Brain Research Bulktin, Vol. 25, pp. 339-344. 0 Pergamon Press pk. 1990. Printed in the U.S.A zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONML REVIEW GABA as a Presumptive Paracrine Signal in the Pineal Gland. Evidence on an Intrapineal GABAergic System RUTH E. ROSENSTEIN, HkTOR E. CHULUYAN, MARIA C. DiAZ AND DANIEL P. CARDINALI’ Departamento de Fisiologia, Fucultad de Medicina, Universidud de Buenos Aires CC243, 1425 Buerlos Aires, Argentina Received 28 August 1989 ROSENSTEIN, R. E., H. E. CHULUYAN, M. C. DfAZ AND D. P. CARDINALI. GABA as a presumprive pcmcrine signal in rhe pined gland. Evidence on nn intrapineal GABAergic system. BRAIN RES BULL 25(2) 339-344. 1990. -CiABA is present in the pineal gland of several mammals, where it is synthesized in situ as well as taken up from the circulation. This article reviews available information suggesting a local, physiological role of pineal GABA. Both the pinealocytes and the glial pineal cells have the capacity to take up GABA from the extracellular space. The GABA synthesizing enzyme glutamic decarboxylase (GAD) is detectable in the pineal gland; in the bovine pineal GAD exhibits “neuronal-like” properties. By employing a specific antibody against GABA, about 15% of pinealocytes gave a positive reaction in bovine pineal glands. After a depolarizing stimulus, GABA was released from bovine and rat pineal glands by both Ca’+-dependent and Ca’+-independent p recesses. By employing neuronal and glial GABA uptake inhibitors, most %GABA release in bovine pineal gland could be attributed to a “neuronal” (presumably pinealocyte) compartment. Several components of the GABA type A receptor supramolecular complex (i.e., GABA binding sites. central-type benzodiazepine binding sites, Cl- ionophore), as well as a minor population of GABA type B receptor sites, were detected in bovine and human pineal glands. In the rat pineals, GABA is released by norepinephrine (NE) acting through alpha,-adrenoceptors. Physiological concentrations of GABA, by its effect on type A receptor sites, impaired NE-induced melatonin release; by acting on GABA type B receptors, it decreased NE release. Another presumable presynaptic effect of GABA (i.e., to augment maximal velocity and to decrease affinity of NE uptake) was mediated by type A receptor sites. It is proposed that pre- and postsynaptic activity of GABA in the pineal does not differ from that found for GABA interneurons in local circuits of the brain. GABA Pineal gland Paracrine relations GABA receptors Benzodiazepine receptors Cl ionophore Glutamic acid decarboxylase Glial uptake Alpha,-adrenoceptors Norepinephtine uptake and release Melatonin release GABAergic interneurons GABA immunohistochemistry THE role of the pineal gland as a neuroendocrine transducer of environmental lighting information into hormonal output, i.e., melatonin release, has been extensively documented in mammals and birds (19, 30, 31). The so-called “melatonin hypothesis of pineal function,” put forth by Wurtman and Axelrod 25 years ago (50), holds that light suppresses, and darkness stimulates, mela- tonin biosynthetic activity, via peripheral sympathetic nerves whose perikarya are located in the superior cervical ganglia. A simple neurochemical paradigm was envisioned for pineal regula- tion involving norepinephrine (NE) release from pineal nerve endings and NE interaction with beta-adrenoceptors on the cell membranes of a homogenous population of pinealocytes. As a consequence, adenylate cyclase becomes activated, de novo syn- thesis of melatonin biosynthetic enzymes takes place, and an increase of pineal melatonin synthesis and release ensues [see (5,9)1. In the last few years, the model had to be modified to include a growing information on additional, alpha,-adrenoceptor-me- diated mechanisms [e.g., Ca’+ entrance, (40); serotonin release, (1.7)], as well as on an increasing number of presumptive ‘Requests for reprints should be addressed to Dr. Daniel P. Cardinali. 339