![]() ![]() 1987 1990), which is double the therapeutic dose. Only a few authors found no effects of cetirizine 20 mg on behavioural performance ( Gengo and Gabos, 1987 Gengo et al. Twice this dose was found to increase subjective drowsiness ( Gengo and Gabos, 1987) and objective drowsiness, as measured by theta and lower alpha frequency band power in the electroencephalography ( Sannita et al., 1996). Many of the studies that failed to find effects of cetirizine used the recommended therapeutic dose of 10 mg, which should be insufficient to induce reliable behavioural effects. On the other hand, there are also studies that did not find behavioural effects of cetirizine ( Seidel et al., 1987 Gengo et al., 1990 Volkerts et al., 1992 Shamsi et al., 2001 Theunissen et al., 2004). On the one hand, there are several studies showing effects of cetirizine on performance and measures of alertness ( Gengo and Gabos, 1987 Ramaekers et al., 1992 Patat et al., 1995 Sannita et al., 1996 Nicholson and Turner, 1998 Vermeeren et al., 2002 Gupta et al., 2004 Vacchiano et al., 2008). Studies investigating the behavioural effects of cetirizine show conflicting results. Taken together, after dexchlorpheniramine, cetirizine is the second in line as a candidate tool drug to induce histamine hypofunction. The 50% receptor occupancy in the central nervous system by cetirizine may be sufficient to induce behavioural effects. In comparison, 2 mg dexchlorpheniramine occupies 77% of the H 1-receptors and has been shown to induce clear behavioural effects and sedation ( van Ruitenbeek et al., 2008). (2002 2004) found that after a double therapeutic dose of 20 mg, cetirizine occupied 20% to 50% of the H 1-receptors in the brain. Although common held opinion is that second generation antihistamines cross the blood-brain barrier to a much lesser extent, which would make them less suitable as a tool drug, one possible exception is cetirizine. ![]() L −1, whereas the IC 50 at calcium channels, α1, D 2, 5-HT 2 and M 1 receptors is more than 10 µmol.The concentration of cetirizine producing 50% inhibition of radioligand binding (IC 50) at H 1-receptors is 0.65 µmol Although, some of the first generation antihistamines used in these studies, like dexchlorpheniramine, are relatively selective ( van Ruitenbeek et al., 2008 Wiech and Martin, 1982), second generation antihistamines are even more selective for H 1-receptors. ![]() Recent studies have attempted to investigate the specific effects of H 1-receptor blockade in humans ( Turner et al., 2006 van Ruitenbeek et al., 2008). Histamine H 1-receptor antagonists are easily accessible and decrease histaminergic activity and may therefore be used as a tool to model histamine hypofunction and the resulting cognitive impairments. However, these substances are not easily accessible for use in healthy humans. Alternatively, decreased histamine neurotransmission may be achieved using H 3-agonists or H 2-antagonists. Yet, such effects have never been confirmed and underlying mechanisms have been investigated, but not found ( Theunissen et al., 2006a). However, some studies have shown stimulating effects of decreased histamine neurotransmission, induced by the administration of H 1-antagonists ( Theunissen et al., 2006c). Most studies performed in animals show that a decrease in histamine neurotransmission results in impaired performance. If histamine hypofunction is involved in cognitive deficits seen in clinical disorders, an artificial histaminergic hypofunction may reveal what cognitive functions are vulnerable in these disorders. These studies have shown that H 3-antagonists improve performance in models of many cognitive deficits and clinical disorders, like Alzheimer's disease, attention deficit hyperactivity disorder and schizophrenia (for review see: Esbenshade et al., 2006). Evidence for histamine as a cognition promoting substance has mainly come from animal studies. Conversely, an increased histamine content has also been found in the brains ( Cacabelos et al., 1989) and blood serum ( Cacabelos et al., 1992) of Alzheimer's patients. For example, decreased H 1-receptor binding and histamine content have been found in brains of patients with Alzheimer's disease as compared with age- matched controls ( Panula et al., 1998 Higuchi et al., 2000). However, the findings are still controversial. Over the past years evidence has accumulated that histamine may play an important role in such disorders. The histaminergic neurotransmitter system has recently been discovered as a possible target for the pharmacological treatment of cognitive deficits in clinical disorders. ![]()
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