Matsuzawa S, Suzuki T, Misawa M, Nagase H
Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan.
Life Sci. 1999;64(21):PL241-9. doi: 10.1016/s0024-3205(99)00144-7.
The effect of the selective 5-HT3 receptor antagonist ondansetron on the ethanol-induced place preference in rats exposed to conditioned fear stress, which stimulates the release of endogenous opioid peptides (beta-endorphin and enkephalins), was investigated using the conditioned place preference paradigm. In addition, we also examined the effect of ondansetron on the ethanol-induced place preference enhanced by the administration of mu- and delta-opioid receptor agonists (exogenous opioids). The administration of ethanol (300 mg/kg, i.p.) induced a significant place preference in rats exposed to conditioned fear stress. Pretreatment with ondansetron (0.01 and 0.1 mg/kg, s.c.) effectively attenuated this ethanol-induced place preference. When the mu-opioid receptor agonist morphine (0.1 mg/kg, s.c.) or the selective delta-opioid receptor agonist 2-methyl-4a(alpha)-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a(alpha)-octah ydroquinolino [2,3,3-g] isoquinoline (TAN-67; 20 mg/kg, s.c.) was administered in combination with 75 mg/kg ethanol (which tended to produce a place preference), the ethanol-induced place preference was significantly enhanced. The selective mu-opioid receptor antagonist beta-funaltrexamine at a dose of 10 mg/kg significantly attenuated the enhancement of the ethanol-induced place preference produced by morphine. Ondansetron (0.1 mg/kg, s.c.) also significantly attenuated the enhancement of the ethanol-induced place preference produced by morphine. Furthermore, the selective delta-opioid receptor antagonist naltrindole at a dose of 3 mg/kg significantly attenuated the enhancement of the ethanol-induced place preference produced by TAN-67. Ondansetron (0.1 mg/kg, s.c.) slightly, but significantly, attenuated the enhancement of the ethanol-induced place preference produced by TAN-67. These results suggest that 5-HT3 receptors may be involved in the rewarding mechanism of ethanol under psychological stress, and may play an important role in the rewarding effect of ethanol through the activation of mu- and delta-opioid receptors.
使用条件性位置偏爱范式，研究了选择性5-羟色胺3（5-HT3）受体拮抗剂昂丹司琼对暴露于条件性恐惧应激（该应激刺激内源性阿片肽（β-内啡肽和脑啡肽）释放）的大鼠乙醇诱导的位置偏爱的影响。此外，我们还研究了昂丹司琼对由μ-和δ-阿片受体激动剂（外源性阿片类药物）给药增强的乙醇诱导的位置偏爱的影响。腹腔注射乙醇（300mg/kg）可在暴露于条件性恐惧应激的大鼠中诱导出显著的位置偏爱。皮下注射昂丹司琼（0.01和0.1mg/kg）预处理可有效减弱这种乙醇诱导的位置偏爱。当μ-阿片受体激动剂吗啡（0.1mg/kg，皮下注射）或选择性δ-阿片受体激动剂2-甲基-4a(α)-(3-羟苯基)-1,2,3,4,4a,5,12,12a(α)-八氢喹啉并[2,3,3-g]异喹啉（TAN-67；20mg/kg，皮下注射）与75mg/kg乙醇联合给药时（75mg/kg乙醇倾向于产生位置偏爱），乙醇诱导的位置偏爱显著增强。剂量为10mg/kg的选择性μ-阿片受体拮抗剂β-芬太尼显著减弱了吗啡产生的乙醇诱导的位置偏爱增强作用。皮下注射昂丹司琼（0.1mg/kg）也显著减弱了吗啡产生的乙醇诱导的位置偏爱增强作用。此外，剂量为3mg/kg的选择性δ-阿片受体拮抗剂纳曲吲哚显著减弱了TAN-67产生的乙醇诱导的位置偏爱增强作用。皮下注射昂丹司琼（0.1mg/kg）略微但显著地减弱了TAN-67产生的乙醇诱导的位置偏爱增强作用。这些结果表明，5-HT3受体可能参与心理应激下乙醇的奖赏机制，并可能通过激活μ-和δ-阿片受体在乙醇的奖赏效应中发挥重要作用。
