Di Giovanni G, De Deurwaerdére P, Di Mascio M, Di Matteo V, Esposito E, Spampinato U
Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Santa Maria Imbaro (Chieti), Italy.
Neuroscience. 1999;91(2):587-97. doi: 10.1016/s0306-4522(98)00655-1.
Electrophysiological techniques and in vivo microdialysis were used to investigate the relative contribution of central serotonin-2C/2B and serotonin-2A receptor subtypes in the control of mesolimbic and nigrostriatal dopaminergic function. Thus, extracellular single-unit recordings were performed from neurochemically identified dopamine neurons in the ventral tegmental area and the substantia nigra pars compacta, as well as simultaneous monitoring of accumbal and striatal basal dopamine release in anesthetized rats following the administration of serotonin-2C/2B (SB 206553), serotonin-2A (SR 46349B) or serotonin-2A/2B/2C (ritanserin) antagonists. Administration of SB 206553 (40-160 microg/kg, i.v.) caused a dose-dependent increase in the basal firing rate of ventral tegmental area and nigral dopamine neurons, reaching its maximum (45.2 and 28.5%, respectively) following 160 microg/kg. Moreover, burst activity was significantly enhanced by SB 206553 in the ventral tegmental area only. In contrast, injection of SR 46349B (40-160 microg/kg, i.v.), and ritanserin (40-160 microg/kg, i.v.) did not cause any significant change in the basal activity of these neurons. Basal dopamine release was significantly enhanced in both the nucleus accumbens (42%) and the striatum (33%) following the intraperitoneal administration of 5 mg/kg SB 206553. In contrast, SR 46349B (0.5 mg/kg, s.c.) and ritanserin (0.63 mg/kg, i.p.) failed to affect basal dopamine output in both regions. Taken together, these data indicate that the central serotonergic system exerts a tonic inhibitory control of mesolimbic and nigrostriatal dopaminergic pathway activity and that the serotonin-2C/2B receptor subtypes are involved in this effect. Moreover, these findings might open new possibilities for the employment of serotonin-2C/2B receptor antagonists in the treatment of neuropsychiatric disorders related to a hypofunction of central dopaminergic neurons.
采用电生理技术和体内微透析法，研究中枢5-羟色胺2C/2B和5-羟色胺2A受体亚型在中脑边缘和黑质纹状体多巴胺能功能调控中的相对作用。因此，在腹侧被盖区和黑质致密部对经神经化学鉴定的多巴胺能神经元进行细胞外单单位记录，并在麻醉大鼠中，于给予5-羟色胺2C/2B（SB 206553）、5-羟色胺2A（SR 46349B）或5-羟色胺2A/2B/2C（利坦色林）拮抗剂后，同时监测伏隔核和纹状体的基础多巴胺释放。静脉注射SB 206553（40 - 160μg/kg）导致腹侧被盖区和黑质多巴胺能神经元的基础放电频率呈剂量依赖性增加，在160μg/kg时达到最大值（分别为45.2%和28.5%）。此外，仅在腹侧被盖区，SB 206553显著增强了爆发性活动。相比之下，静脉注射SR 46349B（40 - 160μg/kg）和利坦色林（40 - 160μg/kg）并未引起这些神经元基础活动的任何显著变化。腹腔注射5mg/kg SB 206553后，伏隔核（42%）和纹状体（33%）的基础多巴胺释放均显著增强。相比之下，皮下注射SR 46349B（0.5mg/kg）和腹腔注射利坦色林（0.63mg/kg）均未影响这两个区域的基础多巴胺输出。综上所述，这些数据表明中枢5-羟色胺能系统对中脑边缘和黑质纹状体多巴胺能通路活动发挥着紧张性抑制作用，且5-羟色胺2C/2B受体亚型参与了这一效应。此外，这些发现可能为5-羟色胺2C/2B受体拮抗剂用于治疗与中枢多巴胺能神经元功能减退相关的神经精神疾病开辟新的可能性。
