Caillé Stéphanie, Parsons Loren H
Department of Neuropharmacology, CVN-7, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Eur J Neurosci. 2003 Dec;18(11):3145-9. doi: 10.1111/j.1460-9568.2003.02961.x.
The present experiments tested the hypothesis that the selective CB1 receptor antagonist SR141716A alters heroin self-administration by attenuating heroin-induced increases in nucleus accumbens dopamine levels. SR141716A pretreatment dose-dependently (0.3-3 mg/kg, i.p.) reduced operant heroin self-administration by male Wistar rats under a fixed ratio schedule of reinforcement, and significantly lowered the breaking point of responding for heroin under a progressive ratio schedule of reinforcement. These observations are consistent with recent reports that CB1 receptor inactivation reduces the rewarding properties of opiates. Operant responding for water reinforcement by water-restricted rats was unaltered by these SR141716A doses. Microdialysis tests revealed that heroin self-administration significantly increases interstitial dopamine levels in the nucleus accumbens shell of vehicle-pretreated control rats. However, whereas SR141716A pretreatment dose-dependently reduced heroin self-administration, it did not alter the heroin-associated increase in nucleus accumbens dopamine. These findings suggest that the CB1 antagonist-induced attenuation of heroin reward does not involve dopaminergic mechanisms in the nucleus accumbens shell.
选择性CB1受体拮抗剂SR141716A通过减弱海洛因诱导的伏隔核多巴胺水平升高来改变海洛因自我给药行为。在固定比率强化程序下，SR141716A预处理以剂量依赖方式（0.3 - 3毫克/千克，腹腔注射）减少了雄性Wistar大鼠的操作性海洛因自我给药行为，并且在累进比率强化程序下显著降低了对海洛因反应的断点。这些观察结果与最近关于CB1受体失活会降低阿片类药物奖赏特性的报道一致。这些SR141716A剂量对限水大鼠的水强化操作性反应没有影响。微透析测试显示，在给予溶媒预处理的对照大鼠中，海洛因自我给药显著增加了伏隔核壳中的细胞外多巴胺水平。然而，虽然SR141716A预处理以剂量依赖方式减少了海洛因自我给药行为，但它并未改变海洛因相关的伏隔核多巴胺增加。这些发现表明，CB1拮抗剂诱导的海洛因奖赏减弱并不涉及伏隔核壳中的多巴胺能机制。
