Carre J B, Boutry J M, Baumann N, Maurin Y
Laboratoire de Neurochimie, INSERM U 134, Paris, France.
Life Sci. 1988;42(7):769-74. doi: 10.1016/0024-3205(88)90649-2.
Previous results indicate a dose-dependent decrease of lysosomal sphingomyelinase activity induced by tricyclic antidepressants in cell cultures. A possible association of this effect with the antidepressant-induced down-regulation of beta-adrenoceptors was postulated. We report here the determination of beta-adrenoceptor binding sites and lysosomal sphingomyelinase activity in the cerebral cortex of rats treated chronically with desipramine or with the potential antidepressant drug midalcipran (which is devoid of effect on beta-adrenoceptors). The effect of midalcipran on lysosomal sphingomyelinase activity was also determined on C6 glioma cells. In C6 glioma cells, midalcipran did not decrease sphingomyelinase activity, at variance with the enzymatic inhibition induced by desipramine (DMI). In the rat cerebral cortex, neither DMI nor midalcipran modified sphingomyelinase activity. In agreement with previously reported effects, DMI induced beta-adrenoceptor desensitization in the rat cerebral cortex, while midalcipran remained ineffective. Our results indicate that in the rat cerebral cortex, the activity of lysosomal sphingomyelinase is not modulated by chronic treatment with antidepressant drugs, whatever their effect on beta-adrenoceptor sites. Our results suggest that sphingomyelinase activity is not associated with the desensitization of beta-adrenoceptors, taken as an index of the therapeutic action of antidepressants. The results indicate that care should be taken when extrapolating to in vivo situations the conclusions derived from cell culture conditions.
先前的结果表明，在细胞培养中，三环类抗抑郁药可导致溶酶体鞘磷脂酶活性呈剂量依赖性降低。有人推测这种效应可能与抗抑郁药诱导的β-肾上腺素能受体下调有关。我们在此报告了对长期接受地昔帕明或潜在抗抑郁药米氮平（对β-肾上腺素能受体无作用）治疗的大鼠大脑皮质中β-肾上腺素能受体结合位点和溶酶体鞘磷脂酶活性的测定。还测定了米氮平对C6胶质瘤细胞中溶酶体鞘磷脂酶活性的影响。在C6胶质瘤细胞中，米氮平并未降低鞘磷脂酶活性，这与地昔帕明（DMI）诱导的酶抑制作用不同。在大鼠大脑皮质中，DMI和米氮平均未改变鞘磷脂酶活性。与先前报道的效应一致，DMI在大鼠大脑皮质中诱导了β-肾上腺素能受体脱敏，而米氮平则无此作用。我们的结果表明，在大鼠大脑皮质中，无论抗抑郁药对β-肾上腺素能受体位点的作用如何，长期使用抗抑郁药治疗均不会调节溶酶体鞘磷脂酶的活性。我们的结果表明，鞘磷脂酶活性与作为抗抑郁药治疗作用指标的β-肾上腺素能受体脱敏无关。结果表明，在将细胞培养条件下得出的结论外推至体内情况时应谨慎。
