Alonso R, Voutsinos B, Fournier M, Labie C, Steinberg R, Souilhac J, Le Fur G, Soubrié P
Sanofi Recherche, Department of Neuropsychiatry, Montpellier, France.
Neuroscience. 1999;91(2):607-20. doi: 10.1016/s0306-4522(98)00675-7.
The present study investigated, in rats, whether blockade of cannabinoid CB1 receptors may alter Fos protein expression in a manner comparable to that observed with antipsychotic drugs. Intraperitoneal administration of the selective CB1 receptor antagonist, SR141716, dose-dependently (1.0, 3.0 and 10 mg/kg) increased Fos-like immunoreactivity in mesocorticolimbic areas (prefrontal cortex, ventrolateral septum, shell of the nucleus accumbens and dorsomedial caudate-putamen), while motor-related structures such as the core of the nucleus accumbens and the dorsolateral caudate-putamen were unaffected. In the ventrolateral septum, taken as a representative structure, the Fos-inducing effect of SR141716 (10 mg/kg) was maximal 2 h after injection and returned to near control levels by 4 h. Within the prefrontal cortex, SR141716 increased the number of Fos-positive cells predominantly in the infralimbic and prelimbic cortices, presumptive pyramidal cells being the major cell types in which Fos was induced. The D1-like receptor antagonist, SCH23390 (0.1 mg/kg), did not prevent the Fos-inducing effect of SR141716 in any brain region examined (prefrontal cortex, nucleus accumbens, ventrolateral septum and dorsomedial caudate-putamen), although SCH23390 significantly reduced Fos expression induced by cocaine (20 mg/kg) in all these regions. By contrast, the dopamine D2-like agonist, quinpirole (0.25 mg/ kg), counteracted SR141716-induced Fos-like immunoreactivity in the ventrolateral septum, the nucleus accumbens and the dorsomedial caudate-putamen, while no antagonism was observed in the prefrontal cortex. Microdialysis experiments in awake rats indicated that SR141716, at doses which increased Fos expression (3 and 10 mg/kg), did not alter dopamine release in the shell of the nucleus accumbens. Finally, SR141716 increased the levels of neurotensin-like immunoreactivity in the nucleus accumbens, but not in the caudate-putamen. Collectively, the present results show that blockade of cannabinoid receptors increases Fos- and neurotensin-like immunoreactivity with characteristics comparable to those reported for atypical neuroleptic drugs.
本研究在大鼠中探究了大麻素CB1受体的阻断是否会以与抗精神病药物所观察到的方式类似的方式改变Fos蛋白表达。腹腔注射选择性CB1受体拮抗剂SR141716，剂量依赖性地（1.0、3.0和10mg/kg）增加了中脑皮质边缘区域（前额叶皮质、腹外侧隔区、伏隔核壳和背内侧尾状核-壳核）的Fos样免疫反应性，而伏隔核核心和背外侧尾状核-壳核等与运动相关的结构未受影响。以腹外侧隔区作为代表性结构，SR141716（10mg/kg）的Fos诱导作用在注射后2小时达到最大值，并在4小时时恢复到接近对照水平。在前额叶皮质内，SR141716主要增加了边缘下皮质和边缘前皮质中Fos阳性细胞的数量，推测锥体细胞是诱导Fos的主要细胞类型。D1样受体拮抗剂SCH23390（0.1mg/kg）在任何检测的脑区（前额叶皮质、伏隔核、腹外侧隔区和背内侧尾状核-壳核）均未阻止SR141716的Fos诱导作用，尽管SCH23390在所有这些区域均显著降低了可卡因（20mg/kg）诱导的Fos表达。相比之下，多巴胺D2样激动剂喹吡罗（0.25mg/kg）抵消了SR141716在腹外侧隔区、伏隔核和背内侧尾状核-壳核中诱导的Fos样免疫反应性，而在前额叶皮质中未观察到拮抗作用。清醒大鼠的微透析实验表明，SR141716在增加Fos表达的剂量（3和10mg/kg）下，并未改变伏隔核壳中的多巴胺释放。最后，SR141716增加了伏隔核中神经降压素样免疫反应性的水平，但在尾状核-壳核中未增加。总体而言，目前的结果表明，大麻素受体的阻断增加了Fos和神经降压素样免疫反应性其特征与非典型抗精神病药物所报道的特征相似。
