Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Departamento de Farmacología Otto Orsingher, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
INFIQC-CONICET, Departamento de Fisicoquímica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Eur J Neurosci. 2024 May;59(10):2450-2464. doi: 10.1111/ejn.16312. Epub 2024 Mar 13.
Amphetamine (AMPH) exposure induces behavioural and neurochemical sensitization observed in rodents as hyperlocomotion and increased dopamine release in response to a subsequent dose. Brain Angiotensin II modulates dopaminergic neurotransmission through its AT receptors (AT-R), positively regulating striatal dopamine synthesis and release. This work aims to evaluate the AT-R role in the development and maintenance of AMPH-induced sensitization. Also, the AT-R involvement in striatal dopamine reuptake was analysed. The sensitization protocol consisted of daily AMPH administration for 5 days and tested 21 days after withdrawal. An AT-R antagonist, candesartan, was administered before or after AMPH exposure to evaluate the participation of AT-R in the development and maintenance of sensitization, respectively. Sensitization was evaluated by locomotor activity and c-Fos immunostaining. Changes in dopamine reuptake kinetics were evaluated 1 day after AT-R blockade withdrawal treatment, with or without the addition of AMPH in vitro. The social interaction test was performed as another behavioural output. Repeated AMPH exposure induced behavioural and neurochemical sensitization, which was prevented and reversed by candesartan. The AT-R blockade increased the dopamine reuptake kinetics. Neither the AMPH administration nor the AT-R blockade altered the performance of social interaction. Our results highlight the AT-R's crucial role in AMPH sensitization. The enhancement of dopamine reuptake kinetics induced by the AT-R blockade might attenuate the neuroadaptive changes that lead to AMPH sensitization and its self-perpetuation. Therefore, AT-R is a prominent candidate as a target for pharmacological treatment of pathologies related to dopamine imbalance, including drug addiction and schizophrenia.
安非他命（AMPH）暴露会导致行为和神经化学敏化，在啮齿动物中表现为多动和多巴胺释放增加，以响应随后的剂量。脑血管紧张素 II 通过其 AT 受体（AT-R）调节多巴胺能神经传递，正向调节纹状体多巴胺的合成和释放。本工作旨在评估 AT-R 在 AMPH 诱导的敏化发展和维持中的作用。此外，还分析了 AT-R 参与纹状体多巴胺再摄取的情况。敏化方案包括每天 AMPH 给药 5 天，然后在停药 21 天后进行测试。在 AMPH 暴露前后给予 AT-R 拮抗剂坎地沙坦，以分别评估 AT-R 在敏化发展和维持中的参与。通过运动活动和 c-Fos 免疫染色评估敏化。在 AT-R 阻断撤回治疗后 1 天，评估多巴胺再摄取动力学的变化，体外有无 AMPH 加入。社交互动测试作为另一种行为输出进行。重复 AMPH 暴露会诱导行为和神经化学敏化，坎地沙坦可预防和逆转这种敏化。AT-R 阻断增加了多巴胺再摄取动力学。无论是 AMPH 给药还是 AT-R 阻断都没有改变社交互动的表现。我们的结果强调了 AT-R 在 AMPH 敏化中的关键作用。AT-R 阻断引起的多巴胺再摄取动力学增强可能会减弱导致 AMPH 敏化及其自我延续的神经适应性变化。因此，AT-R 是治疗与多巴胺失衡相关的病理的药理学治疗的一个重要候选物，包括药物成瘾和精神分裂症。
