Department of Biochemistry, Laboratory of Studies on the Purinergic System, Federal University of Rio Grande do Sul, Health and Basic Sciences Institute, Porto Alegre/RS, Brazil.
Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jan 15;35(1):169-76. doi: 10.1016/j.pnpbp.2010.10.022. Epub 2010 Oct 31.
Methylphenidate (MPH) is the preferred treatment used for attention-deficit/hyperactivity disorder (ADHD). Recently, misuse for MPH due to its apparent cognitive enhancer properties has been reported. Adenosine is a neuromodulator known to exert influence on the dopaminergic neurotransmission, which is the main pharmacological target of MPH. We have reported that an overdosage of MPH up-regulates adenosine A(1) receptors in the frontal cortex, but this receptor was not involved in its anxiolytic effects. In this study, the role of adenosine A(1) receptor was investigated on MPH-induced effects on aversive and recognition memory in adult mice. Adult mice received acute and chronic (15 days) administration of methylphenidate (5mg/kg, i.p.), or an acute overdosage (50mg/kg, i.p) in order to model misuse. Memory was assessed in the inhibitory avoidance and object recognition task. Acute administration 5mg/kg improved whereas 50mg/kg disrupted recognition memory and decreased performance in the inhibitory avoidance task. Chronic administration did not cause any effect on memory, but decreased adenosine A(1) receptors immunocontent in the frontal cortex. The selective adenosine A(1) receptor antagonist, (DPCPX 1mg/kg, i.p.), prevented methylphenidate-triggered recognition memory impairment. Our findings showed that recognition memory rather than aversive memory was differently affected by acute administration at both doses. Memory recognition was fully impaired by the overdosage, suggesting that misuse can be harmful for cognitive functions. The adenosinergic system via A(1) receptors may play a role in the methylphenidate actions probably by interfering with dopamine-enhancing properties of this drug.
哌醋甲酯（MPH）是治疗注意力缺陷多动障碍（ADHD）的首选药物。最近，由于其明显的认知增强特性，MPH 的滥用情况已被报道。腺苷是一种已知的神经调节剂，对多巴胺能神经传递有影响，而多巴胺能神经传递是 MPH 的主要药理学靶点。我们曾报道过，MPH 的过量使用会在上皮层上调腺苷 A（1）受体，但该受体不参与其抗焦虑作用。在这项研究中，我们研究了腺苷 A（1）受体在 MPH 对成年小鼠厌恶和识别记忆的影响中的作用。成年小鼠接受了哌醋甲酯（5mg/kg，ip）的急性和慢性（15 天）给药，或 50mg/kg（ip）的急性过量给药，以模拟药物滥用。在抑制性回避和物体识别任务中评估了记忆。急性给予 5mg/kg 可改善记忆，而给予 50mg/kg 则破坏了识别记忆，并降低了在抑制性回避任务中的表现。慢性给药对记忆没有任何影响，但减少了前额叶皮层中的腺苷 A（1）受体免疫含量。选择性腺苷 A（1）受体拮抗剂（DPCPX 1mg/kg，ip）可预防 MPH 引发的识别记忆障碍。我们的研究结果表明，急性给药时，无论是低剂量还是高剂量，识别记忆而不是厌恶记忆受到不同的影响。高剂量的药物会完全损害记忆识别能力，这表明药物滥用可能对认知功能有害。通过 A（1）受体的腺苷能系统可能在 MPH 的作用中发挥作用，可能是通过干扰这种药物增强多巴胺的特性。
