Pharmacology Biochemistry &Behavior, Vol. 34, pp. 507-510. ©Pergamon Press plc, 1989. Printed in the U.S.A. 0091-3057/89 $3.00 + .00 Behavioral and Electroencephalographic Effects of the Adenosine1 Agonist, L-PIA JOSEPH V. MARTIN,* KAREN FAITH BERMAN,t PHIL SKOLNICK1: AND WALLACE B. MENDELSON§ l *Department of Biology, Rutgers University, Camden, NJ 08102 fClinical Brain Disorders Branch, National Institute of Mental Health, Intramural Research Program NIMH Neurosciences Center at St. Elizabeths, Washington, DC 20032 ~Laboratory of Bioorganic Chemistry, National Institute of Arthritis, Diabetes, and Kidney Diseases Bethesda, MD 20892 §Department of Psychiatry and Behavioral Science State University of New York, Stony Brook, NY 17984-8101 Received 11 January 1989 MARTIN, J. V., K. F. BERMAN, P. SKOLNICK AND W. B. MENDELSON. Behavioraland electroencephalographiceffects"of the adenosinel agonist, L-PIA. PHARMACOL BIOCHEM BEHAV 34(3) 507-510, 1989.--The effects of N6-(L-2-phenylisopropyl) - adenosine (L-PIA), an A~ agonist, were measured on both spontaneous locomotor activity and electroencephalographic (EEG) measures of sleep in rats. L-PIA strongly inhibited motor activity at 100 txg/kg intraperitoneally (IP), a dose which had no statistically significant effects on EEG-defined sleep. A higher dose of L-PIA (200 ixg/kg) increased the latency to sleep initiation and inhibited later REM sleep. These results demonstrate that L-PIA can produce a state of apparent behavioral quiescence in the presence of EEG-defined arousal. N6-(L-2-phenylisopropyl)-adenosine (L-PIA) Sleep Locomotor activity Electroencephalogram REM Adenosine agonist Sedation BEHAVIORAL stimulants such as caffeine and theophylline have been demonstrated to competitively inhibit the effects of adenosine on adenylate cyclase activity in brain (19). This finding stimulated studies on the role of adenosine in the regulation of neural activity (5). Although the role of adenosine as neurotransmitter or neuro- modulator is uncertain (23), it is clear that this nucleoside is present in relatively high concentrations in neural tissue, and has a variety of inhibitory effects on synaptic transmission (5). Based on pharmacological studies, extracellular receptors for adenosine have been classified as A~ and A 2 (9,24). Occupation of A~ receptors leads to an inhibition of adenylate cyclase activity whereas occupation of A 2 receptors mediates an increase in the activity of this enzyme (9,24). N6-(L-2-phenylisopropyl)-adeno - sine (L-PIA), an adenosine analog, has been found to selectively bind to the A t receptor (20). This compound is resistant to degradation by adenosine deaminase and to phosphorylation (22), and has been used extensively to characterize the physiological effects mediated through the A t receptor site (14). Adenosine analogs have been reported to elicit a number of behavioral effects, including anticonvulsant activity (2,6) and an inhibition of spontaneous locomotion (4, 6, 8). However, the role of adenosine in the regulation of sleep is less well-defined. A hypnotic effect of adenosine was reported in dogs (7), and L-PIA was reported to increase deep slow-wave sleep in rats without altering the values for total sleep and wakefulness (15). At somewhat higher doses (0.35 mg/kg) L-PIA was found to increase waking time at the expense of sleep (17). Similarly, inhibition of brain adenosine deaminase activity by deoxycoformycin (DCF) altered the proportion of nonREM slee p characterized by increased slow wave activity (16), while a second inhibitor, erythro- 9-(2-hydroxy-3-nonyl)-adenine (EHNA), had no effect on total nonREM sleep (13). These findings indicate that increasing levels of endogenous adenosine may alter the structure of sleep with little effect on total sleep duration. Thus, administration of adenosine analogs or increasing brain concentrations of adenosine appears to have strong sedative effects as measured by locomotor behavior, but only subtle hypnotic effects with regard to electroencephalo- graphic (EEG) measures of consciousness. In order to examine effects of A~ receptor agonists on the relationship between behavioral quiescence and sleep regulation, we have examined the effects of L-PIA on both EEG and locomotor behavior. 1Requests for reprints should be addressed to Wallace B. Mendelson. 507