Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “GABA Modulators”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 595 records · Page 33Linked to original sources
PubMed2001

Different types of GABA(A) receptors may mediate the anticonflict and response rate-decreasing effects of zaleplon, zolpidem, and midazolam in squirrel monkeys.

RATIONALE: The role of different types of GABA(A) receptors in mediating anticonflict and response rate-decreasing effects of benzodiazepines in primate species is not known. OBJECTIVE: To examine the behavioral effects of the benzodiazepine-site, GABA(A) agonists zolpidem, zaleplon, and midazolam in the presence of two antagonists, flumazenil and beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) in squirrel monkeys. METHODS: Two schedules of operant responding were used: (1) a multiple fixed-ratio (FR) schedule of food presentation involving punished and nonpunished behavior, and (2) an FR schedule of stimulus shock-termination. RESULTS: Midazolam (0.03-1.0 mg/kg), zolpidem (0.1-3.0 mg/kg), and zaleplon (0.1-3.0 mg/kg) increased rates of punished responding and decreased rates of nonpunished responding under the multiple schedule. Pretreatment with flumazenil (0.3-1.0 mg/kg) antagonized the anticonflict and response rate-decreasing effects of all three agonists. Pretreatment with beta-CCt (3-10 mg/kg) antagonized the anticonflict and rate-decreasing effects of midazolam, as well as the rate-decreasing effects of zolpidem and zaleplon. However, beta-CCt did not antagonize the anticonflict effects of zolpidem and zaleplon; instead, these effects of zolpidem and zaleplon were apparently enhanced in the presence of beta-CCt. Under the schedule of stimulus shock-termination, both flumazenil and beta-CCt antagonized zolpidem and zaleplon; however, the effects of beta-CCt were less consistent than the effects of flumazenil. CONCLUSION: In nonhuman primates, different types of GABAA receptors may mediate the anticonflict and the response rate-decreasing effects of the nonselective GABAA agonist midazolam and the selective GABAA1 agonists zolpidem and zaleplon.

Acetamides↗
PubMed2002

Pharmacological suppression of plastic changes in human primary somatosensory cortex after motor learning.

The strict division between motor and somatosensory systems might be less distinct than previously thought. Many brain mapping studies have described changes of somatosensory cortex (S-I) after the execution of a motor task, which supports the idea of a profound interconnectedness in the sensorimotor system. Here we report experiments in which we investigated by means of somatosensory evoked potentials (SSEPs) mapping the reorganizational capacities in primary somatosensory cortex before and after a Hebbian repetitive co-contraction task of the thumb and arm. We investigated the susceptibility of S-I plasticity to the pharmacological modulation of the GABA-neurotransmitter system by application of the GABA(A) agonist lorazepam. We found that repetitive training induced stable motor learning characterized by a significant improvement of performance. The time differences between the onset of contraction of the deltoid muscle and the abductor pollicis brevis were progressively shortened. The process of motor learning was accompanied by plastic changes in the primary somatosensory cortex as indicated by a significant increase in the dipole strength and a significant shift of the median nerve dipole on the hemisphere contralateral to the exercised side. Moreover, the individual shifts of median nerve dipole location were correlated with the individual improvement in motor performance. After administration of lorazepam, motor learning was significantly suppressed. The behavioural effect was accompanied by an abolition of the N20 dipole shift and an unchanged dipole strength. The results imply that motor learning leads to a profound reorganization in S-I which is subject to pharmacological suppression with the GABA agonist lorazepam.

Adult↗
PubMed2001

GABA concentration sets the conductance of delayed GABAA channels in outside-out patches from rat hippocampal neurons.

GABAA channels were activated by GABA in outside-out patches from rat cultured hippocampal neurons. They were blocked by bicuculline and potentiated by diazepam. In 109 of 190 outside-out patches, no channels were active before exposure to GABA (silent patches). The other 81 patches showed spontaneous channel activity. In patches containing spontaneous channel activity, rapid application of GABA rapidly activated channels. In 93 of the silent patches, channels could be activated by GABA but only after a delay that was sometimes as long as 10 minutes. The maximum channel conductance of the channels activated after a delay increased with GABA concentration from less than 10 pS (0.5 microm GABA) to more than 100 pS (10 mm GABA). Fitting the data with a Hill-type equation gave an EC50 value of 33 microm and a Hill coefficient of 0.6. The channels showed outward rectification and were chloride selective. In the presence of 1 microm diazepam, the GABA EC50 decreased to 0.2 microm but the maximum conductance was unchanged. Diazepam decreased the average latency for channel opening. Bicuculline, a GABA antagonist, caused a concentration-dependent decrease in channel conductance. In channels activated with 100 microm GABA the bicuculline IC50 was 19 microm. The effect of GABA on channel conductance shows that the role of the ligand in GABAA receptor channel function is more complex than previously thought.

Animals↗
PubMed2000

Naturally occurring benzodiazepines: current status of research and clinical implications.

Naturally occurring benzodiazepines (BZDs) were first detected in mammalian tissues in 1986. They comprise a variety of 1,4-benzodiazepines corresponding to drugs commercially available for the treatment of anxiety disorders, sleep disturbances and epileptic seizures. Several biosynthetic pathways leading to the formation of BZDs are currently being discussed and have led to the proposition of possible precursor molecules. For years, the identification of naturally occurring BZDs in mammalian organisms was mostly confined to post mortem CNS material for sensitivity reasons. While radioimmunoassay and radioreceptor assay techniques have been tentatively applied to quantitations of genuine BZDs from human milk and cerebrospinal fluid, accurate measurements in peripheral blood have only recently become accessible, e. g., by gas chromatography/selected ion monitoring-mass spectrometry (GC/SIM-MS). This review summarizes existing evidence of benzodiazepines' occurrence in nature and discusses implications for neuropsychiatric disorders.

Animals↗
PubMed1995

Effects of the benzodiazepine antagonist flumazenil in PTSD.

OBJECTIVE: Evidence from preclinical and clinical studies suggests a role for alterations in the benzodiazepine/GABAA receptor complex in stress and anxiety. Flumazenil is a relatively pure benzodiazepine/GABAA antagonist with limited intrinsic activity. In panic disorder patients, but not healthy controls, flumazenil has been demonstrated to provoke panic attacks. METHOD: Vietnam combat veterans with PTSD (n = 14) received 90-second intravenous infusions of flumazenil 2 mg or placebo in a double-blind, crossover study design. PTSD symptomology was assessed using the PTSD Symptom Scale, and anxiety symptoms were measured with visual analogue rating scales. RESULTS: There was no significant difference in PTSD and anxiety symptoms between administration of flumazenil and placebo. CONCLUSION: Flumazenil administration does not produce an increase in anxiety and PTSD symptoms in patients with PTSD. This suggests that PTSD and panic disorder are dissimilar in terms of benzodiazepine/GABAA system function.

Anxiety Disorders↗
PubMed1996

Biphasic actions of the benzodiazepine receptor inverse agonist RU34347 in the rat cerebellar slice.

We have characterised the biphasic response of the benzodiazepine receptor inverse agonist RU34347 in the rat cerebellar slice preparation using extracellular electrophysiological recordings from Purkinje cells. RU34347 (10 fM-10 nM) produced an increase in GABA(A)-mediated inhibition at between 10 fM and 10 nM, a response normally associated with benzodiazepine agonists. This response was biphasic, being dose dependent between 10 fM and the peak effect at 10 pM, and inversely related to concentration between 100 pM and 10 nM. Associated with this increase in inhibition was a decrease in firing rate, also showing a biphasic concentration-response relationship. The agonist-like response was composed of two elements, an initial increase occurring after 5 min followed by a slow decline over the next 20 min. This second, declining, phase was more evident at higher concentrations of RU34347. The peak effect seen at 10 pM was fully antagonised by 1 microM flumazenil, a benzodiazepine receptor antagonist. This concentration of flumazenil also antagonised the decrease in firing rate induced by 10 pM RU34347. The response to 10 nM RU34347 was further characterised since the largest second phase decline was demonstrated at this concentration. 10 nM flumazenil fully antagonised the second, declining, phase of the response, but not the magnitude of the initial increase. A partial antagonism of the peak effect was seen with 1 microM flumazenil, and a full antagonism at 10 microM flumazenil. This effect was similar to that observed with Ro15-4513 in a previous study. Therefore, we investigated the binding of RU34347 to diazepam-insensitive benzodiazepine receptors. [3H]Ro15-4513 was displaced by Ro15-4513, flumazenil and Ro19-4603, but not by RU34347. Therefore, although the electrophysiological data correlate well with that previously reported for Ro15-4513, RU34347 does not displace Ro15-4513 binding at the diazepam-insensitive benzodiazepine receptor. Therefore, either both ligands bind to complimentary sites on the same receptor complex, or both induce a similar physiological response through an action on different receptors.

Animals↗
PubMed1996

Tolerance to the ataxic effects of diazepam in guinea pig is not associated with a reduced sensitivity of GABAA receptors in the vestibular nucleus.

Some studies have suggested that drug tolerance observed following repeated benzodiazepine exposure may be associated with the development of a subsensitivity to gamma-aminobutyric acid (GABA) in dorsal raphe and hippocampal neurons. In other areas such as the substantia nigra such subsensitivity has not been found. The aim of the present study was to determine whether tolerance develops to the ataxic effects of diazepam on the righting reflex following low (i.e. 2 mg/kg i.p.), multiple daily doses and, if so, whether it is correlated with the development of a subsensitivity of medial vestibular nucleus neurons to the selective GABAA receptor agonist, isoguvacine. Guinea pigs which received i.p. vehicle injections three times daily for 5 days, or single daily doses of 2 or 6 mg/kg diazepam, showed increased righting reflex latencies in response to a 6 mg/kg diazepam challenge dose. However, guinea pigs which received 2 mg/kg diazepam i.p., three times daily for 5 days, exhibited minimal or no ataxia when given the same diazepam challenge dose, indicating the development of tolerance. Brain stem slices including the medial vestibular nucleus were removed from guinea pigs which had received the same diazepam and vehicle three times daily injection schedules, and recordings were made from single neurons during superfusion of isoguvacine. Although medial vestibular nucleus neurons from animals which received chronic diazepam administration showed smaller decreases in firing rate in response to 10(-8) M isoguvacine, the difference was not statistically significant compared to neurons from animals which received vehicle treatment or acute diazepam treatment. Resting activity was also similar between the diazepam and vehicle groups, in contrast to a previous study which had shown hyperexcitability in medial vestibular nucleus cells from animals which had received single daily injections for up to 60 days. These results suggest that, in contrast to studies which have employed single daily doses, tolerance to the ataxic effects of diazepam on the righting reflex occurs rapidly with divided daily doses. However, this tolerance is not correlated with significant changes in the sensitivity of GABAA receptors on medial vestibular nucleus neurons.

Animals↗
PubMed1996

Interaction of allosteric ligands with GABAA receptors containing one, two, or three different subunits.

The presence of allosteric binding sites on recombinant GABAA receptors formed after transfection of human embryonic kidney (HEK) 293 cells with alpha 1-, beta 3-, or gamma 2-subunits, or with various combinations of these subunits, was systematically investigated. From all possible subunit combinations, high affinity [3H]muscimol binding sites were induced in cells transfected with alpha 1 beta 3- or alpha 1 beta 3 gamma 2-subunits only. GABAA receptor associated [3H]flunitrazepam binding sites were induced in cells after transfection with alpha 1 gamma 2- or alpha 1 beta 3, gamma 2-subunits, and [35S]r-butylbicyclophosphorothionate (TBPS) binding sites were found in cells transfected with beta 3-, beta 3 gamma 2-, alpha 1 beta 3-, or alpha 1 beta 3 gamma 2-subunits. Binding of [35S]TBPS could be inhibited by pentobarbital, etazolate, (+)-etomidate, alphaxalone, propofol, chlormethiazole, and 4'-chlorodiazepam (Ro 5-4864) with a potency which differed in cells transfected with beta 3-, beta 3 gamma 2-, alpha 1 beta 3-, or alpha 1 beta 3 gamma 2-subunits. Results obtained indicate that receptors with different subunit composition actually can be formed in HEK cells and exhibit distinct pharmacological properties.

Allosteric Site↗
PubMed1996

Anticonvulsant profile of the imidazoquinazolines NNC 14-0185 and NNC 14-0189 in rats and mice.

The anticonvulsant effects of NNC 14-0185 (3-(3-cyclopropyl-5-isoxazolyl)-6-fluoro-5-morpholino-imidazo[1,5- a] quinazoline) and NNC 14-0189 (3-(5-cyclopropyl-1,2, 4-oxadiazol-3-yl)-7-fluoro-5-(4-methyl-1-piperazinyl)-imidazo[1,5- a] quinazoline) in mice and rats were evaluated and compared with those of diazepam, clonazepam and the novel beta-carboline, abecarnil. Following i.p. administration, NNC 14-0185 and NNC 14-0189 prevented audiogenic seizures in DBA/2 mice and the clonic convulsions induced in mice by pentylenetetrazole, DMCM (methyl 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), 3-mercaptopropionic acid and a low dose of bicuculline. NNC 14-0185 and NNC 14-0189 prevented seizures induced by pentylenetetrazole in rats and were also effective anticonvulsants in amygdala-kindled rats. In general, the anticonvulsant potencies of NNC 14-0185 and NNC 14-0189 were comparable to those of the reference benzodiazepines. However, like abecarnil, they were not effective against the seizures induced in mice by maximal electroshock and a high dose of bicuculline. The anticonvulsant effects of NNC 14-0185 and NNC 14-0189 against pentylenetetrazole-induced seizures were apparent within 5 min of i.p. injection and persisted for at least 2 h. These effects appeared to be mediated by benzodiazepine receptors since they were inhibited by concurrent administration of flumazenil. Both NNC 14-0185 and NNC 14-0189 showed greater separation between their anticonvulsant and muscle relaxant effects (measured as impaired rotarod performance) than did diazepam. In this respect, their therapeutic windows were similar (NNC 14-0185) to or better (NNC 14-0189) than that of abecarnil. Tolerance did not develop to the anticonvulsant effects of NNC 14-0185 and NNC 14-0189 over a 4-day test. In comparison, the anticonvulsant effects of diazepam and abecarnil were attenuated by repeated drug administration. Thus, NNC 14-0185 and NNC 14-0189 have a promising anticonvulsant and side-effect profile in comparison with diazepam, clonazepam and abecarnil. The potential use of these compounds in the treatment of epilepsy should be explored further.

Acoustic Stimulation↗
PubMed1996

Presynaptic GABAB-and gamma-hydroxybutyric acid-mediated mechanisms in generalized absence seizures.

gamma-Hydroxybutyric acid (GHB) is a naturally occurring compound which has the ability to induce generalized absence seizures when given to animals. This effect of GHB may be blocked by either GHB or GABAB receptor antagonists. We sought to test the hypothesis that pre-synaptic GHB- and GABAB-mediated mechanisms in thalamus and cortex are operative in the GHB model of generalized absence seizures. Presynaptic Ca(2+)-dependent K+ efflux was determined using Ca(2+)-stimulated Rb86 efflux in synaptosomes prepared from thalamus and cortex in the presence of GHB, a specific GHB receptor antagonist, the specific GABAB agonist (-)baclofen, or the specific GABAB antagonists, phaclofen and CGP 35348. The effect of these compounds was determined also on basal and K(+)-stimulated 45Ca2+ uptake and basal and K(+)-stimulated synaptosomal cytosolic Ca2+([Ca2]i) in synaptosomes prepared from thalamus and cortex and on [125I] omega-conotoxin binding in thalamus and cortex using autoradiographic binding techniques. There was no demonstrable change in Ca(2+)-stimulated Rb86 efflux in any experimental condition studied; however GHB and (-)baclofen both suppressed K(+)-stimulated 45Ca2+ uptake and [Ca2]i in synaptosomes and were associated with a decrease in [125I] omega-conotoxin binding which achieved statistical significance only in frontal cortex, a brain region selectively involved in the genesis of GHB-induced absence seizures. The effects of GHB and (-)baclofen on K(+)-stimulated 45Ca2+ uptake and [Ca2]i in synaptosomes were additive. The effects of GHB in this regard were attenuated by the GHB antagonist and phaclofen while that of (-)baclofen was attenuated by CGP 35348. These data do not support the hypothesis that the GHB and GABAB receptor are one and the same. Rather, they raise the possibility that a presynaptic GHB/GABAB receptor complex might be involved in the pathogenesis of GHB-induced generalized absence seizures.

Animals↗
PubMed1995

Nitrous oxide induces feeding in the nondeprived rat that is antagonized by naltrexone.

Three experiments investigated a possible effect of nitrous oxide (N2O) on food intake in nondeprived male hooded rats in independent groups designs. Experiment 1 demonstrated a concentration-related increase in intake with increasing level of nitrous oxide (10-40% N2O), reaching statistical significance at 20% N2O when compared to room air controls (p < 0.05). In experiment 2, pretreatment with 10 and 20 mg/kg of the benzodiazepine antagonist, flumazenil, failed to significantly attenuate 30% N2O-induced hyperphagia. In Experiment 3, pretreatment with the opioid antagonist, naltrexone, effectively antagonized 30% N2O-induced hyperphagia. Pronounced attenuation (to 59% of 30% N2O-induced intake level over a 1 h period) at the lowest dose of naltrexone (0.1 mg/kg, p < 0.01) compared to vehicle level resulted in a shallow dose-response curve across the dose range tested (0.1-10.0 mg/kg). These results suggest that an endogenous opioid mechanism is prominently involved in the N2O-induced ingestive response.

Animals↗
PubMed1995

Behavioural responsiveness to picrotoxin and desipramine in adult rats prenatally exposed to different benzodiazepine receptor agonists.

The behavioural responsiveness to picrotoxin and desipramine was investigated in adult rats prenatally exposed to different benzodiazepine receptor agonists such as diazepam, alprazolam and zolpidem. Prenatal exposure to diazepam and alprazolam similarly potentiated the anti-immobility effect on the forced swimming test and the inhibitory effect on spontaneous motor activity of picrotoxin and desipramine and increased the seizure sensitivity to picrotoxin. Prenatal zolpidem seems to be ineffective. These data suggest that, despite the differences in their pharmacodynamic profile, prenatal exposure to diazepam and alprazolam, but not zolpidem, may have similar permanent consequences on the behavioural effects of drugs acting on the GABAA receptors.

Adrenergic Uptake Inhibitors↗
PubMed2005

Effects of 5,7-dihydroxytryptamine lesion of the dorsal raphe nucleus on ethanol discrimination in the rat.

It has been shown that ethanol produces a complex interoceptive cue in rodents with distinct GABAergic, glutamatergic, and serotonergic (5-hydroxytryptamine, 5-HT) components. The present study aimed to examine the contribution of the 5-HT system originating in the dorsal raphe nucleus (DRN) to the discriminative stimulus effects of ethanol in male Wistar rats. Therefore, selective lesions of 5-HT neurons in the DRN were induced by microinfusions of 5,7-dihydroxytryptamine. The DRN- and sham-lesioned rats were trained to discriminate ethanol (1.0 g/kg) from saline in a standard two-lever drug discrimination procedure. Acquisition of ethanol discrimination and discrimination performance after consumption of lower doses of ethanol did not differ between the groups. In substitution tests, diazepam (0.5-2.5 mg/kg), a nonselective benzodiazepine receptor agonist, partially generalized from the ethanol cue in both groups. In contrast, m-chlorophenylpiperazine (0.1-0.9 mg/kg), a mixed 5-HT(1B/2C) receptor agonist, did not mimic the ethanol cue. The drug decreased response rates in both groups, but this effect was more evident in the sham-lesioned group. A 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propyloamino)-tetraline (0.05-0.4 mg/kg), did not produce significant increase in ethanol-appropriate responding in either group. These results may indicate that 5-HT neurons of the DRN are not critically involved in ethanol discrimination in the rat.

5,7-Dihydroxytryptamine↗
PubMed2005

Bidirectional effects of benzodiazepine binding site ligands in the passive avoidance task: differential antagonism by flumazenil and beta-CCt.

Recent research on genetically modified mice has attributed the amnesic effect of benzodiazepines mainly to the alpha1-containing GABA(A) receptor subtypes. The pharmacological approach, using subtype selective ligands, is needed to complement genetic studies. We tested the effects of the non-selective antagonist flumazenil (0-20.0 mg/kg), the preferential alpha1-subunit selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) (0-30.0 mg/kg), the non-selective agonist midazolam (0-2.0 mg/kg), the preferential alpha1-subunit selective agonist zolpidem (0-3.0 mg/kg), and the non-selective inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (0-2.0 mg/kg) in the one-trial step-through passive avoidance task in rats. The compounds were administered intraperitoneally, before the acquisition test. Flumazenil and beta-CCt did not affect retention performance. Midazolam and zolpidem induced amnesia in a dose-dependent manner. The complete reversal of amnesia was unattainable. The effects of zolpidem were significantly attenuated by the both, flumazenil (10.0 mg/kg) and beta-CCt (30.0 mg/kg); by contrast, only flumazenil was considerably effective when combined with midazolam. DMCM exerted promnesic effects at 0.2mg/kg, in an inverted U-shape manner. Both antagonists tended to abolish this action. The results indicate that some other alpha-subunit(s), in addition to the alpha1-subunit, contribute to the amnesic actions of non-selective benzodiazepine site agonists in the passive avoidance task. On the other hand, a significant part of the DMCM-induced promnesic effect could involve the alpha1-subunit and/or other putative beta-CCt-sensitive binding site(s).

Animals↗
PubMed2003

Naturally occurring 2'-hydroxyl-substituted flavonoids as high-affinity benzodiazepine site ligands.

Screening of traditional medicines has proven invaluable to drug development and discovery. Utilizing activity-guided purification, we previously reported the isolation of a list of flavonoids from the medicinal herb Scutellaria baicalensis Georgi, one of which manifested an affinity for the benzodiazepine receptor (BDZR) comparable to that of the synthetic anxiolytic diazepam (K(i)=6.4 nM). In the present study, this high-affinity, naturally occurring flavonoid derivative, 5,7,2'-trihydroxy-6,8-dimethoxyflavone (K36), was chosen for further functional and behavioral characterization. K36 inhibited [3H]flunitrazepam binding to native BDZR with a K(i) value of 6.05 nM. In electrophysiological experiments K36 potentiated currents mediated by rat recombinant alpha(1)beta(2)gamma(2) GABA(A) receptors expressed in Xenopus oocytes. This potentiation was characterized by a threshold (1 nM) and half-maximal stimulation (24 nM) similar to diazepam. This enhancement was demonstrated to act via the BDZR, since co-application of 1 microM of the BDZR antagonist Ro15-1788 reversed the potentiation. Oral administration of K36 produced significant BDZR-mediated anxiolysis in the mice elevated plus-maze, which was abolished upon co-administration of Ro15-1788. Sedation, myorelaxation and motor incoordination were not observed in the chosen dosage regimen. Structure-activity relationships utilizing synthetic flavonoids with different 2' substituents on the flavone backbone supported that 2'-hydroxyl-substitution is a critical moiety on flavonoids with regard to BDZR affinities. These results further underlined the potential of flavonoids as therapeutics for the treatment of BDZR-associated syndromes.

Allosteric Regulation↗
PubMed2005

Design and synthesis of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles as benzodiazepine receptor agonists.

A series of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles was designed and synthesized as anticonvulsant agents. Conformational analysis and superimposition of energy minima conformers of the designed molecules on estazolam, a known benzodiazepine receptor agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. Electroshock and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group in position 2 of 1,3,4-oxadiazole ring and a fluoro substituent at para position of benzylthio moiety had the best anticonvulsant activity. It seems this effect is mediated through benzodiazepine receptors mechanism.

Animals↗
PubMed2003

Control of neuronal nitric oxide synthase and brain-derived neurotrophic factor levels by GABA-A receptors in the developing rat cortex.

Gamma-aminobutyric acid (GABA) plays an important morphogenetic role, acting through GABA-A receptors, which are depolarizing in the developing rat brain. Other molecules with major morphogenetic roles are the nitric oxide free radical (NO(.)) and brain-derived neurotrophic factor (BDNF), both of which are involved in the control of synaptic plasticity and apoptosis. In the present work, we investigated the effect of GABA-A receptor activation on neuronal NO(.) synthase (nNOS) and BDNF immunoreactivity in the developing cortex of 5-day-old rats. We also determined the effect of GABA-A receptor activation on phosphorylated cAMP-response element binding protein (pCREB) immunoreactivity in an effort to elucidate the molecular mechanisms involved. Our results show that activation of GABA-A receptors leads to increased numbers of nNOS, BDNF and pCREB, as well as nNOS-pCREB and BDNF-pCREB doubly immunopositive cells. This effect is abolished when L-type Ca(2+) channels are blocked. These results indicate that the following mechanism could be operating: depolarization following GABA-A receptor activation leads to opening of L-type voltage-gated calcium channels, resulting in an increased Ca(2+) influx, which in turn leads to phosphorylation and, thus, activation, of the transcription factor CREB; the phosphorylated CREB can then induce BDNF, as well as nNOS.

Animals↗