Betancur C, Cabrera R, de Kloet E R, Pélaprat D, Rostène W
Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, The Netherlands.
Neuropsychopharmacology. 1998 Oct;19(4):322-32. doi: 10.1016/S0893-133X(98)00028-1.
The present experiments were designed to assess the role of endogenous neurotensin (NT) in the behavioral response to acute and daily cocaine, after administration of the NT receptor antagonist, SR 48692. Given that glucocorticoids increase the sensitivity to the psychomotor effects of drugs of abuse, we also investigated the effects of SR 48692 on basal and cocaine-induced corticosterone secretion. Acute administration of SR 48692 (1 mg/kg i.p.) reduced the number of rearings induced by cocaine (15 mg/kg i.p.), without modifying horizontal activity. Repeated pretreatment with SR 48692 (1 mg/kg x 5 days) markedly reduced locomotion and rearings after an acute cocaine challenge (day 1), whereas the lower dose of SR 48692 (0.1 mg/kg) had no effect. SR 48692 (1 mg/kg), given daily before cocaine, also decreased cocaine-induced rearing on day 2, but had no effect on the following drug challenges (days 3-10). One week after discontinuing repeated cocaine injections, SR 48692 blocked vertical, but not horizontal, activity induced by an acute cocaine challenge. Rats treated repeatedly with cocaine showed an enhanced behavioral response characterized by the development of stereotypes, which were unaffected by SR 48692. Finally, treatment with SR 48692 did not alter corticosterone circadian secretion nor cocaine-stimulated corticosterone levels, indicating that the attenuation of the behavioral effects of cocaine after NT receptor blockade is not associated with blunted glucocorticoid secretion. These results indicate that administration of SR 48692 attenuates the locomotion and rearing response to cocaine but fails to modify stereotyped behavior, suggesting that SR 48692 modulates the behavioral effects of psychostimulant drugs by acting selectively on the mesolimbic dopaminergic system.
本实验旨在评估内源性神经降压素（NT）在给予NT受体拮抗剂SR 48692后，对急性和每日给予可卡因的行为反应中的作用。鉴于糖皮质激素会增加对滥用药物精神运动效应的敏感性，我们还研究了SR 48692对基础和可卡因诱导的皮质酮分泌的影响。急性给予SR 48692（1毫克/千克腹腔注射）减少了可卡因（15毫克/千克腹腔注射）诱导的竖毛次数，而不改变水平活动。用SR 48692（1毫克/千克×5天）重复预处理显著降低了急性可卡因激发（第1天）后的运动和竖毛行为，而较低剂量的SR 48692（0.1毫克/千克）则没有效果。在可卡因给药前每日给予SR 48692（1毫克/千克），在第2天也减少了可卡因诱导的竖毛行为，但对随后的药物激发（第3 - 10天）没有影响。停止重复注射可卡因一周后，SR 48692阻断了急性可卡因激发诱导的垂直活动，但不影响水平活动。反复用可卡因处理的大鼠表现出以刻板行为发展为特征的增强行为反应，而SR 48692对此没有影响。最后，用SR 48692处理并未改变皮质酮的昼夜分泌或可卡因刺激的皮质酮水平，表明NT受体阻断后可卡因行为效应的减弱与糖皮质激素分泌减弱无关。这些结果表明，给予SR 48692可减弱对可卡因的运动和竖毛反应，但不能改变刻板行为，提示SR 48692通过选择性作用于中脑边缘多巴胺能系统来调节精神兴奋药物的行为效应。
