Joyce M P, Rayport S
Department of Psychiatry, New York, NY 10032, USA.
Neuroscience. 2000;99(3):445-56. doi: 10.1016/s0306-4522(00)00219-0.
The mesoaccumbens projection, formed by ventral tegmental area dopamine neurons synapsing on nucleus accumbens gamma-aminobutyric acid neurons, has been implicated in the pathogenesis of schizophrenia and drug addiction. Despite intensive study, the nature of the signal conveyed by dopamine neurons has not been fully resolved. In addition to several slower, dopamine-mediated, modulatory actions, several lines of evidence suggest that dopamine neurons have fast excitatory actions. To test this, we placed dopamine neurons together with accumbens neurons in microcultures. Surprisingly, most dopamine neurons made excitatory recurrent connections (autapses), which provided a basis for their identification; accumbens gamma-aminobutyric acid neurons were identified by their distinctive size. In 75% of mesoaccumbens cell pairs, stimulation of the dopamine neuron evoked a glutamate-mediated, excitatory synaptic response in the accumbens neuron. Immunostaining revealed dopamine neuron varicosities that were predominantly dopaminergic, ones that were predominantly glutamatergic, and ones that were both dopaminergic and glutamatergic. Despite close appositions of both glutamatergic and dopaminergic varicosities to the dendrites of accumbens neurons, only glutamatergic synaptic responses were seen. In the majority of cell pairs, pharmacologic activation of D2-type dopamine receptors inhibited glutamatergic responses, presumably via immunocytochemically-visualized presynaptic D2 receptors. In some cell pairs, the evoked autaptic and synaptic responses were discordant, suggesting that D2 receptors may be differentially trafficked to different presynaptic varicosities.Thus, dopamine neurons appear to mediate both slow dopaminergic and fast glutamatergic actions via separate sets of synapses. Together with evidence for glutamate cotransmission in serotonergic raphe neurons and noradrenergic locus coeruleus neurons, these results add a new dimension to monoamine neuron signaling that may have important implications for neuropsychiatric disorders.
中脑伏隔核投射由腹侧被盖区多巴胺能神经元与伏隔核γ-氨基丁酸能神经元形成突触联系构成，该投射与精神分裂症及药物成瘾的发病机制有关。尽管进行了深入研究，但多巴胺能神经元所传递信号的本质仍未完全明确。除了几种较慢的、多巴胺介导的调节作用外，多项证据表明多巴胺能神经元具有快速兴奋性作用。为验证这一点，我们将多巴胺能神经元与伏隔核神经元共同培养于微培养体系中。令人惊讶的是，大多数多巴胺能神经元形成了兴奋性反馈连接（自突触），这为识别它们提供了依据；伏隔核γ-氨基丁酸能神经元则通过其独特的大小得以识别。在75%的中脑伏隔核细胞对中，刺激多巴胺能神经元可在伏隔核神经元中诱发由谷氨酸介导的兴奋性突触反应。免疫染色显示，多巴胺能神经元的曲张体主要为多巴胺能，部分主要为谷氨酸能，还有部分兼具多巴胺能和谷氨酸能。尽管谷氨酸能和多巴胺能曲张体均与伏隔核神经元的树突紧密相邻，但仅观察到谷氨酸能突触反应。在大多数细胞对中，D2型多巴胺受体的药理学激活抑制了谷氨酸能反应，推测是通过免疫细胞化学可视化的突触前D2受体实现的。在一些细胞对中，诱发的自突触和突触反应不一致，这表明D2受体可能在不同的突触前曲张体中存在差异分布。因此，多巴胺能神经元似乎通过不同的突触组分别介导慢速多巴胺能作用和快速谷氨酸能作用。这些结果与血清素能中缝神经元和去甲肾上腺素能蓝斑神经元中谷氨酸共传递的证据一起，为单胺能神经元信号传导增添了新的维度，这可能对神经精神疾病具有重要意义。
