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首页> 外文期刊>Addiction biology >Glutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system.
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Glutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system.

机译：ghrelin引起的谷氨酸能调节中脑边缘多巴胺系统的激活。

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Recently, we demonstrated that the central ghrelin signalling system, involving the ghrelin receptor (GHS-R1A), is important for alcohol reinforcement. Ghrelin targets a key mesolimbic circuit involved in natural as well as drug-induced reinforcement, that includes a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present study was to determine whether it is possible to suppress ghrelin's effects on this mesolimbic dopaminergic pathway can be suppressed, by interrupting afferent inputs to the VTA dopaminergic cells, as shown previously for cholinergic afferents. Thus, the effects of pharmacological suppression of glutamatergic, orexin A and opioid neurotransmitter systems on ghrelin-induced activation of the mesolimbic dopamine system were investigated. We found in the present study that ghrelin-induced locomotor stimulation was attenuated by VTA administration of the N-methyl-D-aspartic acid receptor antagonist (AP5) but not by VTA administration of an orexin A receptor antagonist (SB334867) or by peripheral administration of an opioid receptor antagonist (naltrexone). Intra-VTA administration of AP5 also suppressed the ghrelin-induced dopamine release in the nucleus accumbens. Finally the effects of peripheral ghrelin on locomotor stimulation and accumbal dopamine release were blocked by intra-VTA administration of a GHS-R1A antagonist (BIM28163), indicating that GHS-R1A signalling within the VTA is required for the ghrelin-induced activation of the mesolimbic dopamine system. Given the clinical knowledge that hyperghrelinemia is associated with addictive behaviours (such as compulsive overeating and alcohol use disorder) our finding highlights a potential therapeutic strategy involving glutamatergic control of ghrelin action at the level of the mesolimbic dopamine system.
机译：最近，我们证明了涉及ghrelin受体（GHS-R1A）的中心ghrelin信号传导系统对于酒精增强很重要。 Ghrelin的目标是涉及天然的和药物诱导的增强的关键中脑边缘回路，其中包括从腹侧被盖区（VTA）到伏隔核的多巴胺投射。本研究的目的是确定是否可以通过中断VTA多巴胺能细胞的传入输入来抑制生长素释放肽对这种中脑边缘多巴胺能途径的影响，如先前对胆碱能传入的显示。因此，研究了药理抑制谷氨酸能，食欲素A和阿片样物质神经递质系统对生长素释放肽诱导的中脑边缘多巴胺系统活化的影响。我们在本研究中发现，通过VTA施用N-甲基-D-天冬氨酸受体拮抗剂（AP5）可以减轻ghrelin诱导的运动刺激，但不能通过VTA施用orexin A受体拮抗剂（SB334867）或通过外周施用来减轻类阿片受体拮抗剂（纳曲酮）的使用。 VTA内AP5的给药也抑制了生长素释放肽诱导的伏隔核中多巴胺的释放。最后，VTA内施用GHS-R1A拮抗剂（BIM28163）阻断了周围Ghrelin对运动刺激和伏安多巴胺释放的影响，这表明VTA内的GHS-R1A信号传导是Ghrelin诱导的中生边缘的活化所必需的多巴胺系统。鉴于高血糖素血症与成瘾行为（例如强迫性暴饮暴食和饮酒障碍）相关的临床知识，我们的发现突出了一种潜在的治疗策略，涉及谷氨酸能控制中饥饿素多巴胺系统水平的ghrelin作用。

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