Rodríguez de Fonseca F, Cebeira M, Ramos J A, Martín M, Fernández-Ruiz J J
Dept. Biochemistry, Faculty of Medicine, Complutense University, Madrid, Spain.
Life Sci. 1994;54(3):159-70. doi: 10.1016/0024-3205(94)00585-0.
Cannabinoid effects on brain dopaminergic activity vary as a function of gonadal status. In this work, we examined whether these variations might be due to sex steroid-dependent differences in brain cannabinoid receptors (CNr). Four experiments were done: (i) male versus females; (ii) females at each stage of the ovarian cycle; (iii) estradiol (E2) and/or progesterone (P)-replaced ovariectomized (OVX) females; and (iv) testosterone (T)-replaced orchidectomized males. The density of CNr in the medial basal hypothalamus fluctuated in females during the estrous cycle. The density was higher in diestrus and decreased in estrus. This parameter did not change after ovariectomy and E2 replacement. However, P increased the density of CNr when administered to OVX rats acutely treated with E2, but not administered alone or after chronic E2 treatment. In the striatum, the affinity of CNr was slightly higher in males than females, with no changes in density. Ovariectomy increased the affinity of CNr, which normalized only after administration of acute E2. Interestingly, the high affinity values observed in this area after P alone or combined with E2, corresponded to low densities as compared with intact females. In the limbic forebrain, the affinity for the cannabinoid ligand was also higher in males than females with no changes in density. Affinity was also higher in diestrus and lower in estrus, whereas density was unchanged. Ovariectomy decreased CNr density. A normal situation was found after administration of acute E2 or P alone, whereas chronic E2 markedly increased the density of CNr as compared with both intact and OVX females. Interestingly, this latter increase was prevented by coadministration of P. Orchidectomy did not affect CNr density, but administration of T produced a marked decrease. In the mesencephalon, the density and affinity of CNr was higher in males than females. Administration of P to OVX rats produced opposite effects, increasing the density when administered alone and decreasing it when administered to acute E2-replaced OVX rats. In summary, these results reveal the existence of subtle, sometimes more pronounced, sex dimorphisms, fluctuations along the ovarian cycle and changes after gonadectomy and sex steroid replacement in CNr density and affinity in certain brain areas. This supports the hypothesis of possible sex steroid-dependent differences in the sensitivity of certain neuronal processes to cannabinoid treatment.
大麻素对脑多巴胺能活性的影响因性腺状态而异。在本研究中，我们研究了这些差异是否可能归因于脑大麻素受体（CNr）中存在的性别类固醇依赖性差异。我们进行了四项实验：（i）雄性与雌性；（ii）处于卵巢周期各阶段的雌性；（iii）用雌二醇（E2）和/或孕酮（P）替代的去卵巢（OVX）雌性；以及（iv）用睾酮（T）替代的去势雄性。在动情周期中，雌性内侧基底下丘脑的CNr密度会发生波动。在动情后期密度较高，而在发情期降低。去卵巢和E2替代后，该参数没有变化。然而，当对急性给予E2的OVX大鼠单独给予P时，CNr密度会增加，但单独给予P或在慢性给予E2后给予P则不会增加密度。在纹状体中，雄性CNr的亲和力略高于雌性，密度没有变化。去卵巢会增加CNr的亲和力，只有在急性给予E2后才恢复正常。有趣的是，单独给予P或与E2联合给予P后，该区域观察到的高亲和力值与完整雌性相比对应于低密度。在边缘前脑，雄性对大麻素配体的亲和力也高于雌性，密度没有变化。动情后期的亲和力也较高，发情期较低，而密度没有变化。去卵巢会降低CNr密度。单独给予急性E2或P后可恢复正常状态，而与完整和OVX雌性相比，慢性给予E2会显著增加CNr密度。有趣的是，后者的增加可通过联合给予P来阻止。去势不影响CNr密度，但给予T会使其显著降低。在中脑，雄性CNr的密度和亲和力高于雌性。对OVX大鼠给予P会产生相反的效果，单独给予P时密度增加，而给予急性E2替代的OVX大鼠时密度降低。总之，这些结果揭示了在某些脑区中，CNr密度和亲和力存在细微的、有时更明显的性别二态性、沿卵巢周期的波动以及性腺切除和性别类固醇替代后的变化。这支持了某些神经元过程对大麻素治疗的敏感性可能存在性别类固醇依赖性差异的假设。
