title: Acute ethanol/cannabinoid-induced ataxia and its antagonism by oral/systemic/intracerebellar A1 adenosine receptor antisense in mice.
abstract: Previous reports from our laboratory have demonstrated that ethanol- and cannabinoid-induced ataxia is modulated by cerebellar adenosine A(1) receptor because intracerebellar (i.c.b.) adenosine A(1) agonists potentiated and A(1) antagonist attenuated ataxia by these psychoactive drugs. In this study, the novel approach involving pretreatment with adenosine A(1) antisense oligodeoxynucleotide via multiple routes provided further direct evidence of mouse cerebellar A(1) modulation of ethanol- and cannabinoid-induced ataxia. Animal groups were pretreated with A(1) antisense and its mismatch by oral (p.o.) (3.12, 6.25, 12.5, 50 microg/12 h; total three treatments/each dose), intraperitoneal (i.p.) (3.12, 5, 10, 50 microg/12 h; total three treatments/each dose), and i.c.b. (2 microg/12 h; total three treatments) routes. Based on our standard rotorod test, marked antagonism to ethanol (2 g/kg; i.p.) and delta(9)-THC (15 microg; i.c.b)-induced ataxia was observed 12 h after the last antisense treatment. Pretreatment with A(1) receptor mismatch was without an effect. The antagonism following systemic (p.o.; i.p.) antisense pretreatment was dose-dependent. No change in the normal motor coordination was observed when the animals were pretreated with antisense or its mismatch followed by vehicle. Results of Western blotting using commercially available antibodies and cerebellar membranes from various animal groups which received antisense and its mismatch via three routes confirmed a significant decrease in the A(1) adenosine receptor protein. These results, for the first time, demonstrated an oral and systemic effectiveness of A(1) antisense towards adenosine receptors in the central nervous system.
authors.affiliation: Department of Pharmacology, Brody Medical School at East Carolina University, Greenville, NC 27858, USA. darm@mail.ecu.edu
authors.forename: M Saeed
authors.initials: MS
authors.lastname: Dar
authors.forename: S Jamal
authors.initials: SJ
authors.lastname: Mustafa
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D015153:Blotting, Western; D002186:Cannabinoids; D002492:Central Nervous System Depressants; D002524:Cerebellar Ataxia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism*; D000431:Ethanol; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists; D013997:Time Factors
chemical_list: D002186:Cannabinoids; D002492:Central Nervous System Depressants; D020319:Oligodeoxyribonucleotides, Antisense; D058915:Purinergic P1 Receptor Antagonists; D000431:Ethanol