Relationship between cocaine-induced hepatotoxic neurobehavioral & biochemical changes in mice: the antidotal effects of buprenorphine.
Cocaine (COCA)-induced neurobehavioral symptoms, which can be observed simultaneously with exacerbation in biochemical markers, were evaluated in mice, and compared with the changes observed in a representative hepatic failure model induced by thioacetamide (TAA). The effects of pretreatment with buprenorphine (BUP) (0.25, 0.5 or 1 mg/kg i.p.), a mixed opioid agonist-antagonist and an antidote against fatal COCA toxicity, were also examined. At 5 min after the COCA administration (65 mg/kg i.p.), the liver ATP levels were attenuated, and an exacerbation of the CNS-stimulating effects of COCA could be characteristically observed for hepatotoxicity-related neurobehavioral symptoms (changes in alertness, interest, body tension, head movement and walking). At 24 h, the ALT (alanine aminotransferase) activity was elevated, and hepatotoxic attenuation was observed for all of the scores on the neurobehavioral symptoms; this was almost identical to the symptoms observed in the TAA-treated group of mice. Recovery was observed by 72 h for all of the morbid changes. The hepatotoxic biochemical changes and the sum score for all five neurobehavioral symptoms were significantly ameliorated by low doses (0.25 and 0.5 mg/kg) of BUP, both at 5 min and 24 h.
Hayase
T
T
Department of Legal Medicine, Kyoto University Graduate School of Medicine, Faculty of Medicine, Japan.
Yamamoto
Y
Y
Yamamoto
K
K
Abiru
H
H
Nishitani
Y
Y
Fukui
Y
Y
D000255:Adenosine Triphosphate / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002047:Buprenorphine / Q000627:therapeutic use*; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004195:Disease Models, Animal; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D009294:Narcotics / Q000633:toxicity*
D000931:Antidotes; D009292:Narcotic Antagonists; D009294:Narcotics; D002047:Buprenorphine; D000255:Adenosine Triphosphate; D000410:Alanine Transaminase; D003042:Cocaine