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.