Nocjar C, Roth B L, Pehek E A
Louis Stokes Cleveland VA Medical Center 151 (W), OH 44106, USA.
Neuroscience. 2002;111(1):163-76. doi: 10.1016/s0306-4522(01)00593-0.
Considerable evidence suggests that a dysfunction of the dopamine and serotonin (5-hydroxytryptamine or 5-HT) neurotransmitter systems contributes to a diverse range of pathological conditions including schizophrenia, depression and drug abuse. Recent electrophysiological and behavioral studies suggest that 5-HT modulates dopaminergic neurons in the ventral tegmental area via activation of 5-HT(2A) receptors. It is currently unknown if 5-HT(2A) receptors mediate their actions on dopaminergic neurons in the ventral tegmental area via direct or indirect mechanisms. This study investigated whether 5-HT(2A) receptors were localized on dopamine cells within the A10 dopamine subnuclei of the rat, including the ventral tegmental area. We discovered that 5-HT(2A) receptor-like immunoreactivity colocalized with tyrosine hydroxylase, a marker for dopamine neurons, throughout the A10 dopamine cell population. Colocalization was most prominent in rostral and mid A10 regions, including the paranigral, parabrachial, and interfascicular subnuclei. Though more rare, non-dopaminergic neurons also expressed 5-HT(2A) receptor immunoreactivity in the ventral tegmental area. Additionally, although a dense population of 5-HT(2A) immunoreactive cells was observed in the rostral dorsal raphe nucleus, rarely were these cells immunoreactive for tyrosine hydroxylase. The linear raphe A10 dopamine subdivisions also displayed a low degree of 5-HT(2A) receptor and tyrosine hydroxylase colocalization. These findings provide an anatomical basis for the physiological modulation of dopamine neurons in the rostral ventral tegmental area either directly, by 5-HT(2A) receptors localized on dopamine cells, or indirectly, through a non-dopaminergic mechanism. Interestingly, 5-HT(2A) receptors were expressed on dopamine neurons in several A10 subnuclei that project to mesolimbic forebrain regions implicated in drug addiction, and recent evidence indicates that ventral tegmental area 5-HT(2A) receptor activation may modulate reward-related behavior in rodents. 5-HT(2A) receptors were also expressed on dopamine cells in A10 subnuclei that project to forebrain areas that have been implicated in schizophrenia, and atypical antipsychotic drugs have high affinities for 5-HT(2A) receptors. Thus, findings in this study could have important implications for understanding 5-HT and dopamine circuitry dysfunction in schizophrenia.
大量证据表明，多巴胺和血清素（5-羟色胺或5-HT）神经递质系统功能失调会导致包括精神分裂症、抑郁症和药物滥用在内的多种病理状况。最近的电生理学和行为学研究表明，5-HT通过激活5-HT(2A)受体来调节腹侧被盖区的多巴胺能神经元。目前尚不清楚5-HT(2A)受体是通过直接还是间接机制对腹侧被盖区的多巴胺能神经元发挥作用。本研究调查了5-HT(2A)受体是否定位于大鼠A10多巴胺亚核内的多巴胺细胞上，包括腹侧被盖区。我们发现，在整个A10多巴胺细胞群体中，5-HT(2A)受体样免疫反应性与多巴胺神经元的标志物酪氨酸羟化酶共定位。共定位在A10区域的前部和中部最为显著，包括黑质旁、臂旁和束间亚核。虽然较少见，但非多巴胺能神经元在腹侧被盖区也表达5-HT(2A)受体免疫反应性。此外，虽然在背侧中缝核前部观察到大量5-HT(2A)免疫反应性细胞，但这些细胞很少对酪氨酸羟化酶呈免疫反应性。中缝A10多巴胺亚区也显示出较低程度的5-HT(2A)受体与酪氨酸羟化酶共定位。这些发现为腹侧被盖区前部多巴胺神经元的生理调节提供了解剖学基础，这种调节可以通过定位于多巴胺细胞上的5-HT(2A)受体直接进行，也可以通过非多巴胺能机制间接进行。有趣的是，5-HT(2A)受体在投射到与药物成瘾有关的中脑边缘前脑区域的几个A10亚核中的多巴胺神经元上表达，最近的证据表明，腹侧被盖区5-HT(2A)受体的激活可能调节啮齿动物与奖赏相关的行为。5-HT(2A)受体也在投射到与精神分裂症有关的前脑区域的A10亚核中的多巴胺细胞上表达，非典型抗精神病药物对5-HT(2A)受体具有高亲和力。因此，本研究结果对于理解精神分裂症中5-HT和多巴胺神经回路功能障碍可能具有重要意义。
