ABSTRACTS

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A190

B-CHLOROPHENYL GABA ISACLOFENI IS A SELECTIVE LIGAND FOR A

NOML GABA RECEPTOR ON NERVE TERMINALS. N.G.Bowery.A.Oobls, 0 R Hill, A.L.Hudson, J.Shau & M.J.TurnbulI, Pharmacology . . Oept. St. Thomas's Hoepital Medical School, London &Biology Dept. ICI, Flacclssfield, UK.

The presence of bicuculline sensitive GABA receptorsoutside the cne in mamutle 15 now well established. Recently. ho~ever‘r bicuculline-insenaitivs rscq,tors for GABA have also been described on autonomic nerve terminals IEowery B Hudson, Br.J.Pharmec. I19791 E, ,OBP, Brown 8 Higgins, Br. J.Pharmac. I19791 2. 1OBPl. GABA stimulates these novel receptors in e dose-dependent manner to reduce evoked trans- mitter output. This effect is neither blocked by blc"cuI- line methobromide nor mimicked by 3-aminopropane sulphonic acid (I-APSI, ieogwecine or isonipecotic acid. I-IBaclo- fen. however. is e potent agonist for this receptor(I+lbaclo- fan is>100 fold less active then l-1 isomerl. GABA and beclotan but not S-APS also inhibit (%ZOSl the K+-evoked release of +l-noradrenaline and %-dopemine from ret cere- bellar and striatal slices respectively. Bicuculline is without effect on the response to CABA or baclofen in these slice preparations.

A188

EFFECT OF SONE PROTECTIVE AGZNTS ON OW TOXICITY: ROLE OF

GABAANOAtQfONLA. R.A. Schatz* and H. Lal. “Ill”. Rhode

Island, Dept. Phmmacol., Kingston. R. I. and *Mental Health Research Institute, Univ. Michigan, Ann Arbor, MI. Exposure to hyperbaric oxygen C&E') (60 paiS) produced co.,- vulsitms, post-exposure lethality and ele"atio,, in lung "eight, lung ".ter content and lung bemaglobin content. Par&in= (PA), euceinic ecid (SA) or ascorbic acid (AA) provided partial protection against all of the above aspects of OW toxicity. OW decreased brain G4P.A levels via inbibi- tion of its symhesirfng enry~e glutmic acid decarboxylase (Cm) without altering the activity of its eataboliring e"zy~! CABA trmsaninase (CAM-T). Both PA and SA increased CAB4 levels in r--air exposed mice md prevented the OW- induced decrease in CAPA. PA inhibited &WA-T activity & JT& vithout altering the activity of GM). Conversely, SA, inn, increased the sctivity of both CAD and GABA-T, GAD to a greater extent than CAM-T, and Prevented the OW- induced decreased in CAD .ctivity. 'Them "as a significant correlation bchaeen OXP seizure susceptibility and brain CAEA lnels in PA or SA treated mice. A4 "as without effect on any of the cnaponmts of the GAM system and it did not prevent any of the OFF-induced alterations in CABA or CAD. Brains of OBP-exposed mice had elevated amania levels and decreased glutamine levels. All three protective agents reduced the mewitude of these OHP-induced alterations. There "as a correlation betveer, brain ammonia levels and OEP seizure suscetiibilitv. Ihe data are consonant tith the hypothesis that decreased CABA and increased anvrnia levels are fnvolred in the etiology of OHP toxicity.

A189

GABA IN NON-NEURONAL SYSTEMS: INTRODUCTION. Roberts. Eugene, Div. of Neurosciences, City of Hope National t&dice1 Center. Duarte, CA 91010

GABA occurs widely in nature. It is found in bacteria, plants, and in tissues of many animal organisms. The presence of high concentrations of GABA In the vertebrate central nervous system has led to intensive study of the formation, utilization, and localization of GABA and related enzymes in wrvous tissue. Physiological studies have identified the nature of the effects of GAEA on excitable membranes. The latter, together with iureunocyto- chemical identification of GABA neurons in various regions of the brain and spinal cord, makes it certain that GABA is d major inhibitory transmitter in vertebrate nervous systems. GAEA is present and is formed in non-neural tissues, ds well. It nlay serve regulatory as well as metabolic functions in these tissues. Although most of the GABA in neural tissues is formed from L-glutamate by glutamic decarboxylase, alternate pathways of synthesis of GABA may exist in other tissues. It is the purpose of this symposium to begin to bring together some of the pertinent observations which (nay lead to our understanding of some of the non-neural roles that GABA may play.

PICROMXIN BINDING SITES XT THE GABA SYNAPSE: A TARGET FOR DRUG ACTION. H.K. TiCkU. rJepertm*nt of Pharmacology, me

O~“ersity of Texes Health Science Center, 7703 Floyd 0x1 Drive, San Antonio, Texas 78284. a-Dihydzoprcrotoxinin (DHPI,a _ synaptic antqonist, having biological activity similar to picmtoxin, binds to rat brain membranes, at a site distinct from GABA recog- nition (receptor) site. DHP binds to rat brain membranes with an apparent KC, of 1-2 pm and a ti of 5 pmle,mg Protein. DHP binding is inhibited by various picrotoxin malosves in a rank order correlation vitb thei= neuro- Phar&olo9ical effects. Besides picrotoxin analogues. DHP binding is inhibited potently by depressant and convulsant barbiturates, bicyclopborpbate esters and related cage con- vulsant ccmpamds, anticonvulsants like diphenylhydantoin, some purines and pyrimidines and benzodiazepines. our results suggest that a variety of drugs "hich affect GABAergic transmission may *ct via the picrotoxin sensitrve site at the am rynapse. The sites appear to be involved in the rwlation of GAm receptor linked chloride ionopbores, and may ilet as possible receptors for some of these drugs or sane endo9emus molecules.

A191

THE EFPECT OF UIBA ON TES BINDDING OF [%]noNITRAzePAM IN WUSE BRAINS DURING DEVELOPMENT. John W. Regan. William R. Koeske and Henry I. Ymmura, University of Arizona Health Sciences Center, Tucson, Arizona 85724.

Stvdies of the benzodiazepine (BZD) and WBA receptors during development have shm similarities in their receptor densities (relative to adult levels) .during the early "eona- tal period. CAB* can increase the affinity of [%l]diazepam binding. It is important to knw "bether this functional relationship exists in the fetal and neonatal periods. Sat- uration isotherms for [%]fllmitrarepam (PLU) binding, using muse brain homogenates from different ages. "ere assayed in the presence of either 10 ,,M GAB* or 100 ,,M (+)bicuculline (BC). Clooarepam "as used as the displacer. GABIL increased the affinity of BZD bindi,,& "bile SC decreased the affinity. An ANOLA indicated that there were no differences in K. be- t"een ages and the pooled results are: 1.05f.21 nH, %o USA;" 0.5lf.14 ti, "plue MBA;" 0.55f.12 nM, "r.o SC;" and 1.76f.15 nH, "plus BC." To see if the BZD receptor "as differentially sensitive to GABA during development, dose- response CurYes for the GABA effect were rm at fetal, neo- natal, and adult ages. The results Sbo" that the concentrs- tion causing a 50X decrease in madma binding "as nearly equal at a11 ages (1.0 "H). The tinetics of the CABA effect

were also investigated. No change ink+, for KU binding "as observed, while a si&fieant decrease in L-1 "as seen (.06f .Ol mir? , “no CABA;” .O% .003 tin- , “plus WA”). We believe these data shar a close biochemical association be- t"een the BZD receptor and at least me of the CABA recep- tors. Supported by "SPHS Sraots and RSDA to B.I.Y.

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TNHE RELATIONSHIP BETWEEN GABA COP;CENTQATIONS IN BNAlN Am CEKEBROSPlW FLUID. P. M!blen*. S. Huot and H.C. Pa1frey.m Centre de Recherche Merrell International. 67084 Strasbourg. France.

GABA concentrations in CSF and brain of rate were detemined before and after intraperitoneal injection of drugs that in- crease brain CASA levels. In untreated tats there is very little free CABA in the CSP (65 t 12 pmol/~) but eonsidsrable amounts of con,uSated GASA (2885 f 100 pmllml) of vhich homo- carnasine is a m,or cmwtlt~ant. After administration of I-vinyl CAM CSP toncentratfane of free and con,ug.trd GAEA rise in a dose-dependent manner. There is an uponeatial correlation (r -0.92, P<O.OOl) betuaan "bole brain CABA concentrations and free CASA in the CSF. Concentrations of brain CABA and con,uSsted CSP CAB* are linearly correlated (r - 0.84, p<0.001). I-acecylenic GABA has qualitatively similar effects to 'I-vinyl CABA. EthanolsmfneQsulfate, at a dose not affecting brain CABA concentrations markedly increases serum GAB*, but only minimally affects CSP-CASA levels. This suggests that concentrations of CAB* in the CSP are primarily related to brain CABA levels.

l Prese"t address: Salk Institute. San Diego. CA. 92112