Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Centro Biomédico, Universidade do Estado do Rio de Janeiro (UERJ), Av. Prof. Manuel de Abreu 444, 5 andar - Vila Isabel, Rio de Janeiro, RJ 20550-170, Brazil.
Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Centro Biomédico, Universidade do Estado do Rio de Janeiro (UERJ), Av. Prof. Manuel de Abreu 444, 5 andar - Vila Isabel, Rio de Janeiro, RJ 20550-170, Brazil.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Mar 8;97:109775. doi: 10.1016/j.pnpbp.2019.109775. Epub 2019 Oct 30.
Ketamine has addictive potential, a troublesome fact due to its promising use as a therapeutic drug. An important phenomenon associated with drug addiction is behavioral sensitization, usually characterized as augmented locomotion. However, other behaviors may also be susceptible to sensitization, and/or interfere with locomotor activity. Thus, this study drew a comprehensive behavioral 'profiling' in an animal model of repeated administration of ketamine. Adult Swiss mice received single daily ketamine injections (30 or 50 mg/Kg, i.p.), which were followed by open field testing for 7 days (acquisition period, ACQ). A ketamine challenge (sensitization test, ST) was carried out after a 5-day withdrawal. Locomotion, rearing, grooming, rotation and falling were assessed during ACQ and ST. All behaviors were affected from the first ACQ day onwards, with no indication of competition between locomotion and the other behaviors. Only locomotion in response to 30 mg/Kg of ketamine both escalated during ACQ and expressed increased levels at ST, evidencing development and expression of locomotor sensitization. Considering the involvement of serotonin 5HT and dopamine D receptors on addiction mechanisms, we further tested the involvement of these receptors in ketamine-induced sensitization. Ketanserin (5HT antagonist, 3 mg/Kg, s.c.) prevented ketamine-evoked development of locomotor sensitization. However, ketanserin pretreatment during ACQ failed to inhibit its expression during ST. Raclopride (D antagonist, 0.5 mg/Kg, s.c.) evoked less robust reductions in locomotion but prevented the development of ketamine-evoked sensitization. Pretreatment during ACQ further inhibited the expression of sensitization during ST. These results indicate that a partial overlap in serotonergic and dopaminergic mechanisms underlies ketamine-induced locomotor sensitization.
氯胺酮具有成瘾潜力，这一事实令人困扰，因为它有作为治疗药物的应用前景。与药物成瘾相关的一个重要现象是行为敏感化，通常表现为运动活动增强。然而，其他行为也可能容易受到敏感化的影响，并且/或者干扰运动活动。因此，本研究在重复给予氯胺酮的动物模型中进行了全面的行为“剖析”。成年瑞士小鼠接受单次每日氯胺酮注射（30 或 50mg/kg，ip），随后进行 7 天的旷场测试（获得期，ACQ）。在 5 天戒断后进行氯胺酮挑战（敏感化测试，ST）。在 ACQ 和 ST 期间评估运动、站立、梳理、旋转和跌倒。所有行为从第一天 ACQ 开始就受到影响，没有运动与其他行为之间竞争的迹象。只有对 30mg/kg 氯胺酮的反应，在 ACQ 期间增加，在 ST 期间表达增加，证明了运动敏感化的发展和表达。考虑到 5-羟色胺 5HT 和多巴胺 D 受体在成瘾机制中的作用，我们进一步测试了这些受体在氯胺酮诱导的敏感化中的作用。酮色林（5HT 拮抗剂，3mg/kg，sc）阻止了氯胺酮引起的运动敏感化的发展。然而，在 ACQ 期间进行酮色林预处理未能抑制其在 ST 期间的表达。氯丙嗪（D 拮抗剂，0.5mg/kg，sc）引起的运动减少不那么明显，但阻止了氯胺酮引起的敏感化的发展。在 ACQ 期间进行预处理进一步抑制了 ST 期间敏感化的表达。这些结果表明，氯胺酮引起的运动敏感化是 5HT 和多巴胺机制部分重叠的结果。
