Life Sciences, Vol. 42, pp. 1355-1360 Pergamon Press Printed in the U.S.A. L-PHENYLISOPROPYLADENOSINE (L-PIA) DIMINISHES HALOTHANE ANESTHETIC REQUIREMENTS AND DECREASES NORADRENERGIC NEUROTRANSMISSION IN RATS Barry D. Birch, Gina L. Louie, Ross G. Vickery, David M. Gaba, Mervyn Maze Department of Anesthesia, Stanford University School of Medicine and Anesthesiology Service, Veterans Administration Medical Center, Palo Alto CA 94304 (Received in final form February 3, 1988) Summary The effect of L-phenylisopropyladenosine (L-PIA), the A I adenosine agonist, on the depth of anesthesia was investigated in halothane- anesthetized rats. L-PIA treatment reduced the minimum anesthetic concentration (MAC) of halothane that prevented 50% of animals from moving in response to a painful stimulus by 49%. MAC experiments performed with L-PIA given in conjunction with A I adenosine receptor antagonists which either permeate the blood-brain barrier (8- phenyltheophylline [8-PT]) or do not (8-sulphophenyltheophylline [8- So-PT]) indicate that central mechanisms are involved. Noradrenergic neurotransmission was diminished following L-PIA administration in halothane-anesthetized rats in all brain regions. These data suggest that acute L-PIA treatment decreases central noradrenergic neurotransmission and may represent the mechanism for the decrease in halothane dose to achieve an anesthetic endpoint anesthetic response to halothane. Central monoaminergic neurotransmission exerts an important role in modulating the depth of the anesthetic response although the relative contributions from noradrenergic, dopaminergic and serotonergic pathways remain unclear. An indirect measure of monoaminergic neurotransmission can be obtained by determining steady-state turnover for norepinephrine, dopamine and serotonin in functionally and anatomically discrete areas of rat brain. Neurotransmission in the respective monoaminergic pathways can then be correlated with changes in anesthetic responsiveness to determine the relative contribution of each pathway. Using this technique, we have obtained evidence for the preeminent role of noradrenergic neurotransmission in anesthetic responsiveness( I ). Adenosine, a purine nucleoside, is present in the brain in concentrations sufficient to be important in the regulation of central nervous system function(2). One of its roles is as an endogenous neuromodulator which tonically inhibits central noradrenergic neurons vim presynaptic A I adenosine receptors(3). Drugs which alter the adenosine concentration are likely to affect noradrenergic neurotransmission and, thereby, enhance or diminish anesthetic depth. Exogenous administration of adenosine(4) and ATP(5) to induce hypotension is increasingly seen in the surgical setting and agents which inhibit adenosine metabolism, i.e. dipyridamole(6) and deoxycoformycin(7), are also in clinical use. The present study was designed to determine if L-phenylisopropyladenosine 0024-3205/88 $3.00 + ~00 Copyright (c) 1988 Pergamon Press plc