Neurite outgrowth-regulating properties of GABA and the effect of serum on mouse spinal cord neurons in culture. (1/1111)

Time-lapse photography was used to examine the effects of gamma-aminobutyric acid (GABA) on the outgrowth and motility of neurites in cultures from mouse spinal cord. GABA at concentrations of 100, 10 and 1 microM caused significant inhibition of neurite outgrowth and the motility of growth cones was significantly reduced by treatment with 100 and 10 microM GABA. This effect was mimicked by the GABA(B) receptor agonist baclofen, whereas the GABA(A) receptor agonist muscimol had no effect. The effect of GABA on outgrowth and motility seems to be dependent on the type of serum employed. The results reported here were obtained only when heat-inactivated serum was used and not when non heat-inactivated serum was added to the culture medium. They suggest that GABA has a role in the regulation of process outgrowth within the embryonic mouse spinal cord.  (+info)

Corticofugal amplification of facilitative auditory responses of subcortical combination-sensitive neurons in the mustached bat. (2/1111)

Recent studies on the bat's auditory system indicate that the corticofugal system mediates a highly focused positive feedback to physiologically "matched" subcortical neurons, and widespread lateral inhibition to physiologically "unmatched" subcortical neurons, to adjust and improve information processing. These findings have solved the controversy in physiological data, accumulated since 1962, of corticofugal effects on subcortical auditory neurons: inhibitory, excitatory, or both (an inhibitory effect is much more frequent than an excitatory effect). In the mustached bat, Pteronotus parnellii parnellii, the inferior colliculus, medial geniculate body, and auditory cortex each have "FM-FM" neurons, which are "combination-sensitive" and are tuned to specific time delays (echo delays) of echo FM components from the FM components of an emitted biosonar pulse. FM-FM neurons are more complex in response properties than cortical neurons which primarily respond to single tones. In the present study, we found that inactivation of the entire FM-FM area in the cortex, including neurons both physiologically matched and unmatched with subcortical FM-FM neurons, on the average reduced the facilitative responses to paired FM sounds by 82% for thalamic FM-FM neurons and by 66% for collicular FM-FM neurons. The corticofugal influence on the facilitative responses of subcortical combination-sensitive neurons is much larger than that on the excitatory responses of subcortical neurons primarily responding to single tones. Therefore we propose the hypothesis that, in general, the processing of complex sounds by combination-sensitive neurons more heavily depends on the corticofugal system than that by single-tone sensitive neurons.  (+info)

A single hydrophobic residue confers barbiturate sensitivity to gamma-aminobutyric acid type C receptor. (3/1111)

Barbiturate sensitivity was imparted to the human rho1 homooligomeric gamma-aminobutyric acid (GABA) receptor channel by mutation of a tryptophan residue at position 328 (Trp328), which is located within the third transmembrane domain. Substitutions of Trp328 with a spectrum of amino acids revealed that nearly all hydrophobic residues produced receptor channels that were both directly activated and modulated by pentobarbital with similar sensitivities. Previous studies with ligand-gated ion channels (including GABA) have demonstrated that even conservative amino acid substitution within the agonist-dependent activation domain (N-terminal extracellular domain) can markedly impair agonist sensitivity. Thus, the lack of significant variation in pentobarbital sensitivity among the Trp328 mutants attests to an intrinsic difference between pentobarbital- and the GABA-dependent activation domain. Compared with the heterooligomeric alphabetagamma receptor channel, the mode of modulation for homooligomeric Trp328 mutants by pentobarbital was more dependent on the GABA concentration, yielding potentiation only at low concentrations of GABA (fractions of their respective EC50 values), yet causing inhibition at higher concentrations. Agonist-related studies have also demonstrated that residue 328 plays an important role in agonist-dependent activation, suggesting a functional interconnection between the GABA and pentobarbital activation domains.  (+info)

Selective pruning of more active afferents when cat visual cortex is pharmacologically inhibited. (4/1111)

Activity-dependent competition is thought to guide the normal development of specific patterns of neural connections. Such competition generally favors more active inputs, making them larger and stronger, while less active inputs become smaller and weaker. We pharmacologically inhibited the activity of visual cortical cells and measured the three-dimensional structure of inputs serving the two eyes when one eye was occluded. The more active inputs serving the open eye actually became smaller than the deprived inputs from the occluded eye, which were similar to those in normal animals. These findings demonstrate in vivo that it is not the amount of afferent activity but the correlation between cortical and afferent activity that regulates the growth or retraction of these inputs.  (+info)

Carbamazepine facilitates effects of GABA on rat hippocampus slices. (5/1111)

AIM: To study the influence of carbamazepine (Car) on GABA effect in hippocampus. METHODS: Evoked potentials were recorded on pyramidal cells in CA1 after stimulation (0.5 Hz, 50 microseconds) to Schaffer collaterals in rat hippocampal slices (350 microns). RESULTS: Car 0.1 and 0.2 mmol.L-1 did not affect field potentials, whereas Car 0.2 mmol.L-1 plus GABA (0.1-1 mmol.L-1) gave rise to a stronger inhibition on field potentials than that of GABA alone. Bicuculline did not reverse Car facilitation on GABA inhibition on field potentials. (-)-Baclofen was more effective in inhibiting field potentials than GABA. Car 0.2 mmol.L-1 plus (-)-baclofen (1-5 mumol.L-1) brought an inhibition stronger than that of (-)-baclofen alone. CONCLUSION: Car facilitates the effects of GABA on pyramidal cells in hippocampal CA1 region, probably related to GABAB receptors.  (+info)

The role of gamma-hydroxybutyric acid in the treatment of alcoholism: from animal to clinical studies. (6/1111)

Since its discovery nearly 40 years ago, gamma-hydroxybutyric acid (GHB) has attracted several waves of scientific interest due to new developments in the knowledge of its mechanisms of action and ideas for its potential use in clinical practice. Its effects have been claimed to treat different psychiatric conditions, but over time its use has become limited to a few specific situations (e.g. sedating patients in non-painful surgical procedures and narcolepsy). New interest in the drug derives from its potential use in the treatment of alcoholism. Recent studies demonstrated a marked effect of the substance in suppressing ethanol (ETOH) withdrawal symptoms and in reducing craving for alcohol, compared to other available drugs. However, GHB has to be given under very careful supervision because of its side-effects, including the risk of abuse and dependence and possible interference with the metabolic pathways of endogenous GHB and ETOH. This short review discusses these and related issues and we hope that it will stimulate further interest in GHB.  (+info)

Tonic activation of presynaptic GABAB receptors in the opener neuromuscular junction of crayfish. (7/1111)

Release of excitatory transmitter from boutons on crayfish nerve terminals was inhibited by (R,S)-baclofen, an agonist at GABAB receptors. Baclofen had no postsynaptic actions as it reduced quantal content without affecting quantal amplitude. The effect of baclofen increased with concentration producing 18% inhibition at 10 microM; EC50, 50% inhibition at 30 microM; maximal inhibition, 85% at 100 microM and higher. There was no desensitization, even with 200 or 320 microM baclofen. Phaclofen, an antagonist at GABAB receptors, competitively antagonized the inhibitory action of baclofen (KD = 50 microM, equivalent to a pA2 = 4.3 +/- 0.1). Phaclofen on its own at concentrations below 200 microM had no effect on release, whereas at 200 microM phaclofen itself increased the control level of release by 60%, as did 2-hydroxy-saclofen (200 microM), another antagonist at GABAB receptors. This increase was evidently due to antagonism of a persistent level of GABA in the synaptic cleft, since the effect was abolished by destruction of the presynaptic inhibitory fiber, using intra-axonal pronase. We conclude that presynaptic GABAB receptors, with a pharmacological profile similar to that of mammalian GABAB receptors, are involved in the control of transmitter release at the crayfish neuromuscular junction.  (+info)

Inhibitory nature of tiagabine-augmented GABAA receptor-mediated depolarizing responses in hippocampal pyramidal cells. (8/1111)

Tiagabine is a potent GABA uptake inhibitor with demonstrated anticonvulsant activity. GABA uptake inhibitors are believed to produce their anticonvulsant effects by prolonging the postsynaptic actions of GABA, released during episodes of neuronal hyperexcitability. However, tiagabine has recently been reported to facilitate the depolarizing actions of GABA in the CNS of adult rats following the stimulation of inhibitory pathways at a frequency (100 Hz) intended to mimic interneuronal activation during epileptiform activity. In the present study, we performed extracellular and whole cell recordings from CA1 pyramidal neurons in rat hippocampal slices to examine the functional consequences of tiagabine-augmented GABA-mediated depolarizing responses. Orthodromic population spikes (PSs), elicited from the stratum radiatum, were inhibited following the activation of recurrent inhibitory pathways by antidromic conditioning stimulation of the alveus, which consisted of either a single stimulus or a train of stimuli delivered at high-frequency (100 Hz, 200 ms). The inhibition of orthodromic PSs produced by high-frequency conditioning stimulation (HFS), which was always of much greater strength and duration than that produced by a single conditioning stimulus, was greatly enhanced following the bath application of tiagabine (2-100 microM). Thus, in the presence of tiagabine (20 microM), orthodromic PSs, evoked 200 and 800 ms following HFS, were inhibited to 7.8 +/- 2.6% (mean +/- SE) and 34.4 +/- 18.5% of their unconditioned amplitudes compared with only 35.4 +/- 12.7% and 98.8 +/- 12.4% in control. Whole cell recordings revealed that the bath application of tiagabine (20 microM) either caused the appearance or greatly enhanced the amplitude of GABA-mediated depolarizing responses (DR). Excitatory postsynaptic potentials (EPSPs) evoked from stratum radiatum at time points that coincided with the DR were inhibited to below the threshold for action-potential firing. Independently of the stimulus intensity with which they were evoked, the charge transferred to the soma by excitatory postsynaptic currents (EPSCs), elicited in the presence of tiagabine (20 microM) during the large (1,428 +/- 331 pA) inward currents that underlie the DRs, was decreased on the average by 90.8 +/- 1.7%. Such inhibition occurred despite the presence of the GABAB receptor antagonist, CGP 52 432 (10 microM), indicating that GABAB heteroreceptors, located on glutamatergic terminals, do not mediate the observed reduction in the amplitude of excitatory postsynaptic responses. The present results suggest that despite facilitating the induction of GABA-mediated depolarizations, tiagabine application may nevertheless increase the effectiveness of synaptic inhibition during the synchronous high-frequency activation of inhibitory interneurons by enhanced shunting.  (+info)