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

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 (10.0-30.0 micromol/kg, i.p.) increased the amplitude of the 1-4 Hz band (Fast Fourier Transform (FFT) analysis, p<0.05), which is indicative of augmented sleep-related slow waves. Theophylline (5.0 micromol/kg, i.p.), a centrally active, non-selective adenosine receptor antagonist, attenuated the effects of ABT-702 (20.0 micromol/kg, i.p.) on EEG, whereas 8-(p-sulfophenyl)-theophylline (8-PST, 150.0 micromol/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 A(1) agonist N6-cyclopentyladenosine (CPA, 30.0 micromol/kg, i.p.) also increased the amplitude of 1-4 Hz band, but was not as efficacious as ABT-702. In contrast, the A(2A) agonist CGS-21680 (1.0-10.0 micromol/kg, i.p.) and the non-selective agonist, N(6)-ethylcarboximidoadenosine (NECA, 0.03-0.1 micromol/kg, ip.), lowered 1-4 Hz amplitude for 2 h after injection. Finally, ABT-702 (10.0 micromol/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.