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PubMed2001

Corticotropin-releasing factor is preferentially colocalized with excitatory rather than inhibitory amino acids in axon terminals in the peri-locus coeruleus region.

Corticotropin-releasing factor(CRF)-immunoreactive terminals form synaptic specializations with locus coeruleus (LC) dendrites in rat brain. Within these terminals, CRF-immunoreactive dense core vesicles are colocalized with non-labeled dense core vesicles and clear vesicles, implicating other neuromodulators in the actions of CRF on LC neurons. Excitatory (glutamate) and inhibitory (GABA) amino acid afferents to the LC, have been identified which regulate noradrenergic responses to sensory stimuli. This study was designed to determine whether these amino acid neurotransmitters are colocalized with CRF in terminals within the LC/peri-LC region in the rat. Sections through the LC region that were dually labeled using immunohistochemical techniques to visualize either CRF and glutamate or CRF and GABA were examined using electron microscopy. Numerous terminals that contained immunolabeling for both CRF and glutamate (e.g. 30% of 106 CRF-immunoreactive terminals and 13% of 232 glutamate-immunolabeled terminals) were observed in the peri-LC. Additionally, single labeled CRF and glutamate terminals were often apposed to one another or found to converge on common dendritic targets. In contrast, relatively few terminals exhibited immunolabeling for both GABA and CRF (5% of 317 CRF-immunoreactive terminals). However, evidence for a postsynaptic effect of CRF on GABA-containing profiles included synapses between CRF axon terminals and GABA-labeled dendrites (10% of 317 CRF-labeled terminals), as well as appositions between CRF- and GABA-labeled terminals. These results indicate that CRF is preferentially colocalized with glutamate in the rostrolateral LC region and may impact on glutamate neurotransmission in the LC via presynaptic or postsynaptic actions. They argue against colocalization of CRF with GABA, although CRF may modulate GABA release via postsynaptic effects in the peri-LC region.

Animals↗
PubMed2003

Investigations of the cholinergic modulation of GABA release in rat thalamus slices.

The thalamus receives a dense cholinergic projection from the pedunculopontine tegmentum. A number of physiological studies have demonstrated that this projection causes a dramatic change in thalamic activity during the transition from sleep to wakefulness. Previous anatomical investigations have found that muscarinic type 2 receptors are densely distributed on the dendritic terminals of GABAergic interneurons, as well as the somata and proximal dendrites of GABAergic cells in the thalamic reticular nucleus. Since these structures are the synaptic targets of cholinergic terminals in the thalamus, it appears likely that thalamic pedunculopontine tegmentum terminals can activate muscarinic type 2 receptors on GABAergic cells. To test whether activation of muscarinic type 2 receptors affects the release of GABA in the thalamus, we have begun pharmacological studies using slices prepared from the rat thalamus. We have found that the application of the nonspecific muscarinic agonist, methacholine, and the muscarinic type 2-selective agonist, oxotremorine.sesquifumarate, diminished both the baseline, and K(+) triggered release of [(3)H]GABA from thalamic slices. This effect was calcium dependent, and blocked by the nonselective muscarinic antagonist atropine, the muscarinic type 2-selective antagonist, methoctramine, but not the muscarinic type 1 antagonist, pirenzepine. Thus, it appears that one function of the pedunculopontine tegmentum projection is to decrease the release of GABA through activation of muscarinic type 2 receptors. This decrease in inhibition may play an important role in regulating thalamic activity during changes in states of arousal.

Acetylcholine↗
PubMed1999

Ambiguous respiratory neurons are modulated by GABA(A) receptor-mediated inhibition.

A group of respiratory neurons in the rostral nucleus ambiguus complex is known to generate the inspiratory and expiratory drives which enable spontaneous respiration to be sustained. Since previous studies indicated that mutual synaptic inhibition is required to produce oscillations between inspiratory and expiratory neurons, it may implicate GABAergic synaptic transmission between each group of neurons. In this study we tried to determine whether most ambiguous respiratory neurons are influenced by GABA(A) receptor-mediated inhibition. Eighty-eight respiratory interneurons showing rhythmic activity in synchrony with the spontaneous respiration were recorded in urethane-chloralose anesthetized Wistar rats. Multibarrel iontophoretic application of GABA(A) antagonist bicuculline produced a remarkable facilitation in maximum burst discharge rate, whereas the agonist muscimol reversed this effect completely. Simultaneous application of GABA and bicuculline increased the discharge rate more than in any single application or in the simultaneous application of GABA and muscimol. These results were statistically significant. These findings suggest strongly that GABA(A) receptors in the ambiguous respiratory neurons may have an inhibitory role in the synaptic transmission for maintaining the respiratory oscillation in the nucleus ambiguus.

Animals↗
PubMed1999

Temporal modulation of GABA(A) receptor subunit gene expression in developing monkey cerebral cortex.

In situ hybridization histochemistry was used to examine the expression of 10 GABA(A) receptor messenger RNAs corresponding to the alpha1-alpha5, beta1-beta3, gamma1 and gamma2 subunits in primary somatosensory and visual areas of macaque monkey cerebral cortex from embryonic day (E) 125 to postnatal day (P) 125. Results were compared with expression patterns in adults. In the sensorimotor cortex at E125, overall levels of all subunit transcripts were low. At E137, there was a major lamina-specific increase in all subunit messenger RNAs except gamma1. For alpha1, alpha2, alpha4, beta2, beta3 and gamma2 subunit transcripts, this increase was highest in areas 3a and 3b, particularly in layers III/IV and VI. Postnatally, there were significant decreases in all transcripts. Alpha1, alpha5, beta2 and gamma2 subunit transcripts, while still at significantly lower levels than at E137, remained expressed at levels higher than other transcripts. Unlike in rodents, there was no obvious "switch" in the major subunits expressed in fetal and adult cortex, alpha1, alpha5, beta2 and gamma2 remaining highest throughout. In area 17, the most prominently expressed subunits at earliest ages were alpha2, alpha5, beta1, beta2, beta3 and gamma2, especially in layers II/III and VI. At E150, expression for alpha2, alpha3, beta1 and beta3 subunit transcripts in these layers decreased, but levels for alpha1, alpha4, alpha5, beta2, gamma1 and gamma2 transcripts increased, particularly within layer IV. The increase at E150 was particularly marked for alpha5 transcripts, which were expressed at levels more than four times those of other transcripts. Alpha1, beta2 and gamma2 remain highest into aduthood. Fetal area 17 displayed lamina-specific patterns of expression not found in adult animals. In particular, alpha3 messenger RNAs were present in layer IVA and gamma1 transcripts were present in layer IVC at E150, despite a lack of expression in these layers in the adult. These data demonstrate increased expression of GABA(A) receptors during the period of establishment of thalamocortical and intracortical connections, and a temporal regulation that may be associated with the period of developmental plasticity.

Aging↗
PubMed1998

Kainate receptor modulation of GABA release involves a metabotropic function.

The mechanism through which kainate receptors downregulate the release of GABA in the hippocampus is not known. We have found that the action of kainate on the hippocampal inhibitory postsynaptic current (IPSC) is mediated by a metabotropic process that is sensitive to Pertussis toxin (PTx) and independent of ion channel current. The downregulation of GABA IPSCs by kainate was also prevented in a dose-dependent manner by calphostin C, a specific inhibitor of PKC, and the inhibition of phospholipase C (PLC) drastically reduced the action of kainate. The effect of kainate was completely occluded by phorbol esters and by increasing extracellular Ca2+ but remained unaltered after inhibition or activation of protein kinase A (PKA). These results demonstrate that the activation of kainate receptors triggers a second messenger cascade, which results in the stimulation of PKC, and therefore document a metabotropic action of kainate receptors, which results in the inhibition of GABA release.

Animals↗
PubMed1983

Modulation of GABA receptor binding by Ca2+.

In frozen-thawed repeatedly washed rat cortical synaptic membranes, Ca2+ (1-5 mM) decreased the binding of [3H]muscimol whereas it increased the binding of [3H]gamma-aminobutyric acid (GABA). However, the binding of [3H]GABA was decreased by the same extent as the binding of [3H]muscimol when the membranes were incubated with baclofen (a selective ligand for the GABAB binding site) and Ca2+. Scatchard analysis of [3H]muscimol binding revealed that Ca2+ reduced the density of GABA binding sites without affecting the dissociation constant. Ca2+ was more potent than Ba2+, Mg2+ was ineffective, and the Ca2+ antagonist La3+ stimulated [3H]muscimol binding. The inhibition of [3H]muscimol binding by Ca2+ was not influenced by calmodulin (50 micrograms/ml), trifluoperazine (10(-5) M), verapamil (10(-6) M), quinacrine (10(-4) M), cordycepin (0.1 mM), leupeptin (20 microM), or soybean trypsin inhibitor (0.1 mg/ml). Moreover, the effect of Ca2+ was additive to that of GABA-modulin. These results indicate that Ca2+ decreases the number of GABAA binding sites while unveiling GABAB binding sites.

Animals↗
PubMed1986

In-vitro release of [14C]glutamate from dentate gyrus is modulated by GABA.

The effect of GABA (10(-3) and 10(-4) M) on the release of preloaded [14C]glutamate from slices of rat dentate gyrus, in response to K+ stimulation, was studied in Ca2+-free and normal Krebs solutions. Release in Ca2+-free solution was significantly enhanced, but there was no change in release in normal Krebs solution. These results imply that Ca2+-dependent (presumably neuronal) release of glutamate from the dentate gyrus is depressed by GABA, while non-neuronal Ca2+-independent release is enhanced.

Animals↗
PubMed2004

Opioid modulation of GABA release in the rat inferior colliculus.

BACKGROUND: The inferior colliculus, which receives almost all ascending and descending auditory signals, plays a crucial role in the processing of auditory information. While the majority of the recorded activities in the inferior colliculus are attributed to GABAergic and glutamatergic signalling, other neurotransmitter systems are expressed in this brain area including opiate peptides and their receptors which may play a modulatory role in neuronal communication. RESULTS: Using a perfusion protocol we demonstrate that morphine can inhibit KCl-induced release of [3H]GABA from rat inferior colliculus slices. DAMGO ([D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin) but not DADLE ([D-Ala2, D-Leu5]-enkephalin or U69593 has the same effect as morphine indicating that micro rather than delta or kappa opioid receptors mediate this action. [3H]GABA release was diminished by 16%, and this was not altered by the protein kinase C inhibitor bisindolylmaleimide I. Immunostaining of inferior colliculus cryosections shows extensive staining for glutamic acid decarboxylase, more limited staining for micro opiate receptors and relatively few neurons co-stained for both proteins. CONCLUSION: The results suggest that micro-opioid receptor ligands can modify neurotransmitter release in a sub population of GABAergic neurons of the inferior colliculus. This could have important physiological implications in the processing of hearing information and/or other functions attributed to the inferior colliculus such as audiogenic seizures and aversive behaviour.

Animals↗
PubMed1984

Avermectin modulation of GABA binding to membranes of rat brain, brine shrimp and a fungus, Mucor miehei.

High affinity [3H]GABA (gamma-aminobutyric acid) binding sensitive to muscimol and bicuculline was detected in membranes derived from rat brain and brine shrimp. Avermectin stimulated this GABA binding with maximum stimulation seen in these membranes at 400 and 40-80 ng/ml, respectively. This avermectin stimulation of GABA binding was Cl--dependent, bicuculline and picrotoxin-sensitive and was associated with an increase in Bm but not Kd of the systems. The membranes from Mucor miehei also exhibited high affinity [3H]GABA binding that was insensitive to classical neuronal GABA receptor agonists/antagonists and other agents. This novel GABA receptor was sensitive to Na+ and extremely sensitive to low levels of avermectin (apparent Ki 20-40 ng/ml). This inhibition of GABA binding by avermectin was associated with a decrease in affinity (increase in Kd) and an increase in concentration of receptors (Bm). It is possible that these GABA receptors might play crucial roles in control of cell metabolism and that avermectin can prevent growth of this organism via interference in the receptor activity.

Animals↗
PubMedDate not supplied

[The role of gamma-aminobutyric acid in the mechanism of action of anticonvulsant drugs].

Decreased activity of gamma-aminobutyric acid, the major inhibitory neurotransmitter in CNS can be epileptogenic. Manipulation of the GABA system has been a target for development of antiepileptic drugs. The different ways for augmenting gabaergic inhibition by conventional and new AEDs are presented in this paper. Among the I generation, barbiturates and benzodiazepines are potent anticonvulsants that act as GABA modulators in postsynaptic GABA-A receptor complex but their usefulness is limited by dependence and tolerance to antiseizure activity. The II generation drugs vigabatrin and tiagabine, and to some extent gabapentin have been developed by a rationale strategy and none of them exert direct action in GABA receptors. Only two former drugs exhibit selective, strictly defined activity: vigabatrine is an irreversible inhibitor of GABA-aminotransferase and tiagabine acts as a GABA-uptake inhibitor from synaptic cleft into neurons and glia. Gabapentin binds to a novel receptors in epileptogenic areas in CNS and enhances GABA turnover. Drugs with multiple mechanisms of action, felbamate and topiramate not only potentiate gabaergic inhibition in several ways but also diminish the activity of excitatory amino acids at their NMDA or AMPA receptors; the later mechanism seems to be essential for their potential neuroprotective activity in epileptogenesis. None of gabamimetic drugs provide optimal seizure control but better tolerability of newer ones and well-established mechanisms of action provide possible harmless therapy.

4-Aminobutyrate Transaminase↗
PubMed1995

Comparison of the effects of full and partial allosteric modulators of GABA(A) receptors on complex behavioral processes in monkeys.

Two baselines involving a repeated acquisition task were used to assess the effects of bretazenil, imidazenil, and triazolam. The first baseline was a multiple schedule of repeated acquisition and performance of conditional discriminations. In the first component, the subject acquired a four-response chain by responding sequentially on three keys in the presence of different combinations of colors and geometric forms displayed on a center key. Acquisition of the discrimination was defined by a decrease in errors as the session progressed. In the performance component, the four-response chain was the same each session. Incorrect responses in either component produced a 5s time out during which responding had no programmed consequence. The second procedure, which has been used to evaluate the effects of drugs on memory, involved the acquisition of a discrimination, followed by a 1h delay and a retest of the same discrimination to assess retention. Triazolam (0.32 and 0.56mg/kg) administered alone, produced dose-related decreases in response rate in each component. In addition, triazolam also produced a dose-related increase in percentage errors in acquisition with no effect in performance. Triazolam (0.32mg/kg) eliminated retention (0 percent savings) in the memory task. Bretazenil (0.1-5.6mg/kg) or imidazenil (0.1-1.8mg/kg) administered alone had little or no effect on either rate of responding or accuracy in either component. Furthermore, bretazenil but not imidazenil disrupted retention at the higher doses tested. The combination of imidazenil or bretazenil with triazolam produced dose-related attenuation of the disruptive effects of triazolam on both behavioral baselines. These data suggest that the disruptive effects of benzodiazepines on learning and memory may be a function of the intrinsic efficacy of these compounds at different GABA(A) receptor subtypes.

Journal Article↗
PubMed2003

Oxytocin regulates neurosteroid modulation of GABA(A) receptors in supraoptic nucleus around parturition.

In this study, we investigate how neurosteroid sensitivity of GABA(A) receptors (GABA(A)Rs) is regulated. We examined this issue in neurons of the supraoptic nucleus (SON) of the rat and found that, during parturition, the GABA(A)Rs become insensitive to the neurosteroid allopregnanolone attributable to a shift in the balance between the activities of endogenous Ser/Thr phosphatase and PKC. In particular, a constitutive endogenous tone of oxytocin within the SON after parturition suppressed neurosteroid sensitivity of GABA(A)Rs via activation of PKC. Vice versa before parturition, during late pregnancy, application of exogenous oxytocin brings the GABA(A)Rs from a neurosteroid-sensitive mode toward a condition in which the receptors are not sensitive. This indicates that there may be an inverse causal relationship between the extent to which the GABA(A)R or one of its interacting proteins is phosphorylated and the neurosteroid sensitivity of the GABA(A)R. Neurosteroid sensitivity was not affected by changes in subunit composition of GABA(A)Rs known to occur concurrently in these cells.

Animals↗
PubMed1992

Modulation of GABA transport in synaptosomes by histamine.

We have examined the effects of exogenous and intrasynaptosomal histamine on the GABA transport in rat brain synaptosomes. Exogenous histamine had no effect on GABA uptake, but inhibited veratridine-evoked GABA release. GABA uptake was susceptible to the modification of histamine synthesis in synaptosomes. The increase of synaptosomal histamine level by incubation under conditions favouring histamine synthesis from 2.6 to 5.2 pmole/mg protein, decreased the GABA uptake by about 75%. As demonstrated in experiments with an inhibitor of histidine decarboxylase--semicarbazide, this effect comprised 15% inhibition evoked by the histamine precursor--histidine, whereas the remaining 60% inhibition could be ascribed to the effect of newly synthesized histamine.

Animals↗