Department of Physiology, Yonsei University College of Medicine, Seoul, South Korea.
Department of Physiology, College of Korean Medicine, Daegu Haany University, Daegu, South Korea.
Addict Biol. 2023 Dec;28(12):e13354. doi: 10.1111/adb.13354.
Administration of cocaine increases synaptic dopamine levels by blocking dopamine reuptake and leads to increased locomotor activity and compulsive drug-seeking behaviour. It has been suggested that the lateral hypothalamus (LH) or lateral habenula (LHb) is involved in drug-seeking behaviours. To explore the role of the LH and the LHb in cocaine-induced psychomotor responses, we tested whether modulation of the LH or the LH-LHb circuit affects cocaine-induced locomotion. Cocaine-induced locomotor activity and dopamine release were suppressed by the activation of the LH with 2-[2,6-difluoro-4-[[2-[(phenylsulfonyl)amino]ethyl]thio]phenoxy]acetamide (PEPA), an AMPA receptor agonist. When the LH was inhibited by microinjection of a GABA receptor agonists mixture prior to cocaine injection, the cocaine's effects were enhanced. Furthermore, optogenetic activation of the LH-LHb circuit attenuated the cocaine-induced locomotion, while optogenetic inhibition of the LH-LHb circuit increased it. In vivo extracellular recording found that the LH sent a glutamatergic projection to the LHb. These findings suggest that the LH glutamatergic projection to the LHb plays an active role in the modulation of cocaine-induced psychomotor responses.
可卡因通过阻断多巴胺再摄取增加突触多巴胺水平，导致运动活动增加和强迫性觅药行为。有人认为外侧下丘脑（LH）或外侧缰核（LHb）参与觅药行为。为了探讨 LH 和 LHb 在可卡因诱导的精神运动反应中的作用，我们测试了调节 LH 或 LH-LHb 回路是否会影响可卡因诱导的运动。2-[2,6-二氟-4-[[2-[(苯磺酰基)氨基]乙基]硫基]苯氧基]乙酰胺（PEPA），一种 AMPA 受体激动剂，激活 LH 可抑制可卡因诱导的运动活动和多巴胺释放。当在可卡因注射前通过微注射 GABA 受体激动剂混合物抑制 LH 时，可卡因的作用增强。此外，LH-LHb 回路的光遗传学激活减弱了可卡因诱导的运动，而 LH-LHb 回路的光遗传学抑制增加了可卡因诱导的运动。体内细胞外记录发现，LH 向 LHb 发出谷氨酸能投射。这些发现表明，LH 向 LHb 的谷氨酸能投射在调节可卡因诱导的精神运动反应中起积极作用。
