Effects of second‐generation histamine H₁ receptor antagonists on the active avoidance response in rats

Abstract

1. The aim of the present study was to establish a new schedule of active avoidance response in rats to estimate the central effects of second-generation histamine H1 receptor antagonists. 2. With the new schedule, a rat was placed into a dark room. A sliding door was opened after a delay of 5 s and, unless the animal moved into the lit room, an electric shock was delivered for 3 s. With the conventional schedule, the sliding door was opened immediately after the rat was placed into the dark room. 3. Ketotifen, at a dose of 50 mg/kg, showed no significant effect on the retrieval of active avoidance response with the conventional schedule. However, with the new schedule, the drug caused significant inhibition of retrieval of the response, even at a dose of 10 mg/kg. 4. Epinastine showed no significant effect on retrieval of the active avoidance response, even at a dose of 50 mg/kg with the new schedule. 5. Cetirizine, at a dose of 50 mg/kg, caused a significant effect, indicating that cetirizine, at this dose, markedly inhibits memory retrieval. 6. Both olopatadine and loratadine had potent effects; at doses of 20 and 50 mg/kg, respectively, these agents showed significant inhibitory effects on retrieval of the response. 7. In conclusion, we have developed a new schedule of active avoidance response that can be used to estimate the central effects of second-generation histamine H1 receptor antagonists.

Brain histamine H1 receptor occupancy of orally administered antihistamines measured by positron emission tomography with 11C‐doxepin in a placebo‐controlled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen

“…This assumption corresponds with a recent human study demonstrating that olopatadine 10 mg (a double oral dose in Japan) induced mild psychomotor impairment among healthy subjects [39]. In addition, animal studies may provide further suggestions [33, 36–38]. No EEG changes were observed after oral administration of olopatadine in rabbits [33] and in rats [36], whereas oral ketotifen induced significant sedation in both animal studies [33, 36].…”

“…Previous studies have compared its efficacy with that of other antiallergic drugs [24–35]. However, only few animal studies [36–38] and one human study [39] have investigated sedative profile of olopatadine. The primary aim of the present study is to measure H 1 RO of olopatadine using PET and to compare it with that of ketotifen, a typical sedative antihistamine [40–43], in a placebo‐controlled crossover study design.…”

Ketotifen induced inhibition of histamine release in a non‐IgE model of middle ear effusion

“…The dose of ketotifen administered in our animal model was three to six times greater than the recommended daily therapeutic dose in children that is on the order of 0.1–0.14 mg/kg, yet smaller than the dose administered to neonatal and young rats via intraperitoneal (20) or oral (21) routes. Considering the wide range of dose‐dependent inhibition of histamine release in various human organs (10 −7 to 10 −5 m in skin and adenoid mast cells and 10 −11 to 10 −4 m in conjunctival mast cells; 22, 9) and the therapeutic plasma level of ketotifen in humans [1–4 mcg/ml (2.35 × 10 −6 to 9.4 × 10 −6 m )] (23), the concentration of ketotifen in our study is well within the effective range of inhibition of histamine release from mast cells in humans.…”