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Release-Regulating Autoreceptors of the GABAB-Type in Human Cerebral Cortex

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Release-Regulating Autoreceptors of the GABAB-Type in Human Cerebral Cortex Br. J. Pharmacol. (1989), 96, 341-346 Release-regulating autoreceptors of the GABAB-type in human cerebral cortex Giambattista Bonanno *Paolo Cavazzani, *Gian Carlo Andrioli, Daniela Asaro, Graziella Pellegrini & tMaurizio Raiteri Istituto di Farmacologia e Farmacognosia, Universita degli Studi di Genova, Viale Cembrano 4, 16148 Genova, Italy & *Divisione di Neurochirurgia, Ospedali Galliera, Via A. Volta 8, 16128 Genova, Italy 1 The depolarization-evoked release of y-aminobutyric acid (GABA) and its modulation mediated by autoreceptors were investigated in superfused synaptosomes prepared from fresh human cerebral cortex. 2 The release of [3H]-GABA provoked by 15 mmK+ from human cortex nerve endings was almost totally (85%) calcium-dependent. 3 In the presence of the GABA uptake inhibitor SK&F 89976A (N-4,4-diphenyl-3-butenyl)-nipe- cotic acid), added to prevent carrier-mediated homoexchange, GABA (1-10 pM) decreased in a concentration-dependent manner the K+-evoked release of [3H]-GABA. The effect of GABA was mimicked by the GABAB receptor agonist (-)-baclofen (1-100 pM) but not by the GABAA receptor agonist muscimol (1-100 uM). Moreover, the GABA-induced inhibition of [3H]-GABA release was not affected by two GABAA receptor antagonists, bicuculline or SR 95531 (2-(3'-carbethoxy-2'- propenyl)-3-amino-6-paramethoxy-phenyl-pyridazinium bromide). 4 (-)-Baclofen also inhibited the depolarization-evoked release of endogenous GABA from human cortical synaptosomes. 5 It is concluded that GABA autoreceptors regulating the release of both newly taken up and endogenous GABA are present in human brain and appear to belong to the GABAB subtype. Introduction Studies on the laboratory animal have shown that GABA in the rat brain of the GABAB receptor autoregulation of transmitter release mediated by subtype (Anderson & Mitchell, 1985; Pittaluga et al., receptors sited on the releasing terminals 1987; Waldmeier et al., 1988). (autoreceptors) appears to be a common feature of It has been proposed that abnormalities in GABA the major transmitter systems (Langer, 1981; Starke, transmission are associated with various human 1981; de Belleroche, 1982; Raiteri et al., 1984). Auto- disease states. The GABA system appears to be receptors for noradrenaline (for reviews see: Langer, altered in certain types of epilepsy (Meldrum, 1975), 1981; Starke, 1981), 5-hydroxytryptamine (Engel et in Huntington's and Parkinson's disease al., 1986; Maura et al., 1986; Bonanno et al., 1986) (Hornykiewicz et al., 1976; Schwarcz et al., 1977) and and acetylcholine (Marchi & Raiteri, 1985; Meyer & in a number of neuropsychiatric disorders including Otero, 1985; Mash & Potter, 1986) have been widely depression (Lloyd et al., 1985). studied and characterized in terms of types and sub- Due to this postulated involvement of GABA in types. In the case of y-aminobutyric acid (GABA) the neurological and psychiatric diseases and in view of mechanisms of autoregulation have been less investi- the existence of different types of GABA receptors gated. GABA autoreceptors have been reported to (Bowery, 1983) it was of relevance to determine: (a) be muscimol-sensitive (Mitchell & Martin, 1978; whether GABA autoreceptors are present in human Brennan et al., 1981) and therefore of the GABAA brain; (b) whether or not their pharmacological type. However a number of recent papers suggest the properties are similar to those of the autoreceptors presence of autoreceptors regulating the release of found in the rodent brain. We here show that func- tional autoreceptors belonging to the GABA, 'Author for correspondence. subtype are present in the cerebral cortex of man. © The Macmillan Press Ltd 1989 342 G. BONANNO et al. Methods 6 min sample (evoked release). A 90 s period of depo- larization with 15 mM KCI was applied at the end of Characteristics ofhuman specimens the first fraction collected. GABA, (-)-baclofen or muscimol was added to the superfusion medium Samples of human cerebral cortex were obtained concomitantly with the depolarizing stimulus. from patients undergoing neurosurgery. The tissues Bicuculline, or the novel GABAA receptor antagonist used were removed by the surgeon to reach deeply SR 95531 [2-(3'-carbethoxy-2'-propenyl)-3-amino-6- located tumours. The samples used represented parts paramethoxy-phenyl-pyridazinium bromide] (Wer- of frontal (2), temporal (3), parietal (2) and occipital muth & Biziere, 1986) was added 8 min before (2) lobes and were obtained from 5 female and 4 GABA. SK&F 89976A [4,4-diphenyl-3-butenyl)- male patients (aged 45-69 years). The tissues were nipecotic acid], a novel and potent inhibitor of obtained and processed separately on different days. GABA uptake (Yunger et al., 1984; Bonanno & After premedication with atropine and meperidine, Raiteri, 1987; Larsson et al., 1988) was present in the anaesthesia was induced with Pentothal and main- superfusion medium at a final concentration of 30 uM tained with 70% nitrous oxide in 30% oxygen and to minimize carrier-mediated exchange between 0.5-1% isoflurane. Pancuronium was employed to intraterminal [3H]-GABA or endogenous GABA obtain muscular relaxation. and extrasynaptosomal GABA or muscimol. Amino- oxyacetic acid (AOAA; final concentration 50pM) Preparation ofsynaptosomes was present throughout the experiment to prevent [3H]-GABA metabolism. AOAA was not used in Immediately after removal, the tissue was placed in a experiments on endogenous GABA release. physiological salt solution kept at 2-40C and a syn- Endogenous GABA in the superfusates was mea- aptosomal fraction was obtained within 60 min. sured with a radioreceptor assay, essentially as Crude synaptosomes were prepared essentially as described by Enna & Snyder (1976). High per- previously described (Gray & Whittaker, 1962) with formance liquid chromatography with fluorescent minor modifications. Briefly, the brain cortex was detection after pre-column derivatization by o- homogenized in 40 vol of 0.32M sucrose buffered at phathalaldehyde according to Tonnaer et al. (1983) pH 7.4 with phosphate using a glass-teflon tissue was applied in some cases. The results obtained did grinder (clearance 0.25 mm). The homogenate was not differ significantly from those obtained with the centrifuged (5 min, 0009g at 0-40C) to remove nuclei radioreceptor assay. At the concentration used in and debris and synaptosomes were isolated from the our experiments (-)-baclofen did not interfere in the supernatant by centrifugation at 12,000g for 20min. radioreceptor assay (Hill & Bowery, 1981). The synaptosomal pellet was then resuspended in a The amount of radioactivity released into each physiological medium having the following composi- fraction was expressed as the percentage of the tion (mM): NaCl 125, KCI 3, CaCl2 1.2, MgSO4 1.2, tritium content of synaptosomes at the start of the NaH2PO4 1, NaHCO3 22, glucose 10 (aerated with respective collection period. The depolarization- 95% 2 and 5% CO2 at 370C) pH 7.2-7.4. Protein evoked overflow was estimated by subtracting the was measured by the method of Petersen (1977). percent of tritium content of the basal release from the release evoked in the 6min fraction collected Release experiments during and after the depolarization pulse. The endogenous GABA released was expressed as pmol Synaptosomes were incubated in a rotatory water of amino acid per mg of synaptosomal protein. The bath at 37°C for 15min in the presence of 0.04.uM drug effects were evaluated as the ratio of the [3H]-GABA or without label (experiments on depolarization-evoked overflow calculated in the endogenous GABA release). After incubation, identi- presence of the drugs vs. that calculated under cal aliquots of the synaptosomal suspension (ranging control conditions. between 0.4-0.8mg protein in different experiments) were distributed on 0.65 pm Millipore filters placed Drugs at the bottom of a set of parallel superfusion cham- bers maintained at 37°C (Raiteri et al., 1974; Raiteri [3H]-GABA (105 Ci mmolP 1) was obtained from & Levi, 1978) and layered under moderate vacuum Amersham Radiochemical Centre; aminooxyacetic filtration. Superfusion was then started with stan- acid and (+)-bicuculline were purchased from Sigma dard medium aerated with 95% 02 and 5% CO2 at Chemical Co (St. Louis, MO, U.S.A.); GABA from a rate of 0.6mlmin-1 and continued for 48min. Serva (Heidelberg, F.R.G.). The following drugs were After 36 min to equilibrate the system, fractions were generous gifts by the companies indicated: (-)- collected according to the following scheme: two baclofen (Ciba Geigy, Basel, Switzerland); muscimol 3min samples (basal release) before and after one (Zambon Farmaceutici, Milan, Italy); SK&F 89976A GABAB AUTORECEPTORS IN HUMAN BRAIN 343 Table 1 Calcium-dependence of the K +-evoked release of [3H]-GABA from human cortical brain synaptosomes Standard mediuma Ca2+-free medium Basal release min -1 0.62 + 0.08 0.56 + 0.06 K + (15 mM)-evoked overflow 2.96 + 0.38 0.32 + 0.05* Values are the mean + s.e. mean of four experiments in triplicate. a Measured as percentage of total [3H]-GABA content. * Statistical significance of changes versus the K+ (15mM)-evoked overflow in standard medium were determined by Student's t test: P < 0.001. (Smith Kline & French, Welwyn, England) and SR endogeneous GABA from human synaptosomes are 95531 (Sanofi, Bruxelles, Belgium). shown in Table 3. While the basal release was not significantly affected, the depolarization-evoked overflow was inhibited by about 50% when the Results agonist was present at 10 M. As
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