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Naltrexone과 ondansetron의 병합투여가 C57BL/6형 생쥐의 알코올 섭취량에 미치는 영향

Effect of Ondansetron Alone and Combination of Naltrexone and Ondansetron on Alcohol Intake in C57BL/6 Mice

  • 김현경 (부산대학교병원 의학연구소) ;
  • 김성곤 (부산대학교 의과대학 정신과학교실) ;
  • 강철중 (부산대학교 의과대학 정신과학교실) ;
  • 박상익 (질병관리본부 국립보건연구원 생명의과학센터 난치성질환팀) ;
  • 김원호 (질병관리본부 국립보건연구원 생명의과학센터 난치성질환팀)
  • Kim, Hyeun-Kyeung (Medical Research Institute, Pusan National University Hospital) ;
  • Kim, Sung-Gon (Department of Pshychiatry, Pusan National University) ;
  • Kang, Cheol-Joong (Department of Pshychiatry, Pusan National University) ;
  • Park, Sang-Ick (Division of Intractable Disease, Center for Biomedical Science, National Institute of Health) ;
  • Kim, Won-Ho (Division of Intractable Disease, Center for Biomedical Science, National Institute of Health)
  • 발행 : 2007.11.30

초록

알코올 의존의 음주 행동에 VTA에서 NA로 뻗어 있는 도파민 대뇌 보상 경로가 중요하다. 이러한 경로의 토파민 활성도가 $5-HT_3$계 신경에 의하여 조정되고 있으며, $5-HT_3$ 수용체 길항제인 ondansetron (OND)이 알코올리즘 환자에서 음주량을 감소시키고 금주률을 높인다는 보고가 있다. 이에 생쥐의 섭취량에 대하여 $5-HT_3$ 수용체 길항제인 ondansetron의 투여 효과와, 이러한 ondansetron 및 비 특이적 아편계 수용체 길항제인 naltrexone (NTX)과의 병합 투여 효과를 검증하는데 목적이 있다. 알코올 의존화 된 C57BL/6형 수컷 생쥐를 4군으로 나눈 뒤, 10일간 각 군에 vehicle, OND 0.01 mg/kg 단독, NTX 1.0 mg/kg 단독, 및 OND 0.01 mg/kg과 NTX 1 mg/kg 병합 투여하면서 2시간 알코올의 섭취량, 22시간 물 섭취량, 24시간 사료 섭취량 및 체중을 조사하였다. 본 연구의 결과로 2시간 알코올 섭취량의 10일간 변화에 대해 vehicle 투여 군과 나머지 3군의 약물 투여군과 repeated measure ANOVA를 이용하여 각각 비교하였을 때, vehicle 투여군과 NTX 단독 투여군간에 유의한 교차가 관찰되었으나 (p=0.042), OND 단독 투여군과 NTX과 OND 병합 투여군은 vehicle 투여군과 유의한 차이가 없었다. 일별 2시간 알코올 섭취량에 대하여 NTX 투여군과 vehicle 투여군의 군간 비교시 vehicle 투여군에 비하여 NTX 투여군에서 약물 투여 4일부터 10일까지 유의하게 감소하였다(4일 p=0.010; 6일 p=0.050; 8일 p=0.017; 10일 p=0.005). 그리고 NTX과 OND 병합 투여군과 vehicle 투여군의 양군을 비교하였을 때에는 2시간 알코올 섭취량이 4일과 10일에만 유의하게 감소하였다(4일 p=0.049; 10일 p=0.022). 그러나 22시간 물 섭취량, 24시간 사료 섭취량 및 체중의 10일간 변화에 대해 vehicle 투여군과 나머지 3 군의 약물 투여군과의 repeated measure ANOVA를 이용하여 각각 비교하였을 때, 모두 유의한 교차효과가 없었다. 이상의 결과는 생쥐의 섭취량에 대하여 OND의 투여 효과는 없었으며, OND과 NTX의 병합 투여시에는 NTX의 알코올의 섭취량 억제 효과가 감소되었다. 따라서 앞으로 $5-HT_3$ 신경계와 도파민 및 아편 신경계와의 상관관계에 대한 연구가 필요할 것으로 생각된다.

Dopamine reward pathway projecting from ventral tegmental area to nucleus accumbens is well known as playing an important role in alcohol dependence. It is supposed that this dopamine pathway is modulated by $5-HT_3$ nervous system, and it was reported that ondansetron (OND), $5-HT_3$ receptor antagonist, reduced drinking amount and increased abstinence rate in alcohol-dependent patients. The purpose of this study is to investigate the effect of combination of OND and naltrexone (NTX), non-specific opioid receptor antagonist, on alcohol intake in C57BL/6 mice. In 40 C57BL/6 mice in the state of alcohol dependence, vehicle, while OND 0.01 mg/kg, or NTX 1.0 mg/kg administrated respectively, or OND 0.01 mg/kg and NTX 1.0 mg/kg administrated simultaneously for ten days, medication effects on 2-hr alcohol, 22-hr water, 24-hr food intake and body weight were studied. When vehicle group was compared with 3 medication groups respectively, using a repeated measure ANOVA, NTX alone and vehicle groups showed a significant medication by time interaction (p=0.042) in 2-hr alcohol intake, but in the other 2 groups, OND and NTX combination group and OND alone group, there was no significant interaction with vehicle group in 2-hr alcohol intake. From these results, it is suggested that there is no effect on alcohol intake in mice treating with OND, and naltrexone#s suppression effect on alcohol intake in mice is attenuated when treating with OND and NTX simultaneously. It is supposed that a further study looking at the interactions of serotonin, dopamine and opioid nerves systems will be needed.

키워드

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