (Miyazaki etal. 1995,1997). Similarly, thioperamide enhances passive avoidance responding in senescence-accelerated mice, but not in normal mice (Meguro et al. 1995). GT-2227, an experimental H3 antagonist, improved passive avoidance responding in 3 week-old rat pups (Yates etal. 1999). H3 agonists reduce cortical acetylcholine release, and impair object recognition and passive avoidance responding (Blandina et al. 1996). A case can therefore be made that H3 antagonists show cognition-enhancing properties, and may be useful in several clinical settings (Leurs etal. 1998), even though the mechanisms by which these drugs act remain to be completely clarified. H2 agonists seem to impair cognitive performance, an effect reversed by H2 blockers, but the H2 blocker alone had no effect (Onodera et al. 1998). There are extensive interactions between the histaminergic and cholinergic systems which seem consistent with a cognitive role for the former as well as the latter (Passani et al. 2000; Passani and Blandina 1998).
Several studies suggest that components of the histaminergic system may be altered in aging or dementia. Compared with age-matched controls, HA content was reduced by 42-53 per cent in hypothalamus, hippocampus, and temporal cortex of post-mortem Alzheimer brains (Panula et al. 1998). Alzheimer's patients also show reduced H1 receptor binding in frontal and temporal cortical areas when compared with age-matched controls (Higuchi et al. 2000). Older humans show decreases in brain H1 receptors as compared with younger controls (Yanai etal. 1992a).
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