GABA-ergic control of alpha-melanocyte-stimulating hormone (alpha-MSH) release by frog neurointermediate lobe in vitro

Measurement of glutamate decarboxylase (GAD) activity in the intermediate lobe of the frog pituitary and brain showed that neurointermediate lobe extracts represented 12% of the GAD activity detected in the whole brain. No significant activity was measured in distal lobe extracts. Immunocytochemical studies revealed GAD-containing fibers among the parenchymal cells of the pars intermedia. The localization of GAD-like material in the intermediate lobe of the frog pituitary suggested a possible role of gamma-aminobutyric acid (GABA) in the regulation of melanotropic cell secretion. Administration of GABA (10(-6) to 10(-4) M), to perifused neurointermediate lobes caused a brief stimulation of alpha-melanocyte stimulating hormone (alpha-MSH) release followed by an inhibition. Picrotoxin (10(-4) M), a Cl- channel blocker, abolished only the stimulatory effect of GABA (10(-4) M), whereas bicuculline (10(-4) M), a specific antagonist of GABAA receptors, totally inhibited the effects of GABA (both stimulatory and inhibitory phases). Bicuculline induced by itself a slight stimulation of alpha-MSH release, suggesting that GABA-ergic nerve fibers present in the intermediate lobe are functionally active in vitro. The GABAA agonist muscimol (10(-7) to 10(-4) M) mimicked the biphasic effect of GABA on alpha-MSH release. Administration of baclofen, a specific GABAB agonist (10(-7) to 10(-4) M) induced a dose-dependent inhibition of alpha-MSH secretion. In contrast to GABA or muscimol, baclofen did not cause any stimulatory effect whatever the dose. Taken together these result suggested that GABAA and GABAB receptors were present on frog melanotrophs.(ABSTRACT TRUNCATED AT 250 WORDS)     

gamma-Aminobutyric acid inhibits the release of alpha-melanocyte-stimulating hormone from rat hypothalamic slices

The effect of gamma-aminobutyric acid (GABA) on release of alpha-melanocyte-stimulating hormone (alpha-MSH) from hypothalamic neurons was investigated in vitro using the perifusion technique. Rat hypothalamic slices were continuously superfused with Krebs-Ringer medium and the release of alpha-MSH in the effluent perifusate was monitored by means of a sensitive and specific radioimmunoassay method. Infusion of 50 mM K+ for 15 min induced a transient increase of alpha-MSH release (5- to 8-fold above the spontaneous level). Infusion of the same dose of K+ for 75 min caused a brief discharge of alpha-MSH during the first 30 min followed by sustained release of the neuropeptide. The effect of GABA was investigated 27 min after the onset of KCl infusion. Application of GABA (5 x 10(-5) M) resulted in a significant and reversible inhibition of K+-induced alpha-MSH release. The GABAA agonist, muscimol (10(-4) M), produced a prolonged inhibition of K+-evoked alpha-MSH release, while the GABAB agonist, baclofen (10(-4) M), was devoid of effect on hypothalamic alpha-MSH release. Bicuculline (10(-4) M), a specific GABAA antagonist, had no effect when added alone to the medium but totally reversed the inhibitory effect of GABA on K+-induced alpha-MSH release. Taken together, these data suggest that exogenous GABA exerts an inhibitory control on alpha-MSH neurons. Our data also show that the effect of GABA on alpha-MSH release by hypothalamic neurons is mediated through GABAA-type receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Molecular biology and ontogeny of gamma-aminobutyric acid (GABA) receptors in the mammalian central nervous system

gamma-Aminobutyric acid (GABA) is the predominant inhibitory neurotransmitter in the mammalian central nervous system. After release from nerve terminals, GABA binds to at least two classes of postsynaptic receptors (ie, GABAA and GABAB), which are nearly ubiquitous in the brain. GABAA receptors are postsynaptic heteropentameric complexes that display unique physiologic and pharmacologic properties based on subunit composition. Activation of GABAA receptors in mature neurons results in membrane hyperpolarization, which is mediated principally by inward chloride flux, whereas in early stages of brain development, GABAA receptor activation causes depolarization of the postsynaptic membrane. GABA, receptors reside both presynaptically and postsynaptically, exist as heterodimers and are coupled to voltage-dependent ion channels through interactions with heterotrimeric G proteins. This review summarizes the molecular biology and ontogeny of GABAA and GABAB receptors, highlighting some of their putative roles during normal brain development as well as in disease states such as epilepsy.     

Serotonin-induced depolarization of rat facial motoneurons in vivo: Comparison with amino acid transmitters

Intracellular recordings were obtained from facial motoneurons in anesthetized rats. The effects of iontophoretically applied serotonin were compared to those of the excitatory amino acids glutamate and DL-homocysteic acid (DLH), and the inhibitory amino acids, glycine, GABA and muscimol, under various conditions of membrane polarization and intracellular chloride concentration. Iontophortically applied serotonin caused a depolarization of facial motoneurons which was accompanied by increased input resistance and increased neuronal excitability. Experiments comparing the response to serotonin with those of glycine, GABA, and muscimol demonstrated that the serotonin effect does not involve changes in membrane conductance to chloride. Comparisons of serotonin with glutamate and DLH at varying levels of membrane hyperpolarization indicated that the serotonin-induced depolarization is not caused by increased conductance to sodium or calcium, and differs in its underlying ionic mechanism from depolarizations induced by glutamate and DLH. Results were consistent with the hypothesis that serotonin causes depolarization, increased input resistance, and increased excitability in rat facial motoneurons by decreasing resting membrane conductance to potassium ions. Such changes in motoneurons in the brain stem and spinal cord probably account for some of the physiological and behavioral effects observed during pharmacological activation of serotonin receptors.     

GABA-mediated positive autofeedback loop controls horizontal cell kinetics in tiger salamander retina.

Horizontal cells (HCs) appear to release, and also to be sensitive to, GABA. The external GABA concentration is increased with depolarization of the HC membrane via an electrogenic GABA transporter. This extracellular GABA opens a GABAA-gated Cl- channel in the HC membrane. Since the equilibrium potential for Cl- (ECl) is near -20 mV, GABA released by the HC further depolarizes the HC. The GABA transporter and the GABAA receptor thus constitute a positive feedback loop in the HC membrane. This loop can slow down the kinetics of the light responses in HCs. GABA released via the GABA transporter can affect the GABAA receptor, probably because diffusion from the extracellular space is normally restricted by the intact retinal structure. We therefore used retinal slices rather than isolated HCs to maintain that structure. To measure single-cell currents in the slice, HCs were electrically uncoupled by including cAMP in the patch pipette. Under these conditions, bath application of GABA elicited two currents: (1) a picrotoxin-blocked current reversing near ECl, probably mediated by GABAA receptors, and (2) a picrotoxin-insensitive current similar to that elicited by cis-4-hydroxynipecotic acid (NIP) shown in other preparations to act at the GABA transporter. Under physiological conditions, the HC membrane potential is controlled by two major conductances, the GABAA-gated Cl- conductance described above, and the glutamate-gated conductance modulated by photoreceptor input. A bright light flash eliminates the glutamate-gated conductance, leaving only the GABA-gated Cl- conductance to control the membrane. With the Cl- conductance a significant fraction of the overall membrane conductance the GABAergic positive feedback loop can decrease the response kinetics. We increased the ambient extracellular GABA concentration by adding 50 microM GABA to the extracellular medium. This increased the ambient Cl- conductance, but the transporter still modulated Cl- conductance because responses to light stimuli were significantly slowed. The slowdown of the HC response could be reversed by interrupting the loop in two ways: (1) picrotoxin opened the loop and speeded the responses by uncoupling the GABA concentration from control of the membrane conductance, and (2) NIP opened the loop by uncoupling the extracellular GABA concentration from the Cl- conductance and therefore the membrane potential.(ABSTRACT TRUNCATED AT 400 WORDS)     

GABAA and GABAB receptors are functionally active in the regulation of catecholamine secretion by bovine chromaffin cells

GABA stimulates the basal catecholamine release from adrenal bovine chromaffin cells in a calcium-dependent manner. This release represents about 70% of that obtained by similar doses of nicotine under similar experimental conditions. This effect is mediated by GABAA receptor sites present in chromaffin cells, since it was mimicked by muscimol and reversed by bicuculline. In addition, GABA, through its GABAA receptors, increases the catecholamine release evoked by submaximal doses of nicotine, but it has no effect on nicotine-evoked secretion of catecholamines when nicotine was given at maximal doses. These results seem to indicate that both nicotine and GABA release catecholamines from the same intracellular pool. In contrast, baclofen, a GABAB receptor agonist, depressed both basal and nicotine-evoked catecholamine release; this result indicates that in addition to GABAA control of catecholamine secretion by chromaffin cells, there is a GABAB control of this function. These results support the existence of a dual regulation of catecholamine secretion by both the GABAA and GABAB receptors in a similar way as that proposed for muscarinic and nicotinic cholinergic receptors.     

Conformational specificity of GABA binding to the presynaptic GABAA receptor.

GABAA receptors on the synaptic terminal of retinal bipolar neurons mediate the inhibition by GABA of presynaptic calcium influx in these non-spiking interneurons. To characterize the conformational specificity of GABA binding to the receptor underlying this presynaptic inhibition, we have recorded the conductance change induced in isolated bipolar cells by GABA and by two conformationally locked analogs of GABA, cis- and trans-4-aminocrotonic acid (ACA). Trans-ACA (the extended conformation) is more potent than GABA in activating the GABAA chloride conductance of the synaptic terminal, while cis-ACA (the folded conformation) is 20-fold less potent than GABA. These results show that the extended conformation of GABA is the preferred form for the presynaptic GABAA receptor.     

GABAA receptor mediated elevation of Ca2+ and modulation of gonadotrophin-releasing hormone action in alphaT3-1 gonadotropes

gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter in the CNS, mediating fast inhibitory synaptic transmission, by activating GABAA receptors. However, these GABA-gated Cl- channels can also be excitatory, causing depolarization, and increasing Ca2+ entry via voltage-operated Ca2+ channels (VOCCs). Evidence exists for excitatory ionotropic GABA receptors in anterior pituitary cells, including gonadotropes, but these have not been directly characterized and their pharmacology remains controversial. Here we have measured the cytosolic Ca2+ concentration ([Ca2+]i) in alphaT3-1 gonadotropes, to test for expression of excitatory GABA receptors. The GABAA agonists, GABA and muscimol, both caused rapid, robust and dose-dependent increases in [Ca2+]i (EC50 values 2.7 and 1 microM), whereas the GABAB agonist, baclofen, did not. The GABAA antagonist, bicuculline, inhibited muscimol's effect, whereas the GABAB antagonist, phaclofen, did not. The neuroactive steroid 5alpha-pregnan-3alpha-ol-11,20-dione (an allosteric activator of GABAA receptors) increased [Ca2+]i, and this effect, like that of muscimol, was inhibited by picrotoxin. The muscimol effect on [Ca2+]i was blocked by the VOCC antagonist, nifedipine, or by Ca2+-free medium. When cells were pretreated with muscimol this increased the spike phase of the [Ca2+]i response to subsequent stimulation with gonadotropin-releasing hormone (GnRH). Similar amplification was seen in muscimol-pretreated cells stimulated with GnRH in Ca2+-free medium, but not when cells were pretreated with muscimol in Ca2+-free medium. The amplification was not, however, GnRH receptor-specific, because the spike response to ionomycin was also increased by muscimol pretreatment. These data provide the first direct evidence for expression of excitatory GABAA receptors, and the first demonstration of acute steroid effects, on GnRH-responsive pituitary cells. They also reveal a novel mechanism by which GABAA activation modulates GnRH action, raising the possibility that this may also influence gonadotrophin secretion from non-immortalized gonadotropes.     

Direct muscarinic and nicotinic receptor-mediated excitation of rat medial vestibular nucleus neurons in vitro

We have utilized intracellular recording techniques to investigate the cholinoceptivity of rat medial vestibular nucleus (MVN) neurons in a submerged brain slice preparation. Exogenous application of the mixed cholinergic agonists, acetylcholine (ACh) or carbachol (CCh), produced predominantly membrane depolarization, induction of action potential firing, and decreased input resistance. Application of the selective muscarinic receptor agonist muscarine (MUSC), or the selective nicotinic receptor agonists nicotine (NIC) or 1,1-dimethyl-4-phenylpiperazinium (DMPP) also produced membrane depolarizations. The MUSC-induced depolarization was accompanied by decreased conductance, while an increase in conductance appeared to underlie the NIC- and DMPP-induced depolarizations. The muscarinic and nicotinic receptor mediated depolarizations persisted in tetrodotoxin and/or low Ca²⁺/high Mg²⁺ containing media, suggesting direct postsynaptic receptor activation. The MUSC-induced depolarization could be reversibly blocked by the selective muscarinic-receptor antagonist, atropine, while the DMPP-induced depolarization could be reversibly suppressed by the selective ganglionic nicotinicreceptor antagonist, mecamylamine. Some neurons exhibited a transient membrane hyperpolarization during the depolarizing response to CCh or MUSC application. This transient inhibition could be reversibly blocked by the γ-aminobutyric acid (GABA) antagonist, bicuculline, suggesting that the underlying hyperpolarization results indirectly from the endogenous release of GABA acting at GABA receptors. This study confirms the cholinoceptivity of MVN neurons and establishes that individual MVN cells possess muscarinic as well as nicotinic receptors. The data provide support for a prominent role of cholinergic mechanisms in the direct and indirect regulation of the excitability of MVN neurons.     

Relationship between tolerance to GABAA agonist and bursting properties in neocortical neurons during GABA-withdrawal syndrome

The interruption of intracortical, chronic GABA infusion is known to give rise to 'GABA withdrawal syndrome' (GWS) consisting of electroencephalographic paroxysmal focal activities, associated with behavioral epileptic signs. Neocortical slices were obtained from rats presenting the GWS (GWS slices), and intracellular recordings were performed in the vicinity of the gamma-aminobutyric acid (GABA)-infused site. Electrical stimulation of the underlying white matter induced paroxysmal depolarization shifts (PDSs) in virtually all neurons. Bath-applied GABA (1-10 microM) had no effect on these neurons, while the same dose range was found effective in blocking action potentials in saline-infused cortex slices obtained from control rats. In the GWS slices a population of neurons presented, in addition to synaptically induced PDSs, voltage-dependent and cobalt-sensitive PDSs and bursts of action potentials induced by depolarizing current injections. These intrinsic bursting neurons were unresponsive to high doses of GABA (100 microM). Dose-response curves of isoguvacine, a specific GABAA agonist, showed a shift to the right for the intrinsic bursting cells whatever the parameter measured (depolarization or conductance increase): the ED50 was 50-100 times higher for intrinsic bursting cells than for other non-intrinsic bursting cells, thus indicating that intrinsic bursting cells are tolerant to GABAA agonist. This tolerance may result from a decreased number of receptors or from a change in their properties as a consequence of the previous prolonged GABA infusion. The decrease in the GABA efficacy could lead to disinhibition and could thus give the appearance of epileptic events.     

Voltage-clamp studies of the inhibition of gamma-aminobutyric acid response by glucocorticoids in bullfrog primary afferent neurons

Acute effects of glucocorticoids on the response to gamma-aminobutyric acid (GABA) were examined in primary afferent neurons in bullfrog spinal ganglia, using intracellular and voltage-clamp recording techniques. Prednisolone and hydrocortisone (5 microM to 1 mM) caused a dose-dependent decrease in the amplitude of GABA-induced depolarization, while having no effect on the membrane potential and resistance of the neuron. Prednisolone depressed the muscimol-induced depolarization. Nipecotic acid, a blocker of GABA uptake, did not influence the inhibitory action of prednisolone. Voltage-clamp analyses showed that the inward current induced by an iontophoretic application of GABA (GABA current) was suppressed by prednisolone and hydrocortisone. The depression of the GABA current is neither due to a blockage of open channels nor a facilitation of the desensitization of GABA receptors. Prednisolone shifted the dose-response curve of the GABA current downward. The double-reciprocal (Lineweaver-Burk) plot showed that the maximum GABA current was reduced by prednisolone, suggesting a non-competitive antagonism. These results suggest that glucocorticoids suppress the GABA-induced chloride current, decreasing the number of functional channels associated with GABAA receptor.     

Chloride channels activated by gamma-aminobutyric acid in normal bovine lactotrophs

The effect of gamma-aminobutyric acid (GABA) on normal bovine lactotrophs was investigated using the patch clamp technique. GABA application (1-10 microM) induced fluctuations of membrane current, accompanied by an increase in inward current. The mean conductance of GABA-activated channels was estimated to be 19 pS from statistical analysis of these fluctuations whereas the mean conductance for GABA-activated single ion channels was 16 pS. The reversal potential of the current was near to the equilibrium potential for chloride ions. These results indicate that the one possible mechanism for inhibition of prolactin release induced by GABA is probably mediated by activation of chloride channels.     

GABA induces norepinephrine exocytosis from hippocampal noradrenergic axon terminals by a dual mechanism involving different voltage-sensitive calcium channels.

GABA can evoke norepinephrine (NE) release by activating GABAA receptors or GABA transporters on noradrenergic terminals. The heterocarrier-induced release occurs by conventional exocytosis. We here characterized the mechanism of the GABAA receptor-induced release and investigated what type(s) of voltage-sensitive Ca2+ channels (VSCCs) are involved in the GABA heterocarrier and GABA(A) receptor-evoked release. The effect of GABA in superfused rat hippocampal synaptosomes prelabeled with [(3)H]-NE was partially prevented by bicuculline or the GABA uptake inhibitor SKF 89976A and abolished by blocking both GABAA receptors and GABA transporters. The release elicited through GABAA receptors was Ca2+-dependent, prevented by Cd2+ or by botulinum toxin C, and modulated through alpha2 autoreceptors. The GABAA receptor-evoked release was insensitive to nifedipine and to omega-conotoxin MVIIC, but was inhibited ( approximately 50%) by omega-conotoxin GVIA. The heterocarrier-evoked release, nifedipine-insensitive, was inhibited approximately 30% either by omega-conotoxin GVIA or by omega-conotoxin MVIIC; the combined toxins produced approximately 60% inhibition. To conclude: a) the releases of NE evoked by activation of GABA(A) receptors and GABA heterocarriers are additive, although they both occur by conventional exocytosis; b) the heterocarrier-induced release requires activation of N and P/Q type channels, whereas the GABAA receptor-induced release only involves channels of the N type.     

Activation of GABAA receptors causes presynaptic and postsynaptic inhibition at synapses between muscle spindle afferents and motoneurons in the spinal cord of bullfrogs

The functional role of GABAA receptors in inhibition of synaptic transmission between muscle spindle afferents and spinal motoneurons was studied in the isolated spinal cord of bullfrogs. Extracellular recording from the ventral root showed that activation of GABAA receptors by muscimol (primarily a GABAA receptor agonist) at 50 microM produced a 38% reduction in the amplitude of the excitatory postsynaptic potential (EPSP) evoked by stimulation of triceps muscle sensory afferents and a 66% reduction in the EPSP half-width, suggesting a large increase in the conductance of the motoneuronal membrane. Quantal analysis of unitary triceps EPSPs recorded intracellularly from motoneurons showed that muscimol reduced the quantal content of release (presynaptic inhibition). In addition, muscimol decreased the quantal size (postsynaptic inhibition) when the postsynaptic conductance change was large. Because the effects of muscimol were completely and reversibly blocked by 100 microM bicuculline (a specific GABAA receptor antagonist), both the pre- and the postsynaptic inhibition caused by muscimol were due to activation of GABAA receptors. Activation of GABAA receptors thus causes both pre- and postsynaptic inhibition of synaptic transmission between muscle afferents and spinal cord motoneurons in the frog.     

Effect of benzodiazepines and pentobarbital on the GABA-induced depolarization in cultured astrocytes

We have previously shown that cultured astrocytes from neonatal rat cerebral cortex are depolarized by GABA. The underlying ionic mechanism, activation of a Cl- conductance and responses to an agonist and antagonists were found to be similar to those of the neuronal GABAA receptor (Kettenmann et al.: Brain Research 404:1-9, 1987; Kettenmann and Schachner: Journal of Neuroscience 5:3295-3301, 1985). To characterize further the pharmacological properties of the GABA receptor we have tested the influence of pentobarbital and benzodiazepines on the GABA response. Pentobarbital potentiated and prolonged the GABA-induced depolarization and enhanced the velocity of the depolarization. Agonists of the neuronal benzodiazepine receptor, flunitrazepam, diazepam, and midazolam, increased the GABA-induced depolarization. As in neurons, an antagonist of the benzodiazepine receptor, Ro 15-1788, blocked the flunitrazepam-induced enhancement of the GABA response. In contrast to their effects on neurons, the inverse agonists Ro 22-7497 and DMCM increased the GABA-induced depolarization. The ligand of the putative peripheral benzodiazepine binding site, Ro 5-4864, did not show consistent effects on the GABA response. These studies confirm that cultured astrocytes express GABAA receptors. This receptor is similar to the neuronal GABAA receptor with regard to Cl- conductance and its pharmacological responses to muscimol, bicuculline, picrotoxin, pentobarbital, and benzodiazepine agonists and an antagonist, but it is different in its responses to inverse agonists of the benzodiazepine site. The physiological role of the glial GABAA receptor is at present unknown.     

The effect of D-aspartate on luteinizing hormone-releasing hormone,alpha-melanocyte-stimulating hormone,GABA and dopamine release

Since D-aspartate stimulates prolactin and LH release, our objective was to determine whether D-aspartate modifies the release of hypothalamic and posterior pituitary factors involved in the control of their secretion and whether its effects on these tissues are exerted through NMDA receptors and mediated by nitric oxide. In the hypothalamus, D-aspartate stimulated luteinizing hormone-releasing hormone (LHRH), alpha-melanocyte-stimulating hormone (alpha-MSH) and GABA release and inhibited dopamine release through interaction with NMDA receptors. It increased nitric oxide synthase (NOS) activity, and its effects on LHRH and hypothalamic GABA release were blunted when NOS was inhibited. In the posterior pituitary gland, D-aspartate inhibited GABA release but had no effect on dopamine or alpha-MSH release. We report that D-aspartate differentially affects the release of hypothalamic and posterior pituitary factors involved in the regulation of pituitary hormone secretion.     

Electrophysiology of the GABAergic synapses

GABA is the most widely distributed inhibitory transmitter in the brain, and it acts commonly by augmenting chloride permeability. When resting membrane potential (Vm) is equal to chloride equilibrium potential (EC1) GABA tends to keep Vm to its resting value. In some synapses, a pump carries chloride actively out of the cell and EC1 is different from Vm. An increased permeability leads to a hyperpolarization. In presynaptic inhibition a chloride pump brings chloride ions actively inside the cell and an increased permeability leads to a depolarization. GABAA receptors are associated with chloride channels, whereas GABAB receptors cause a selective decrease of a voltage sensitive calcium channels which operates at synaptic terminals.     

Chemoreceptors for serotonin (5-HT), acetylcholine (ACh), bradykinin (BK), histamine (H) and γ-aminobutyric acid (GABA) on rabbit visceral afferent neurons

The somata of type ‘C’ neurons in rabbit nodose ganglion are endowed with receptor sites for 5-HT, BK, ACh, II and GABA. 5-HT and ACh application to type ‘C’ neurons in the nodose ganglion of rabbits produced a rapid depolarization associated with an increased membrane conductance, most likely to Na⁺ and K⁺. BK and H elicited slow depolarizations accompanied by a decreased membrane conductance probably to K⁺. GABA induced a rapid depolarization associated with an increased conductance to Cl⁻. In contrast, type ‘A’ neurons were insensitive to the four algesic agents but responded to GABA. d-Tubocurarine or picrotoxin at relatively low concentrations blocked ACh, 5-HT and GABA depolarizations without affecting membrane properties. Hexamethonium blocked ACh responses but not 5-HT responses. In addition, no desensitization occurred between the substances 5-HT, ACh or BK. The results suggest that the depolarizing effect of these agents on visceral neurons might be exerted via different receptors.     

The GABAA receptor: new insights from single-channel recording

The GABAA receptor of mammalian neurons exists as a macromolecular complex incorporating several interacting components. These include a chloride-permeable ion channel and a recognition site for GABA. The binding of GABA molecules at the latter site triggers the transient opening of the chloride ion channel, resulting in a flow of charge which inhibits the generation of action potentials in the cell. The precise amount of charge passed during this event is modulated by ligand binding at at least three regulatory sites. These sites act as receptors for barbiturates, benzodiazepines, and certain convulsants. The extracellular patch clamp method has now been used to study the gating of chloride channels by GABA and the modulation of this process by drugs. Even in the absence of drugs, GABAA channels exhibit complex gating behavior, indicating the presence of multiple open and closed states and of substate conductance levels. GABAA channels from different preparations show considerable diversity in their detailed gating characteristics. In the presence of the barbiturate pentobarbital, GABAA channels open in prolonged bursts, consistent with the potentiating effect of this drug on macroscopic GABA responses. In contrast, the convulsant penicillin decreases charge transfer through open GABAA channels by shortening the average duration of the open state. Benzodiazepine receptor ligands exert complex effects on the GABAA channel. A general model of barbiturate and benzodiazepine potentiation of GABAA receptor responses is proposed.     

Synaptic signaling between neurons and glia

Rapid signaling between vertebrate neurons occurs primarily at synapses, intercellular junctions where quantal release of neurotransmitter triggers rapid changes in membrane conductance through activation of ionotropic receptors. Glial cells express many of these same ionotropic receptors, yet little is known about how receptors in glial cells become activated in situ. Because synapses were thought to be the sole provenance of neurons, it has been assumed that these receptors must be activated following diffusion of transmitter out of the synaptic cleft, or through nonsynaptic mechanisms such as transporter reversal. Two recent reports show that a ubiquitous class of progenitors that express the proteoglycan NG2 (NG2 cells) engage in rapid signaling with glutamatergic and gamma-aminobutyric acid (GABA)ergic neurons through direct neuron-glia synapses. Quantal release of transmitter from neurons at these sites triggers rapid activation of aminomethylisoxazole propionic acid (AMPA) or GABA(A) receptors in NG2 cells. These currents exhibit properties consistent with direct rather than spillover-mediated transmission, and electron micrographic analyses indicate that nerve terminals containing clusters of synaptic vesicles form discrete junctions with NG2 cell processes. Although activation of AMPA or GABA(A) receptors depolarize NG2 cells, these receptors are more likely to serve as routes for ion flux rather than as current sources for depolarization, because the amplitudes of the synaptic transients are small and the resting membrane potential of NG2 cells is highly negative. The ability of both glutamate and GABA to influence the morphology, physiology, and development of NG2 cells in vitro suggests that this rapid form of signaling may play important roles in adapting the behavior of these cells to the needs of surrounding neurons in vivo.