Facultad de Ciencias Químicas, Departamento de Farmacología, IFEC-CONICET, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, 5000, Córdoba, Argentina.
Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Mol Neurobiol. 2020 Jan;57(1):450-460. doi: 10.1007/s12035-019-01725-3. Epub 2019 Aug 3.
Behavioral sensitization to psychostimulants hyperlocomotor effect is a useful model of addiction and craving. Particularly, cocaine sensitization in rats enhanced synaptic plasticity within the hippocampus, an important brain region for the associative learning processes underlying drug addiction. Nitric oxide (NO) is a neurotransmitter involved in both, hippocampal synaptic plasticity and cocaine sensitization. It has been previously demonstrated a key role of NOS-1/NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic plasticity. The aim of the present investigation was to determine whether NOS-1 inhibition after development of cocaine sensitization was able to reverse it, and to characterize the involvement of the hippocampus in this phenomenon. Male Wistar rats were administered only with cocaine (15 mg/kg/day i.p.) for 5 days. Then, animals received 7-nitroindazole (NOS-1 inhibitor) either systemically for the next 5 days or a single intra-hippocampal administration. Development of sensitization and its expression after withdrawal were tested, as well as threshold for long-term potentiation in hippocampus, NOS-1, and CREB protein levels and gene expression. The results showed that NOS-1 protein levels and gene expression were increased only in sensitized animals as well as CREB gene expression. NOS-1 inhibition after sensitization reversed behavioral expression and the highest level of hippocampal synaptic plasticity. In conclusion, NO signaling within the hippocampus is critical for the development and expression of cocaine sensitization. Therefore, NOS-1 inhibition or NO signaling pathways interferences during short-term withdrawal after repeated cocaine administration may represent plausible pharmacological targets to prevent or reduce susceptibility to relapse.
行为敏化作用对精神兴奋剂的高活动作用是成瘾和渴望的有用模型。特别是，可卡因敏化作用增强了海马体中的突触可塑性，海马体是与药物成瘾相关的联想学习过程的重要脑区。一氧化氮（NO）是一种涉及海马体突触可塑性和可卡因敏化作用的神经递质。先前已经证明，NOS-1/NO/sGC/cGMP 信号通路在可卡因敏化作用的发展及其相关的海马体突触可塑性增强中起着关键作用。本研究的目的是确定可卡因敏化作用发展后抑制 NOS-1 是否能够逆转它，并确定海马体在这一现象中的参与。雄性 Wistar 大鼠仅接受可卡因（15mg/kg/天，腹腔内给药）5 天。然后，动物在接下来的 5 天内接受 7-硝基吲唑（NOS-1 抑制剂）全身给药，或单次海马内给药。测试了敏化作用的发展及其戒断后的表达，以及海马体、NOS-1 和 CREB 蛋白水平和基因表达的长时程增强阈值。结果表明，只有敏化动物的 NOS-1 蛋白水平和基因表达以及 CREB 基因表达增加。敏化作用后抑制 NOS-1 逆转了行为表达和海马体突触可塑性的最高水平。总之，海马体内的 NO 信号对于可卡因敏化作用的发展和表达至关重要。因此，重复可卡因给药后短期戒断期间抑制 NOS-1 或干扰 NO 信号通路可能代表预防或减少复发易感性的合理药理学靶点。
