The adenosine kinase inhibitor ABT-702 augments EEG slow waves in rats

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• 作者：Radek ; Richard J. ; Decker ; Michael W. ; Jarvis ; Michael F.
• 关键词：EEG ; Adenosine ; Adenosine kinase inhibitor ; Slow waves ; Sleep
• 刊名：Brain Research
• 出版年：2004
• 期刊代码：8_00068993
• 类别：neu
• 出版时间：November 5, 2004
• 卷：1026
• 期：1
• 页码：74-83
• 文件大小：542 K

摘要

ABT-702 is a novel and selective non-nucleoside adenosine kinase (AK) inhibitor that produces increases in endogenous extracellular adenosine. Adenosine (ADO) is thought to be an important neuromodulator of sleep, therefore, the effects of ABT-702 and AK inhibition were examined on rat EEG and sleep, and compared to ADO receptor agonists to further evaluate the role of ADO receptor activation on sleep related EEG patterns. ABT-702 (10.0芒芒芒30.0 芒芒mol/kg, i.p.) increased the amplitude of the 1芒芒芒4 Hz band (Fast Fourier Transform (FFT) analysis, p<0.05), which is indicative of augmented sleep-related slow waves. Theophylline (5.0 芒芒mol/kg, i.p.), a centrally active, non-selective adenosine receptor antagonist, attenuated the effects of ABT-702 (20.0 芒芒mol/kg, i.p.) on EEG, whereas 8-(p-sulfophenyl)-theophylline (8-PST, 150.0 芒芒mol/kg, i.p.), a peripherally active antagonist, did not, indicating that the EEG effects of ABT-702 are mediated by a central ADO receptor mechanism. The selective A₁ agonist N6-cyclopentyladenosine (CPA, 30.0 芒芒mol/kg, i.p.) also increased the amplitude of 1芒芒芒4 Hz band, but was not as efficacious as ABT-702. In contrast, the A_2A agonist CGS-21680 (1.0芒芒芒10.0 芒芒mol/kg, i.p.) and the non-selective agonist, N⁶-ethylcarboximidoadenosine (NECA, 0.03芒芒芒0.1 芒芒mol/kg, ip.), lowered 1芒芒芒4 Hz amplitude for 2 h after injection. Finally, ABT-702 (10.0 芒芒mol/kg, i.p.) was found to significantly increase slow wave sleep and decrease REM sleep in rats implanted with both EEG and EMG electrodes for evaluation of sleep. These studies demonstrate that increased extracellular adenosine through AK inhibition can elicit modulatory effects on EEG slow waves via an interaction with central ADO receptor subtypes.