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At least 847 records · Page 47Linked to original sources
PubMed2000

Antinociceptive effects of the neuroactive steroid, 3alpha-hydroxy-5alpha-pregnan-20-one and progesterone in the land snail, Cepaea nemoralis.

Results of investigations with vertebrates have implicated neuroactive steroids and in particular 5alpha-reduced metabolites of progesterone such as 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP/3A5P and originally allopregnanolone) in the rapid modulation of diverse functions including that of nociceptive sensitivity. These effects have been indicated to involve modulation of GABA receptors. Results of recent phylogenetic studies have revealed the presence of GABA receptors in invertebrates that may also be subject to modulation by steroids and neuroactive steroids. The present study examined the effects of the neuroactive steroid, 3alpha-hydroxy-5alpha-pregnan-20-one, as well as progesterone on aversive thermal (nociceptive) responses in a mollusc, the land snail, Cepaea nemoralis. 3alpha-Hydroxy-5alpha-pregnan-20-one had significant dose-related (0.01-1.0 microg) antinociceptive effects in Cepaea increasing the latency of response to a 40 degrees C surface, with maximum effects being evident 15-30 min after administration. These effects of 3alpha-hydroxy-5alpha-pregnan-20-one were stereospecific, with the stereoisomer 3beta-hydroxy-5alpha-pregnan-20-one (3B5P) failing to affect nociceptive responses. Progesterone also had significant dose-related (0.10-10 microg) antinociceptive effects that, however, were delayed in onset and relatively prolonged (60-120 min), suggestive of the formation of active metabolites. The presence of endogenous progesterone (12.36+/-0.17 ng/g tissue) was ascertained by a radioimmunoassay further supporting a functional role for steroids in Cepaea. The antinociceptive effects of 3alpha-hydroxy-5alpha-pregnan-20-one and progesterone were blocked by the GABA antagonists, bicuculline and picrotoxin, while being relatively insensitive to opioid and N-methyl-D-aspartate antagonists. These results suggest an early evolutionary development and phylogenetic continuity of neuroactive steroid and GABA involvement in the mediation of nociception.

Anesthetics↗
PubMed2001

Neuronal mechanisms of the anoxia-induced network oscillations in the rat hippocampus in vitro.

1. A spindle of fast network oscillations precedes the ischaemia-induced rapid depolarisation in the rat hippocampus in vivo. However, this oscillatory pattern could not be reproduced in slices and the underlying mechanisms remain poorly understood. We have found that anoxia-induced network oscillations (ANOs, 20-40 Hz, lasting for 1-2 min) can be reproduced in the intact hippocampi of postnatal day P7-10 rats in vitro, and we have examined the underlying mechanisms using whole-cell and extracellular field potential recordings in a CA3 pyramidal layer. 2. ANOs were generated at the beginning of the anoxic depolarisation, when pyramidal cells depolarised to subthreshold values. Maximal power of the ANOs was attained when pyramidal cells depolarised to -56 mV; depolarisation above -47 mV resulted in a depolarisation block of pyramidal cells and a waning of ANOs. 3. A multiple unit activity in extracellular field recordings was phase locked to the negative and ascending phases of ANOs. Pyramidal cells recorded in current-clamp mode generated action potentials with an average probability of about 0.05 per cycle. The AMPA receptor-mediated EPSCs and the GABA receptor-mediated IPSCs in CA3 pyramidal cells were also phase locked with ANOs. 4. ANOs were prevented by tetrodotoxin and glutamate receptor antagonists CNQX and APV, and were slowed down by the allosteric GABA(A) receptor modulator diazepam. In the presence of the GABA(A) receptor antagonist bicuculline, ANOs were transformed to epileptiform discharges. 5. In the presence of the A1 adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), the anoxia induced an epileptiform activity and no ANOs were observed. 6. In normoxic conditions, a rise of extracellular potassium to 10 mM induced an epileptiform activity. Increasing extracellular potassium in conjunction with a bath application of the adenosine A1 receptor agonist cyclopentyladenosine induced oscillations similar to ANOs. 7. Multisite recordings along the septo-temporal hippocampal axis revealed that ANOs and anoxic depolarisation originate in the temporal part, and propagate towards the septal pole at a speed of 1.9 mm x min(-1). 8. ANOs were observed starting from P7, i.e. at a developmental stage when the effects of GABA change from depolarisation to hyperpolarisation. 9. These results suggest that the synchronisation of anoxia-induced oscillations relies on synaptic mechanisms; that the inhibition by GABA and adenosine sets the tune for a generation of oscillations and prevents an epileptiform activity; and that a synchronous GABAergic inhibition is instrumental in a phase locking neuronal activity similarly to other types of oscillatory activities in the gamma frequency range.

2-Amino-5-phosphonovalerate↗
PubMed2006

Estradiol-induced modulation of estrogen receptor-beta and GABA within the adult neocortex: a potential transsynaptic mechanism for estrogen modulation of BDNF.

Estrogen influences brain-derived neurotrophic factor (BDNF) expression in the neocortex. However, BDNF-producing cortical neurons do not express detectable levels of nuclear estrogen receptors; instead, the most abundant cortical nuclear estrogen receptor, ER-beta, is present in GABAergic neurons, prompting us to test the hypothesis that estrogen effects on BDNF are mediated via cortical inhibitory interneurons. Adult female ovariectomized rats were provided acute estrogen replacement and the number of cortical GABA, ER-beta, and ER-beta/GABA double-labeled neurons was examined. Within 48 hours of injection of 17-beta-estradiol, the number of perirhinal neurons double-labeled for ER-beta/GABA was reduced by 28% (P<0.01 compared to vehicle-treated ovariectomized controls), and all cells expressing detectable levels of GABA were reduced by 19% (P<0.01). To investigate potential relationships between estrogen receptors, GABAergic neurons, and BDNF-expressing cells, brain sections were double- or triple-labeled for ER-beta, GABAergic, and BDNF immunomarkers. The findings indicated that ER-beta-bearing inhibitory neurons project onto other GABAergic neurons that lack nuclear estrogen receptors; these inhibitory neurons in turn innervate BDNF-expressing excitatory cells. High estrogen states reduce cortical GABA levels, presumably releasing inhibition on BDNF-expressing neurons. This identifies a putative two-step transsynaptic mechanism whereby estrogen availability modulates expression of inhibitory transmitters, resulting in increased BDNF expression.

Animals↗
PubMed1989

A role for protein kinase C in the electrically evoked release of [3H] gamma-aminobutyric acid in rabbit caudate nucleus.

A possible participation of protein kinase C (PKC) in depolarization-induced release of gamma-aminobutyric acid (GABA) in rabbit caudate nucleus was examined by means of phorbol esters and staurosporine. Slices of caudate nucleus were loaded with [3H]GABA, then superfused and stimulated electrically (3 ms, 5 Hz, 24 mA, 5 V/cm) for 2 min. Aminooxyacetic acid and the uptake inhibitor nipecotic acid were present throughout. The PKC activator 4 beta-phorbol 12,13-dibutyrate (4 beta-PDB) markedly enhanced the evoked [3H]GABA release. In contrast, its biologically inactive isomer, 4 alpha-PDB, did not facilitate transmitter release. Staurosporine, an inhibitor of PKC, diminished [3H]GABA release and counteracted the effects caused by 4 beta-PDB. The above results suggest a participation of PKC in depolarization-induced GABA release in rabbit caudate nucleus. The mechanism underlying the modulation of GABA release by PKC seems to be independent of presynaptic GABA, dopamine and 5-hydroxytryptamine receptors.

Alkaloids↗
PubMed1996

Pharmacological profile of benzodiazepine site ligands with recombinant GABAA receptor subtypes.

Using [3H]flumazenil as a probe we investigated how benzodiazepine site pharmacology of alpha beta gamma ternary combinations of GABAA receptors can be influenced upon expression of different isoforms of alpha, beta and gamma subunits. The nature of the beta subunit did not alter the pharmacology of this site in that the affinities of alpha 5-containing GABAA receptors for various benzodiazepine modulatory ligands were essentially unchanged upon a comparison of different beta-variant forms (alpha 5 beta 1 gamma 2, alpha 5 beta 2 gamma 2 and alpha 5 beta 3 gamma 2). In contrast, both alpha and gamma variants contributed to notable differences in benzodiazepine site pharmacology. Thus alpha 1 beta 2 gamma 2, alpha 3 beta 2 gamma 2 and alpha 5 beta 2 gamma 2 receptors showed high, intermediate and low affinities for zolpidem, respectively. Exchanging gamma 2 for gamma 3 reduced the affinities of alpha 1 beta 2 gamma and alpha 3 beta 2 gamma receptors for zolpidem by factors of > 150 and > 5.8, respectively. The alpha 1 beta 2 gamma 3, alpha 3 beta 2 gamma 3 and alpha 5 beta 2 gamma 3 receptors exhibited, in contrast, higher affinity for CL218872 than their corresponding gamma 2 receptors. The information on these different recombinant GABAA receptor pharmacological profiles should help in the elucidation of native GABAA receptor subtype diversity.

Animals↗
PubMed1997

Blockade of behavioral effects of bretazenil by flumazenil and ZK 93,426 in pigeons.

Benzodiazepine receptor partial agonists manifest full efficacy in preclinical tests of anxiolytic drug action but do not fully reproduce the discriminative stimulus effects of benzodiazepine receptor full agonists in pigeons. The partial agonist, bretazenil, binds to both diazepam-sensitive and diazepam-insensitive GABAA receptors. Previous studies have suggested a role for each of these receptor populations in some behavioral effects of bretazenil in pigeons. A possible role for these receptor subtypes in the behavioral effects of bretazenil was further investigated through drug interaction studies with the benzodiazepine receptor antagonists, flumazenil and ZK 93,426. Whereas flumazenil binds with high affinity to both receptor isoforms, ZK 93,426 binds preferentially to diazepam-sensitive binding sites. Bretazenil markedly increased punished responding of pigeons without significantly affecting nonpunished responding. In pigeons discriminating the full benzodiazepine receptor agonist, midazolam, from saline, bretazenil produced only 60-75% maximal effect. Flumazenil and ZK 93,426 neither increased punished responding nor substituted for midazolam, but dose-dependently blocked the effects of bretazenil on punished responding. Flumazenil also dose-dependently blocked the effects of bretazenil in midazolam-discriminating pigeons, whereas ZK 93,426 only attenuated this effect. These results indicate that bretazenil's actions as a partial agonist at diazepam-sensitive benzodiazepine receptors mediate increases in punished responding and substitution for the discriminative stimulus effects of midazolam in pigeons. The differences in the effects of flumazenil and ZK 93,426 on the discriminative stimulus effects of bretazenil suggest a potential contribution of diazepam-insensitive sites to this behavioral effect.

Animals↗
PubMed2000

The role of the benzodiazepine-GABA system in the memory processes of the day-old chick.

This series of experiments investigated the effect of the benzodiazepine diazepam on memory formation in day-old chicks trained on a single-trial, passive-avoidance task. The findings indicate that diazepam has a dose-specific and time-dependent effect on memory processes. A 0.125-mg/kg dose of diazepam administered immediately after training led to amnesia in these subjects only after 30 min following learning. Pretreatment with bicuculline and flumazenil were effective in ameliorating the memory deficits caused by diazepam, and consolidated memory function in saline-treated controls following strong and weak aversant training. These findings suggest that benzodiazepine effects on memory are mediated by their effects on arousal, possibly by the release of noradrenaline, which is critical to the establishment of long-term memory.

Animals↗
PubMed2001

Human GABA(B)R genomic structure: evidence for splice variants in GABA(B)R1 but not GABA(B)R2.

The type B gamma-aminobutryic acid receptor (GABA(B)R) is a G protein coupled receptor that mediates slow pre- and post-synaptic inhibition in the nervous system. We find that the human GABA(B)R2 gene spans greater than 350 kb and contains 2.8 kb of coding region in 19 exons. The overall similarity in genomic structure with regard to conservation of intron position and exon size between human or Drosophila GABA(B)R1 and GABA(B)R2 genes suggests a common ancestral origin. Multiple transcripts GABA(B)R1a-c and GABA(B)R2a-c have been described and alternative splicing has been proposed to result in GABA(B)R1c, GABA(B)R2b and GABA(B)R2c. The results described here provide support for the existence of GABA(B)R1c but not for GABA(B)R2b and GABA(B)R2c. Splice junctions present in the GABA(B)R1 gene sequence are consistent with the formation of GABA(B)R1c by exon skipping of one sushi domain module. The GABA(B)R2 gene lacks canonical splice junctions for the reported variants. Consistent with this, RNA analysis demonstrates the presence of GABA(B)R1c and GABA(B)R2 transcripts in fetal and adult human brain RNA but GABA(B)R2b and GABA(B)R2c transcripts are not detected. These results provide insight into the evolution and transcript diversity of the mammalian GABA(B)R genes.

Alternative Splicing↗
PubMedDate not supplied

A structure-activity relationship study of the affinity of selected imidazo[1,2-a]pyridine derivatives, congeners of zolpidem, for the omega 1-subtype of the benzodiazepine receptor.

A series of 6-substituted 2-aryl-N,N-dimethylimidazol[1,2-a] pyridine-3-acetamides, congeners of zolpidem and alpidem, was synthesized and tested in vitro for binding with the benzodiazepine receptor in the competition with 3H-zolpidem as an omega 1-selective radioligand. Molecular electrostatic potential (MEP) and the HOMO and LUMO energies were calculated for the compounds by semi-empirical quantum chemistry methods. The lipophilicity parameter of the compounds, expressed as the logarithm of the octanol-water partition coefficient (log P), was calculated; alternatively, standard values of the Hansch hydrophobic substituent constants pi were used. In agreement with earlier investigations on the benzodiazepine receptor ligands with a high preference for the omega 1-subtype, a quantitative correlation of the biological data with molecular parameters has revealed a significant dependence (r = 0.954) of the binding affinity (IC50) on the deepest MEP minimum, in this case associated with the amide carbonyl oxygen atom. The lipophilicity parameters were found to be of lower significance.

Animals↗
PubMed1984

Biochemical pharmacology of the gamma-aminobutyric acid receptor/ionophore protein.

The synaptic receptor sites for the neurotransmitter gamma-aminobutyric acid (GABA) can be assayed in vitro with several radiolabeled agonists and one antagonist. Numerous criteria of specificity have been met for these binding sites. All of the ligands show heterogeneity in binding affinities. The subpopulations thus defined have a remarkably similar specificity for GABA analogs, which suggests an intimate relationship and possible interconvertibility. Modulation of GABA receptor binding by barbiturates, anions, and other membrane treatments that affect agonists and antagonists in an opposite manner suggests a three-state model of interconvertible affinities. The complex of GABA receptor and chloride ion channel contains modulatory sites for barbiturates and benzodiazepines, drugs that enhance GABA responses in neurons. The receptor complex can be solubilized in detergent with the three mutually interacting receptor activities intact. The complex has an apparent molecular weight of 355,000 and has been partially purified. GABA agonist function has been assayed at the biochemical level by measuring the activation of 36Cl- efflux from preloaded hippocampal slices by GABA, muscimol, and barbiturates. This response is blocked by the antagonists of the GABA site (bicuculline) and the barbiturate site (picrotoxin). Comparison of binding and function on the same tissue should be useful in analyzing the mechanism of action of GABA.

Allosteric Regulation↗
PubMed1994

Muscarinic M1 receptor mediated inhibition of GABA release from rat cerebral cortex.

Presynaptic modulation of [3H]GABA release was examined using rat cerebral cortical slices. In vitro addition of carbachol, a muscarinic receptor agonist, resulted in a significant suppression of the release of [3H]GABA evoked by high potassium (50 mM) stimulation in a dose dependent manner, while noradrenaline, isoproterenol, dopamine, 5-hydroxytryptamine, histamine and glutamic acid had no significant effect on the evoked release of [3H]GABA. This suppressive effect of carbachol was antagonized invariably by atropine. Furthermore, it was found that the suppressive action of carbachol could be antagonized by pirenzepine, a selective M1 muscarinic receptor antagonist, but not by AF-DX 116 and 4-DAMP, M2 and M3 receptor antagonists, respectively. These results suggest that the release of GABA from cerebral cortical GABA neurons may be modulated by presynaptic M1 muscarinic receptor.

Animals↗
PubMed2003

GABAergic mechanisms gate tactile discrimination learning.

In contrast to mechanisms mediating synaptic plasticity, the pharmacological basis of perceptual learning remains to be clarified. Here we report that a specific form of perceptual learning is influenced by GABAergic mechanisms. We induced perceptual learning by Hebbian co-activation of the skin of the tip of the right index fingers in human subjects. Under placebo conditions, tactile 2-point discrimination was improved on the co-activated, but not on the left, index finger. This augmentation was completely eliminated by lorazepam, a GABAA receptor agonist. No drug effects were found on the left index finger indicating that the drugs had no effect per se on performance. The results demonstrate that perceptual learning is subject to pharmacological gating by basic mechanisms known to mediate and modulate synaptic plasticity.

Adult↗
PubMed2004

Effects of diazepam and zolpidem on EEG beta frequencies are behavior-specific in rats.

A pharmacological dissociation of the relation between electroencephalographic (EEG) activity and behavior has been described for the benzodiazepines. While a decrease in high frequency EEG activity is associated with a decrease in arousal in drug-free conditions, sedative benzodiazepines increase beta activity. Non-benzodiazepine GABA(A) receptor modulators can increase beta activity as well. To further study the relationship between rat behavior and EEG under GABA(A) receptor modulation, EEG effects of diazepam (2.5 mg/kg) and zolpidem (2.5 mg/kg) were studied during different behaviors. Both drugs modulate the GABA(A) receptor, albeit that zolpidem shows alpha(1) subunit selectivity while diazepam is non-selective. A detailed analysis of rat open field behavior was made with a distinction of 25 behavioral elements. The EEG was segmented according to each behavioral element and a corresponding power spectrum calculated. Both diazepam and zolpidem increased EEG beta frequencies, characteristic for the benzodiazepines. However, the beta and gamma increase was specific for active behavior and not for inactivity. Interestingly, diazepam and zolpidem seemed to amplify, rather than dissociate, the relation between behavior and the EEG. It is hypothesized that the large increase in beta-3/gamma activity caused by diazepam and zolpidem is a compensatory mechanism that allows for behavioral activation, despite pharmacologically induced sedation.

Animals↗
PubMed2004

Inhibition of type A GABA receptors by L-type calcium channel blockers.

Modulation of type A GABA receptors (GABAA) by L-type Ca++ channel blockers was investigated. The dihydropyridines nifedipine and nitrendipine, and the phenylalkylamine verapamil inhibited recombinant rat alpha1beta2gamma2 receptors recorded from human embryonic kidney (HEK) 293 cells; nifedipine at low concentrations also elicited modest stimulatory effects on GABA-gated current. The IC50 for GABA current inhibition was lowest for nitrendipine (17.3 +/- 1.3 microM), so subsequent studies were focused on further exploring its mechanism and possible site of action. When co-applied with GABA, nitrendipine had minimal effects on initial current amplitude, but significantly enhanced current decay rate. Nitrendipine-mediated inhibition was subunit-selective, as its IC50 was 10-fold lower in alpha1beta2 receptors. Nitrendipine's effect in recombinant human alpha1beta2gamma2 receptors was similar (IC50=23.0 +/- 1.3 microM) to that observed in rat receptors of the same configuration, indicating the site of action is conserved in the two species. The inhibitory effects were dependent on channel gating, were independent of transmembrane voltage, and were also observed in GABAA receptors recorded from hypothalamic brain slices. The pharmacologic mechanism of inhibition by nitrendipine was non-competitive, indicating it does not act at the GABA binding site. Nitrendipine block was retained in the presence of the benzodiazepine antagonist flumazenil, indicating it does not interact at the benzodiazepine site. The actions of nitrendipine were not affected by a mutation (beta2T246F) that confers resistance to the channel blocker picrotoxin, and they were not altered in the presence of the picrotoxin site antagonist alpha-isopropyl-alpha-methyl-gamma-butyrolactone, demonstrating nitrendipine does not act at the picrotoxin site of the GABAA receptor. Possible interaction of nitrendipine with the Zn++ site was also eliminated, as mutation of beta2 H267 to A, which confers resistance to Zn++, had no effect on nitrendipine-mediated inhibition. Our data suggest some of the central effects of dihydropyridines may be due to actions at GABAA receptors. Moreover, the effects may be mediated through interaction with a novel modulatory site on the GABAA receptor.

4-Butyrolactone↗