Autoradiographic localization of gamma-aminobutyric acid (GABA) receptors in the rat cerebellum.

[3H]Muscimol was used in the light microscopic autoradiographic localization of gamma-aminobutyric acid (GABA) receptors in the rat cerebellum. The binding of [3H]-muscimol to the slide-mounted tissue sections had all of the characteristics associated with a GABA receptor. It was saturable with appropriate kinetic constants and was blocked only by other GABAergic drugs. Autoradiographic studies revealed a very high density of receptors over the granule cell layer, a low level over the molecular layer, and negligible receptor binding over white matter. This suggested a high localization of GABA receptors to granule cells, which is supported by other neurochemical studies. The autoradiographic procedure used here should be a useful method in further studies of receptors requiring high sensitivity and increased anatomical resolution.     

Site of gamma-aminobutyric acid (GABA)-mediated inhibition of growth hormone secretion in the rat

The effect of altering gamma-aminobutyric acid (GABA) activity on growth hormone (GH) secretion of freely moving chronically cannulated male rats was studied. Systemic injection of the GABA agonist muscimol (2 mg/kg i.v.) inhibited the anticipated secretory episode. Increasing brain GABA levels by gamma-acetylenic-GABA (50 mg/kg i.v.) also inhibited the expected GH rise. When injected before the expected secretory episode, the GABA receptor antagonist bicuculline methiodide (2 mg/kg i.v.) triggered an early secretory peak. GABA and muscimol failed to change GH secretion by cultured anterior pituitary cells. When the somatostatin input to the stalk-median eminence region was interrupted by an anterolateral cut around the medial basal hypothalamus, the GH level was steadily increased and muscimol injections caused a prompt decrease of plasma GH levels. These results are consistent with the hypothesis that GABAergic tonic inhibition participates in the control of GH secretion and that GABA inhibits spontaneous GH release by inhibiting the secretion of a GH-releasing factor.     

An Intrinsic gamma-aminobutyric acid (GABA)ergic system in the adrenal cortex: findings from human and rat adrenal glands and the NCI-H295R cell line

gamma-Aminobutyric acid (GABA), a major neurotransmitter in the central nervous system, also acts as a paracrine or autocrine signaling molecule in endocrine tissues such as the pancreatic islets, adenohypophysis, and testis. In the present study, we describe local GABA production and functional GABA(B) receptors in the adrenal cortex, possibly forming an auto- or paracrine GABAergic system. Using immunohistochemistry and RT-PCR, we localized the GABA-synthesizing enzyme glutamate decarboxylase 67 and the vesicular GABA transporter in steroid-producing cells of the human and rat adrenal cortex. Immunocytochemistry, Western blots, and RT-PCR experiments demonstrated the presence of glutamate decarboxylase 67 in the human adrenocortical cell line NCI-H295R. Measurements of glutamate decarboxylase activity confirmed that, in these cells and in rat adrenals, glutamate is decarboxylated to form GABA. In addition, we found expression of the GABA(B(1a)), GABA(B(1e)), and GABA(B(2)) subunits of the heterodimeric GABA(B) receptor in NCI-H295R cells as shown by RT-PCR. GABA(B(1a)) and its truncated splice variant GABA(B(1e)) were also found in human and rat adrenal glands. Immunostaining for the GABA(B(2)) subunit revealed its presence in the human and rat adrenal cortex and in NCI-H295R cells. The GABA(B) receptors we identified were functional because the GABA(B) agonist baclofen inhibited T-type Ca(2+) currents in whole-cell patch clamp experiments on NCI-H295R cells. This effect was blocked by pertussis toxin. Furthermore, the alpha(2)-, alpha(3)-, beta(2)-, beta(3)- gamma(2)-, and epsilon-subunits of the GABA(A) receptor were detected in this cell line by RT-PCR. Hence, we conclude that GABA is synthesized and stored by steroid-producing cells of the adrenal cortex and may influence these cells in a paracrine or autocrine manner.     

Serum gamma-aminobutyric acid (GABA) levels in patients with hepatic encephalopathy

Serum levels of the potent inhibitory neurotransmitter gamma aminobutyric acid (GABA) were measured in 10 patients with chronic liver disease and hepatic encephalopathy, 11 patients with chronic liver disease and no evidence of hepatic encephalopathy, 7 patients with end-stage renal disease and 11 healthy volunteers. Serum GABA levels were elevated in all 10 patients with hepatic encephalopathy, 5/11 with liver disease and no encephalopathy and 4/7 renal disease patients. The mean serum GABA level for the encephalopathic patients (0.92 +/- 0.13 microM, mean +/- SEM) was significantly greater than the mean for liver disease patients without encephalopathy (0.48 +/- 0.05 microM, p less than 0.05), renal disease patients (0.46 +/- 0.04 microM, p less than 0.05) and healthy volunteers (0.39 +/- 0.03 microM, p less than 0.001). These results would tend to support the hypothesis that GABA may play a role in the pathogenesis of hepatic encephalopathy.     

Selective clustering of glutamate and gamma-aminobutyric acid receptors opposite terminals releasing the corresponding neurotransmitters.

Several immunocytochemical and physiological studies have demonstrated a concentration of neurotransmitter receptors at postsynaptic sites on neurons, but an overall picture of receptor distribution has not emerged. In particular, it has not been clear whether receptor clusters are selectively localized opposite terminals that release the corresponding neurotransmitter. By using antibodies against the excitatory glutamate receptor subunit GluR1 and the inhibitory type A gamma-aminobutyric acid (GABA) receptor beta 2/3 subunits, we show that these different receptor types cluster at distinct postsynaptic sites on cultured rat hippocampal neurons. The GABAA receptor beta 2/3 subunits clustered on cell bodies and dendritic shafts opposite GABAergic terminals, whereas GluR1 clustered mainly on dendritic spines and was associated with glutamatergic synapses. Chronic blockade of evoked transmitter release did not block receptor clustering at postsynaptic sites. These results suggest that complex mechanisms involving nerve terminal-specific signals are required to allow different postsynaptic receptor types to cluster opposite only appropriate presynaptic terminals.     

Mechanisms governing dendritic gamma-aminobutyric acid (GABA) release in the rat olfactory bulb

In the olfactory bulb, synaptic transmission between dendrites plays an important role in the processing of olfactory information. Glutamate released from the dendrites of principal mitral cells excites the dendritic spines of granule cells, which in turn release gamma-aminobutyric acid (GABA) back onto mitral cell dendrites. Slow N-methyl-d-aspartate (NMDA) receptors on granule dendrites are particularly effective in driving this reciprocal dendrodendritic inhibition (DDI), raising the possibility that calcium influx through NMDA receptors may trigger GABA exocytosis directly. In this study, I show that NMDA receptor activation is not an absolute requirement and that DDI can be evoked solely by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors when granule cell excitability is increased or under conditions that slow AMPA receptor kinetics. In physiological extracellular Mg(2+), DDI elicited by photolysis of caged calcium in mitral dendrites is blocked by cadmium and toxins to N- and P/Q-type voltage-gated calcium channels. DDI is largely unaffected after granule dendrites have been loaded with the slow calcium chelator EGTA, suggesting a tight coupling between the site of calcium influx and the release machinery governing GABA exocytosis. These results indicate that voltage-gated calcium channels play an essential role in dendritic GABA release during reciprocal feedback inhibition in the olfactory bulb.     

老年大鼠视皮层γ-氨基丁酸的代谢变化

目的 研究衰老过程中视皮层γ-氨基丁酸（GABA）的代谢变化及其性别差异。方法 采用纸电泳法检测青年大鼠和老年大鼠视皮层中GABA含量,采用比色法测定GAD与GABA-T活性。结果 老年大鼠较青年大鼠视皮层GABA含量显著下降,GAD活性明显降低,GABA-T活性老年雄性组显著上升,老年雌性组变化不显著。老年雌性组GABA含量明显高于老年雄性组,两组间GAD活性无显著差异,GABA-T活性老年雄性组较高。结论 老年大鼠视皮层GABA含量明显下降,可能与GAD活性的下降及GABA-T活性的上升有关,此外老年雌性GABA含量明显高于老年雄性,这可能是由于老年雄性GABA-T活性较高所导致的。     

Cyclothiazide potently inhibits gamma-aminobutyric acid type A receptors in addition to enhancing glutamate responses

Ionotropic glutamate and gamma-aminobutyric acid type A (GABAA) receptors mediate critical excitatory and inhibitory actions in the brain. Cyclothiazide (CTZ) is well known for its effect of enhancing glutamatergic transmission and is widely used as a blocker for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor desensitization. Here, we report that in addition to its action on AMPA receptors, CTZ also exerts a powerful but opposite effect on GABAA receptors. We found that CTZ reversibly inhibited both evoked and spontaneous inhibitory postsynaptic currents, as well as GABA application-induced membrane currents, in a dose-dependent manner. Single-channel analyses revealed further that CTZ greatly reduced the open probability of GABAA receptor channels. These results demonstrate that CTZ interacts with both glutamate and GABAA receptors and shifts the excitation-inhibition balance in the brain by two independent mechanisms. Understanding the molecular mechanism of this double-faceted drug-receptor interaction may help in designing new therapies for neurological diseases.     

Ethanol modulation of gamma-aminobutyric acid (GABA)-mediated inhibition of cerebellar Purkinje neurons: relationship to GABAb receptor input

BACKGROUND: Electrophysiological recording reveals that only a portion of cerebellar Purkinje neurons are sensitive to ethanol enhancement of gamma-aminobutyric acid (GABA) responses. Although activation of beta-adrenergic receptors permits ethanol enhancement of GABA function from some cerebellar Purkinje neurons, other neurons remain insensitive to ethanol. These findings are consistent with the finding that other external neural inputs are required to allow ethanol enhancement of GABA responses from Purkinje neurons. Because of a high expression of GABA(B) receptors on Purkinje cells, we tested whether activation of GABA(B) receptors might modulate the action of ethanol on GABA responsiveness. METHODS: Extracellular single-unit electrophysiological recording was used to investigate the effects of ethanol on responses to GABA and muscimol (a GABA(A) agonist) from cerebellar Purkinje neurons. Drugs tested were baclophen (a GABA(B) agonist) and CGP35348 (a GABA(B) antagonist). RESULTS: Ethanol did not enhance responses to GABA and muscimol from all Purkinje neurons. Systemic administration of the GABA(B) agonist, baclophen (3 mg/kg intravenously), permitted ethanol to enhance GABA inhibition from approximately 75% of cerebellar Purkinje neurons not initially enhanced by ethanol. Local iontophoretic application of baclophen to Purkinje neurons also allowed ethanol to enhance GABA and muscimol responsiveness from a portion of neurons in which ethanol initially did not affect their actions. An inhibitory action of ethanol on responses to GABA and muscimol, which was also influenced by baclophen, was observed from some Purkinje neurons. From Purkinje neurons initially sensitive to ethanol enhancement of GABA and muscimol function, administration of CGP35348, a GABA(B) antagonist, diminished the effect of ethanol on the responsiveness of these agonists from the majority (9/15) of neurons. CONCLUSIONS: The present findings demonstrated that baclophen allows ethanol enhancement of GABA and muscimol responsiveness from some, but not all, cerebellar Purkinje neurons initially not sensitive to ethanol. Likewise, a GABA(B) antagonist can diminish ethanol enhancement of GABA and muscimol responses from some ethanol-sensitive neurons. Thus, these results emphasize that GABA(B) receptors on a portion of Purkinje neurons act as an auxiliary neural input that allows ethanol enhancement of GABA responses. Consequently, receptor structure alone does not account for the action of ethanol on GABA(A) receptor function on this cell type.     

A single amino acid in gamma-aminobutyric acid rho 1 receptors affects competitive and noncompetitive components of picrotoxin inhibition.

A class of bicuculline-insensitive gamma-aminobutyric acid (GABA) receptors, GABAC, has been identified in retina. Several lines of evidence indicate that GABAC receptors are formed partially or wholly of GABA rho subunits. These receptors generate a Cl- current in response to GABA but differ from GABAA receptors in a number of ways. Picrotoxin, widely accepted as a noncompetitive antagonist of GABAA receptors, displays competitive and noncompetitive antagonism of GABAC receptors in perch and bovine retina and GABA rho 1 receptors expressed in Xenopus oocytes. The aim of this study was to identify the molecular basis of the two components of picrotoxin inhibition of GABA rho 1 receptors. By using a domain-swapping and mutagenesis strategy, a difference in picrotoxin sensitivity between rho 1 and rho 2 receptors was localized to a single amino acid in the putative second transmembrane domain. Substitution of this amino acid with residues found in the analogous position in highly picrotoxin-sensitive glycine alpha and GABAA subunits increased the sensitivity of rho 1 mutants 10- to 500-fold. Importantly, the competitive component of picrotoxin inhibition of the rho 1 mutant receptors was almost eliminated. These findings demonstrate that an amino acid in the putative channel domain of GABA rho 1 receptors influences picrotoxin sensitivity and mediates agonist binding by an allosteric mechanism.     

An arylaminopyridazine derivative of gamma-aminobutyric acid (GABA) is a selective and competitive antagonist at the GABAA receptor site.

In view of finding a new gamma-aminobutyric acid (GABA) receptor ligand we synthesized an arylaminopyridazine derivative of GABA, SR 95103 [2-(carboxy-3'-propyl)-3-amino-4-methyl-6-phenylpyridazinium chloride]. SR 95103 displaced [3H]GABA from rat brain membranes with an apparent Ki of 2.2 microM and a Hill number near 1.0. SR 95103 (1-100 microM) antagonized the GABA-mediated enhancement of [3H]diazepam binding in a concentration-dependent manner without affecting [3H]diazepam binding per se. SR 95103 competitively antagonized GABA-induced membrane depolarization in rat spinal ganglia. In all these experiments, the potency of SR 95103 was close to that of bicuculline. SR 95103 (100 microM) did not interact with a variety of central receptors--in particular the GABAB, the strychnine, and the glutamate receptors--did not inhibit Na+-dependent synaptosomal GABA uptake, and did not affect GABA-transaminase and glutamic acid decarboxylase activities. Intraperitoneally administered SR 95103 elicited clonicotonic seizures in mice (ED50 = 180 mg/kg). On the basis of these results it is postulated that St 95103 is a competitive antagonist of GABA at the GABAA receptor site. In addition to being an interesting lead structure for the search of GABA ligands, SR 95103 could also be a useful tool to investigate GABA receptor subtypes because it is freely soluble in water and chemically stable.     

Effect of androgens on sexual differentiation of pituitary gamma-aminobutyric acid receptor subunit GABA(B) expression

Previous work demonstrated a sexually dimorphic ontogenic expression of gamma-aminobutyric acid receptors (GABA(B)R) in rat pituitary. As sex steroids determine sex-specific expression patterns, we now studied the effect of sex hormones on pituitary GABA(B)R expression. GABA(B)R subunits, measured by Western blot and by semi-quantitative RT-PCR and luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone measured by RIA were determined in two experimental designs: First experimental design: 8- and 15-day-old females (8F, 15F); 8F and 15F treated with 100 mug testosterone propionate (TP) on day 1 of life (8F100TP, 15F100TP), 8- and 15-day-old males (8M, 15M) and 8M and 15M castrated on day 1 (8MC, 15MC). Second experimental design: 8-day-old female and male animals: 8F, 8F100TP, 8F treated with 1 mug/day TP on days 1-4 (8F1TP), 8F treated with the androgen antagonist Flutamide (Flut: 2.5 mg/100 g BW of pregnant mother on days E17-E23) (8F-Flut), 8M, 8MC, 8M treated with Flut as above (8M-Flut) and 8MC-Flut. In these animals, in addition, GABA, glutamate, aspartate and taurine were measured by HPLC in hypothalami and cortex. In the first set of experiments, GABA(B1)R mRNA/protein expression was higher in 8F than in 15F, 8M or 15M. In 8F100TP, GABA(B1)R mRNA/protein decreased to male levels. TP treatment did not alter GABA(B1)R expression in 15F. There was no difference in GABA(B1)R expression between 8M and 15M and neonatal castration did not modify its expression. In the second set of experiments, TP (1 mug) or Flut did not modify GABA(B1)R in 8F, while 100 microg TP continued to decrease GABA(B1)R expression. In 8M, Flut, alone or with castration, increased GABA(B1)R mRNA/protein expression to 8F. Hypothalamic GABA content followed the same pattern as pituitary GABA(B)R expression in 8-day-old animals, suggesting a cross-regulation. With regard to hormonal levels, 100 microg, but not 1 microg TP altered gonadotropins at 8 days, although both treatments effectively androgenized females as evidenced by lack of cycling. We conclude that androgens, acting pre- and postnatally, decrease pituitary GABA(B)R subunit expression.     

Relationship between presynaptic calcium transients and postsynaptic currents at single γ-aminobutyric acid (GABA)ergic boutons

Postsynaptic responses to stereotyped activation of single axons are known to fluctuate, but the origin of synaptic variability in the vertebrate central nervous system is still unclear. To test the hypothesis that fluctuations of inhibitory postsynaptic currents reflect variations in presynaptic Ca2+ concentration, we examined single GABAergic axodendritic contacts in low-density cultures. Collicular neurons from rat embryos were loaded with the Ca2+ indicator Oregon Green 488 BAPTA-1. Presynaptic axon terminals were visualized by staining with the styryl dye RH414. Under the condition of action potential block, RH414-labeled boutons were activated selectively by current pulses applied through a fine-tipped glass pipette. Short (1- to 3-ms) depolarization of isolated boutons resulted in stimulus-locked changes of presynaptic Ca2+ concentration ([Ca2+]pre) and in evoked inhibitory postsynaptic currents (eIPSCs). Varying the strength of the stimulating currents produced a wide amplitude range of both presynaptic fluorescence transients (up to 220% of the resting value) and postsynaptic conductance changes (up to 2-3 nS). It was found that average eIPSCs displayed an approximately third-power dependency on [Ca2+]pre. Transmitter release retained its probabilistic character throughout the range of observed [Ca2+]pre values. In any tested single bouton, maximal eIPSCs occurred in association with the largest [Ca2+]pre transients, but failures were present at any [Ca2+]pre. The increase of maximal eIPSC amplitudes in connection with higher [Ca2+]pre supports the hypothesis that GABAergic boutons have the capacity to regulate synaptic strength by changing the number of simultaneously released vesicles.     

Stimulation of luteinizing hormone release by gamma-aminobutyric acid (GABA) agonists: mediation by GABAA-type receptors and activation of chloride and voltage-sensitive calcium channels

The mechanism by which gamma-aminobutyric acid (GABA) stimulates the release of LH was analyzed in cultured female rat pituitary cells. In 3-h incubations, GABA (1-100 microM) caused a dose-dependent increase in LH release, with the maximal response about 16% of that evoked by 10 nM GnRH. GABA action was independent of the GnRH receptor, since 1 microM GnRH antagonist [( N-acetyl-D-p-Cl-Phe1,2,D-Trp3,D-Lys6,D-Ala10] GnRH), which completely inhibits GnRH action, did not affect the response to GABA. In studies on the effects of GABA receptor agonists and antagonists, 4,5,6,7-tetrahydoisoxazolo-[5,4-c]pyridin-3(2H)-one (THIP) and muscimol (GABAA agonists) gave similar response patterns, with the same maximal stimulation as GABA but much higher potencies. In contrast, the GABAB receptor agonist baclofen did not stimulate LH release. The GABAA receptor antagonist SR95531 caused dose-dependent inhibition of the LH-releasing effects of GABA and muscimol (10 microM), with complete blockade at 10 microM SR95531. T-Butylbicyclophosphorothionate, an inhibitor of the GABAA receptor-associated chloride channel, also dose-dependently reduced the releasing effect of 100 microM GABA. These results indicate that GABA action is mediated by the chloride channel-associated GABAA receptor. However, the other GABAA receptor antagonists, including bicuculline, picrotoxin, and strychnine, did not attenuate the LH-releasing effect of 100 microM GABA in concentrations up to 100 microM, suggesting that GABA action is mediated by nonclassical GABAA receptors. Incubation in the presence of nifedipine (1 microM) or in calcium-free medium inhibited the LH-releasing action of GABA, indicating that calcium influx through voltage-sensitive calcium channels (VSCC) is required for GABA-induced LH release. Such entry of Ca2+ would result from activation of VSCC by depolarization due to the increased Cl- conductance caused by GABAA receptor activation. In cell perfusion studies, the actions of GABA and muscimol were attenuated or abolished after repetitive stimulation, consistent with desensitization of the GABA receptors. These findings have demonstrated that the stimulation of LH release by GABA is independent of GnRH action, occurs via binding to nonclassical GABAA receptors, which rapidly desensitize, and is mediated by the activation of VSCC.     

Aniracetam reduces glutamate receptor desensitization and slows the decay of fast excitatory synaptic currents in the hippocampus.

Aniracetam is a nootropic drug that has been shown to selectively enhance quisqualate receptor-mediated responses in Xenopus oocytes injected with brain mRNA and in hippocampal pyramidal cells [Ito, I., Tanabe, S., Kohda, A. & Sugiyama, H. (1990) J. Physiol. (London) 424, 533-544]. We have used patch clamp recording techniques in hippocampal slices to elucidate the mechanism for this selective action. We find that aniracetam enhances glutamate-evoked currents in whole-cell recordings and, in outside-out patches, strongly reduces glutamate receptor desensitization. In addition, aniracetam selectively prolongs the time course and increases the peak amplitude of fast synaptic currents. These findings indicate that aniracetam slows the kinetics of fast synaptic transmission and are consistent with the proposal [Trussell, L. O. & Fischbach, G. D. (1989) Neuron 3, 209-218; Tang, C.-M., Dichter, M. & Morad, M. (1989) Science 243, 1474-1477] that receptor desensitization governs the strength of fast excitatory synaptic transmission in the brain.     

gamma-Aminobutyric acid (GABA)-induced currents of skate Muller (glial) cells are mediated by neuronal-like GABAA receptors.

Radial glia (Muller cells) of the vertebrate retina appear to be intimately involved in regulating the actions of amino acid neurotransmitters. One of the amino acids thought to be important in mediating retinal information flow is gamma-aminobutyric acid (GABA). The findings of this study indicate that enzymatically isolated skate Muller cells are depolarized by GABA and the GABAA agonist muscimol and that the actions of these agents are reduced by bicuculline and picrotoxin. Membrane currents induced by GABA under voltage clamp were dose dependent, were associated with an increase in membrane conductance, and showed marked desensitization when the concentration of GABA exceeded 2.5 microM. The responses had a reversal potential close to that calculated for chloride, indicating that the currents were generated by ions passing through channels. These data support the view that skate Muller cells possess functional GABAA receptors. The presence of such receptors on retinal glia may have important implications for the role of Muller cells in maintaining the constancy of the extracellular milieu, for neuron-glia interactions within the retina, and for theories concerning the generation of the electroretinogram.     

GABA inhibition of immortalized gonadotropin-releasing hormone neuronal excitability involves GABA(A) receptors negatively coupled to cyclic adenosine monophosphate formation

γ-Aminobutyric acid (GABA) has been implicated in the regulation of reproduction, particularly in the developmental modulation of gonadotropin-releasing hormone (GnRH) secretion. GnRH neurons are innervated by GABA-containing processes, and the administration of GABA stimulates and inhibits GnRH secretion in vivo and in vitro. We have previously shown that GABA can exert both of these actions in sequence, by acting directly on immortalized GnRH neurons. While the stimulation is the result of a GABA_A receptor-mediated depolarization of the plasma membrane, the mechanism involved in the delayed inhibition is the subject of the present investigation. GABA (1 nM-10 μM) decreased the intracellular concentration of cyclic adenosine monophosphate (cAMP) in a dose- and time-dependent fashion. This effect was blocked by bicuculline and mimicked by muscimol but not by baclofen. To analyze the effect of GABA on cellular excitability, we used fura-2 loaded GT1-7 cells. Activation of voltage-sensitive calcium channels by high K⁺-induced depolarization (35 mM) increased [Ca²⁺]_i. GABA (10μM) and muscimol (10 μM) reduced the amplitude of K⁺-induced [Ca²⁺]_i transients. This inhibition was blocked by forskolin (20μM) or 8-Br-cAMP (1 mM). Altogether, these results show that GABA_A receptors mediate a sustained inhibitory effect of GABA on GnRH neurons, and suggest the involvement of the cAMP pathway decreasing cellular excitability.     

Expression of mammalian gamma-aminobutyric acid receptors with distinct pharmacology in Xenopus oocytes.

Gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in mammalian brain, is known to interact with two classes of GABA receptors denoted GABAA and GABAB. Using Xenopus oocytes, we compared the electrical and pharmacological properties of GABA receptors expressed by poly(A)+ RNA isolated from mammalian brain and retina. RNA from cerebral cortex expressed GABA responses with features characteristic of currents mediated by GABAA receptors. In contrast, RNA from retina expressed responses mediated by GABAA receptors and, in addition, GABA responses that were insensitive to the GABAA antagonist bicuculline and the GABAB agonist baclofen and showed no modulation by barbiturates or benzodiazepines. The bicuculline/baclofen-insensitive GABA response was a Cl- current that was blocked by picrotoxin but showed little desensitization or outward rectification. Our results suggest that mammalian retina contains RNAs encoding GABA receptors with distinct pharmacology.