Recent evidence has emerged supporting a role for the cholinergic system in schizophrenia, including the potential of α7 modulators as a treatment strategy. However, preclinical studies to date have relied on studies in normal systems rather than on a validated developmental model of schizophrenia. Furthermore, there have been only few studies on whether orthosteric and allosteric modulators have differential impacts in such models. Thus, we investigated the effects of α7 agonists and positive allosteric modulators (PAMs) on dopamine (DA) neuron activity in the ventral tegmental area (VTA) in the methylazoxymethanol acetate (MAM) developmental disruption model of schizophrenia. Four different drugs were evaluated: PNU282987 (full agonist), SSR180711 (partial agonist) NS1738 (PAM type I) and PNU120596 (PAM type II). PNU120596 increased the number of spontaneously active VTA DA neurons in normal rats. In contrast, PNU282987 and SSR180711 reduced the hyperdopaminergic tone in MAM rats. This appeared to be due to effects on DA afferent regulation, in that PNU282987 or SSR180711 infusion into the ventral hippocampus of MAM rats replicated the decrease in the number of spontaneously active VTA DA neurons. In contrast, infusion of the same drugs into the basolateral amygdala increased the number of spontaneously active VTA DA neurons in normal rats without impacting MAM rats. These data suggest that α7 receptors may represent a promising target in the development of new pharmacological therapies for schizophrenia.

中文翻译：

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α7烟碱受体调节剂可逆转精神分裂症MAM模型中的高多巴胺能基调。

最近的证据支持胆碱能系统在精神分裂症中的作用，包括α7调节剂作为治疗策略的潜力。然而，迄今为止的临床前研究均依赖于正常系统的研究，而不是经过验证的精神分裂症的发展模型。此外，关于正构和变构调节剂在此类模型中是否具有不同影响的研究很少。因此，我们在精神分裂症的甲基丙烯酸甲酯氧基乙酸（MAM）发育破坏模型的腹侧被盖区（VTA）中研究了α7激动剂和正构构调节剂（PAM）对多巴胺（DA）神经元活性的影响。评价了四种不同的药物：PNU282987（完全激动剂），SSR180711（部分激动剂）NS1738（PAM I型）和PNU120596（PAM II型）。PNU120596增加了正常大鼠中自发活跃的VTA DA神经元的数量。相反，PNU282987和SSR180711降低了MAM大鼠的高多巴胺能音。这似乎是由于对DA传入调节的影响，因为将PNU282987或SSR180711输注到MAM大鼠的腹侧海马中，可以复制自发活跃的VTA DA神经元数量的减少。相反，将相同药物输注到基底外侧杏仁核可增加正常大鼠中自发活跃的VTA DA神经元的数量，而不会影响MAM大鼠。这些数据表明，α7受体可能代表精神分裂症的新药理疗法的发展中的有希望的目标。这似乎是由于对DA传入调节的影响，因为将PNU282987或SSR180711输注到MAM大鼠的腹侧海马中，可以复制自发活跃的VTA DA神经元数量的减少。相反，将相同药物输注到基底外侧杏仁核可增加正常大鼠中自发活跃的VTA DA神经元的数量，而不会影响MAM大鼠。这些数据表明，α7受体可能代表精神分裂症的新药理疗法的发展中的有希望的目标。这似乎是由于对DA传入调节的影响，因为将PNU282987或SSR180711输注到MAM大鼠的腹侧海马中，可以复制自发活跃的VTA DA神经元数量的减少。相反，将相同药物输注到基底外侧杏仁核可增加正常大鼠中自发活跃的VTA DA神经元的数量，而不会影响MAM大鼠。这些数据表明，α7受体可能代表精神分裂症的新药理疗法的发展中的有希望的目标。在正常大鼠中，将相同药物输注到基底外侧杏仁核中可增加自发活跃的VTA DA神经元的数量，而不会影响MAM大鼠。这些数据表明，α7受体可能代表精神分裂症的新药理疗法的发展中的有希望的目标。在正常大鼠中，将相同药物输注到基底外侧杏仁核中可增加自发活跃的VTA DA神经元的数量，而不会影响MAM大鼠。这些数据表明，α7受体可能代表精神分裂症的新药理疗法的发展中的有希望的目标。