Effects of H3 receptor modulators on the sedative effects induced by ethanol. Didone V. & Quertemont E. CNCC, University of Liège, Belgium Introduction Methods

Histaminergic system and its H 3 receptors (H3R) are Animals involved in numerous (patho)physiological and higher 310 Female Swiss mice (8-10weeks) were used for the experiments. brain functions. However, despite its central role, very few Drugs studies are available on the link between histamine, H3R, Alcohol injections (3.0-4.0 g/kg) were 20% (v/v), diluted from 99.99% and ethanol-induced behaviours. ethanol with 0.9% saline solution Immepip(10.0-20.0mg/kg), (5.0- 20.0mg/kg), A331440(5.0-20.0mg/kg) and (10.0-20.0mg/kg) Therefore, the rationale of this study was to explore the were dissolved in 0.9% saline and injected at a volume of 0.01 ml/g of body weight. The various H3R modulators were injected (i.p.) 30 minutes before role of histamine and H3R in alcohol-induced sedation . the ethanol injections . We assessed the actions of two H3R agonists, immepip and Sedation imetit, and of two H3R antagonists, thioperamide and To assess the sedative effects of alcohol, 3.0 and 4.0 g/kg of ethanol were A331440, on the loss of righting reflex (LORR) induced by injected and the duration of the induced LORR was measured ethanol in mice.

Results H3R agonists H3R antagonists 6000 Immepip * 5000 0.0 mg/kg Thioperamide 5.0 mg/kg 0.0 mg/kg 5000 10.0 mg/kg 10.0 mg/kg ** 20.0 mg/kg 4000 20.0 mg/kg

4000

3000 3000

2000 2000 *** * * Durationof LORR (sec.) * Durationof LORR (sec.) * 1000 1000

0 0 3.0 4.0 * p<0.05 3.0 4.0 Ethanol doses (g/kg) Ethanol doses (g/kg) 6000 Imetit ** p<0.01 8000 0.0 mg/kg ***p<0.001 A331440 10.0 mg/kg 0.0 mg/kg *** 5000 20.0 mg/kg 7000 5.0 mg/kg 10.0 mg/kg *** 6000 20.0 mg/kg 4000 *** 5000

3000 *** 4000

3000 2000 Duration of LORR (sec.) Duration of LORR (sec.) 2000 1000 1000

0 0 3.0 4.0 3.0 4.0 Ethanol doses (g/kg) Ethanol doses (g/kg)

Conclusion Surprisingly, the H3R antagonist/inverse agonist (A331440 and thioperamide) and the H3R agonists (immepip and imetit) produce a statistically significant enhancement of the sedative effects induced by ethanol. Future investigations are needed to better understand the mechanism(s) underlying these unexpected results, that might be related to unspecific effects of these drugs.