Central nervous system effects and behavioral interactions with ethanol of centrally administered dilazep and its metabolites in mice.
Dilazep (i.p.), a coronary vasodilator and an uptake inhibitor of adenosine, dose dependently potentiated acute ethanol-induced motor incoordination in mice. In view of peripheral cardiovascular depressive effects of dilazep, the effect of i.c.v. dilazep (25, 50 and 75 micrograms), and its metabolites, 1,4-bis(3-hydroxypropyl)perhydro-1,4-diazepine (BHPD) (15, 31 and 62 micrograms) and 1-[3-(3,4,5-trimethoxybenzoyloxy)propyl]perhydro-1,4-diazepine (TBPD) (62 and 125 micrograms) on ethanol-induced motor incoordination was studied. Dose-related potentiation of ethanol-induced motor incoordination was noted with dilazep and its metabolites. Whereas dilazep (i.p.) produced no apparent central nervous system (CNS) effects, by i.c.v. route, it caused CNS excitation including tonic-clonic seizures. Adenosine uptake inhibition, Ca2+ entry blockade or direct activation of adenosine receptors was ruled out as the possible mechanism of seizures because dipyridamole, verapamil or N6-(2-phenylisopropyl)-adenosine (R-PIA) administered i.c.v., while potentiating ethanol (i.p.)-induced motor incoordination did not produce seizures. The CNS excitation was minimal with BHPD and none with TBPD. Theophylline pretreatment partially blocked potentiation of ethanol-induced motor incoordination by dilazep and BHPD and not by TBPD. The data suggest dilazep-induced potentiation of ethanol-induced motor incoordination is partially due to central adenosine receptor mechanism and partly due to other yet unknown mechanism(s) and further supported our earlier reports about adenosine involvement in the CNS effects of ethanol. The data also suggest that dilazep (i.c.v.)-induced seizures are due to mechanism(s) other than adenosine uptake inhibition, Ca2+ entry blockade or direct adenosine receptor activation.
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27834.
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D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D002490:Central Nervous System / Q000187:drug effects*; D004109:Dilazep / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008845:Microinjections; D011597:Psychomotor Performance / Q000187:drug effects; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
D001381:Azepines; D000431:Ethanol; D014700:Verapamil; D004109:Dilazep