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PubMed1985

Brain benzodiazepine receptor binding and purine concentration in Lesch-Nyhan syndrome.

Benzodiazepine receptor [( 3H]flunitrazepam) binding and purine concentration were measured in autopsied cerebral cortex of 4 patients who died with Lesch-Nyhan syndrome. Receptor density was normal in all 4 regions of Lesch-Nyhan cortex examined. However, an enhancement of benzodiazepine receptor affinity (25% reduction in Kd) was found in well-washed parietal and occipital cortex homogenates. Maximal gamma-aminobutyric acid (GABA) stimulation of [3H]flunitrazepam binding was normal in temporal, parietal and occipital cortex but markedly reduced (by 50-80%) in frontal cortex. Increased sensitivity to hypoxanthine inhibition (30% reduction in Ki) was also observed in parietal cortex. The concentrations of the purines hypoxanthine, xanthine and inosine in Lesch-Nyhan parietal cortex were about twice the values measured in control material matched for postmortem time. We suggest that the above-normal concentrations of purines estimated to be present in Lesch-Nyhan brain may be sufficient to significantly affect the ability of the benzodiazepine receptor to modulate GABA-mediated brain mechanisms.

Adolescent↗

PubMed2002

Modulation of human corticomotor excitability by somatosensory input.

In humans, somatosensory stimulation results in increased corticomotoneuronal excitability to the stimulated body parts. The purpose of this study was to investigate the underlying mechanisms. We recorded motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) from abductor pollicis brevis (APB), first dorsal interosseous (FDI), and abductor digiti minimi (ADM) muscles. MEP amplitudes, recruitment curves (RC), intracortical inhibition (ICI), intracortical facilitation (ICF), resting (rMT) and active motor thresholds (aMT) were recorded before and after a 2-h period of ulnar nerve electrical stimulation at the wrist. Somatosensory input was monitored by recording somatosensory evoked potentials. To differentiate excitability changes at cortical vs. subcortical sites, we recorded supramaximal peripheral M-responses and MEPs to brainstem electrical stimulation (BES). In order to investigate the involvement of GABAergic mechanisms, we studied the influence of lorazepam (LZ) (a GABA(A) receptor agonist) relative to that of dextromethorphan (DM) (an NMDA receptor antagonist) and placebo in a double-blind design. We found that somatosensory stimulation increased MEP amplitudes to TMS only in the ADM, confirming a previous report. This effect was blocked by LZ but not by either DM or placebo and lasted between 8 and 20 min in the absence of (i) changes in MEPs elicited by BES, (ii) amplitudes of early somatosensory-evoked potentials or (iii) M-responses. We conclude that somatosensory stimulation elicited a focal increase in corticomotoneuronal excitability that outlasts the stimulation period and probably occurs at cortical sites. The antagonistic effect of LZ supports the hypothesis of GABAergic involvement as an operating mechanism.

Adolescent↗

PubMed1998

Evidence of GABAergic modulation in melatonin-induced short-term memory deficits and food consumption.

Many of the pharmacological effects of melatonin have been found to be similar to those of benzodiazepines. In the present study, we analyzed the role of melatonin on short-term memory retrieval on transfer latency in elevated plus maze and food consumption behavior, and the effects were compared with those of diazepam. Melatonin dose-dependently (10-100 mg/kg) produced short-term memory deficit and it potentiated diazepam- (1 mg/kg) induced cognitive deficit in mice. Flumazenil (1 and 4 mg/kg) could reverse enhancement in diazepam-induced memory deficit by melatonin. Chronic treatment with melatonin (10 mg/kg/7d) produced a similar profile in transfer latency on elevated plus maze compared with that of diazepam. In a food consumption behavior study, melatonin (25 and 50 mg/kg) produced a significant hyperphagic effect compared to control. Flumazenil (4 mg/kg) could significantly reverse the hyperphagic effects induced by diazepam (2 mg/kg), but would be insignificant with regard to that due to melatonin. These findings provide further evidence that some of the pharmacological effects of melatonin are comparable with those of diazepam and may involve central GABAergic mechanism.

Animals↗

PubMed2002

The bindings of [3H]muscimol and [3H]flunitrazapam are elevated in discrete brain regions of butorphanol-withdrawal rats.

We have investigated the effects of continuous infusion of butorphanol on the modulation of GABA(A) receptor binding. Butorphanol was infused continuously into intracerebroventricle (ICV) at a constant rate of 26 nmol/microl/h for 3 days, and the withdrawal from opioid was rendered 7 h after the cessation of infusion. The GABA(A) receptor bindings in rat brain slices were analyzed by quantitative autoradiography using [3H]muscimol and [3H]flunitrazepam. In the rats withdrawn from butorphanol, the levels of [3H]muscimol binding were significantly elevated in cortex, thalamus, and part of the hippocampus. The levels of [3H]flunitrazepam binding were elevated in almost all of brain regions including cortex, caudate putamen, thalamus, hippocampus, brainstem, and cerebellum in the rats withdrawn from butorphanol. The levels of binding of either [3H]muscimol or [3H]flunitrazepam were not changed in the rats tolerant to butorphanol. However, the activity of GABAergic neuron was not found to have been modulated by butorphanol withdrawal, because the level of glutamic acid decarboxylase was not changed markedly either in rats that were tolerant to or withdrawn from butorphanol by Western blot and immunohistochemical data. These results suggest that the withdrawal from butorphanol infusion markedly elevates the binding of [3H]muscimol and [3H]flunitrazepam throughout the brain in a region-specific manner, and that the regulatory mechanisms in butorphanol tolerance and withdrawal may be different.

Animals↗

PubMed1993

Enteric GABA-containing nerves projecting to the guinea-pig inferior mesenteric ganglion modulate acetylcholine release.

1. The effect of GABA and GABA receptor-modulating drugs on release of [3H]acetylcholine was studied in the guinea-pig inferior mesenteric ganglion. 2. GABA caused a dose-dependent increase in [3H]acetylcholine release during stimulation of the lumbar colonic nerves. Muscimol (10 microM) and diazepam (5 microM) also increased [3H]acetylcholine release during stimulation of the lumbar colonic nerves whereas baclofen (10 microM) had no effect. 3. Bicuculline (20-100 microM) and picrotoxin (50 microM) alone reduced [3H]acetylcholine release during electrical stimulation of the lumbar colonic nerves whereas phaclofen (300 microM) had no effect. 4. Bicuculline (100 microM) significantly decreased whereas diazepam (5 microM) significantly increased distension-induced [3H]acetylcholine release. 5. Colonic distension significantly increased [3H]GABA release in the inferior mesenteric ganglion compared to basal periods when the colon was not distended. Distension-induced release of [3H]GABA resulted from active neuronal transmission from the colon to the inferior mesenteric ganglion, since perfusion of the inferior mesenteric ganglion with tetrodotoxin (1 microM) reduced basal release of [3H]GABA and abolished distension-evoked increases in the release of [3H]GABA. 6. In contrast to its excitatory effects on peripheral colonic afferent cholinergic nerves, exogenous GABA caused a dose-dependent decrease in [3H]acetylcholine release during electrical stimulation of the central lumbar splanchnic nerves. Baclofen (10 microM) also inhibited [3H]acetylcholine release whereas muscimol (10 microM) or diazepam (5 microM) had no effect. Phaclofen (300 microM) antagonized the inhibitory effects of exogenous GABA (10 microM) and of baclofen (10 microM). Bicuculline (100 microM), picrotoxin (50 microM) and phaclofen (300 microM) alone had no effect on [3H]acetylcholine release during splanchnic nerve stimulation. 7. Phaclofen (300 microM) increased [3H]acetylcholine release during simultaneous electrical stimulation of the lumbar colonic nerves and splanchnic nerves and when GABAA receptors were blocked by bicuculline (20 microM). 8. The data suggest that GABAA receptors facilitate release of acetylcholine from peripheral cholinergic mechanosensory nerves projecting from the colon to the inferior mesenteric ganglion and that GABAB receptors inhibit release of acetylcholine from central cholinergic nerves. Enteric GABA-containing nerves projecting to the inferior mesenteric ganglion are mechanosensory. Endogenous release of GABA may act on GABAA receptors to facilitate peripheral cholinergic mechanosensory transmission and/or on GABAB receptors to inhibit central cholinergic transmission.

Acetylcholine↗

PubMed1998

Functional characterization and visualization of a GABAA receptor-GFP chimera expressed in Xenopus oocytes.

The GABAA receptor is a ligand-gated chloride channel belonging to the superfamily of ligand-gated ion channels of which the nicotinic acetylcholine (nACh) receptor is prototypic. In the central nervous system the GABAA receptor mediates fast neuronal inhibition. To facilitate the study of this receptor, a GABAA receptor-green fluorescent protein (GABAAR-GFP) chimera was constructed by fusing green fluorescent protein (GFP) to the C-terminus region of the GABAA receptor alpha1 subunit. When expressed in Xenopus oocytes, this chimera responded in a manner indistinguishable from the wild-type GABAA receptor with respect to agonist potency, receptor desensitization, allosteric modulation, rectification, and ion selectivity of the channel. The addition of GFP to the GABAA receptor alpha1 subunit did not appear to alter the assembly or efficiency of expression of the GABAA receptor complex. The GABAAR-GFP chimera generated a strong fluorescent signal that was restricted to the animal pole of the oocyte plasma membrane. This signal was readily detectable using either epifluorescence or laser confocal microscopy. To confirm the extracellular location of the GFP portion of the chimera, non-permeabilized oocytes were immunolabeled with an anti-GFP antibody. Fluorescence microscopy showed that GFP was located extracellularly since it was accessible to the GFP antibody. These results confirm the predicted extracellular location of the C-terminus of the GABAA receptor alpha1 subunit and also demonstrate that GFP retains its fluorescent property when expressed extracellularly. The usefulness of the GABAAR-GFP chimera in receptor trafficking was investigated using non-hydrolyzable GTP analogues since GTP binding proteins participate in protein transport in oocytes. Microinjections of GTP-gamma-S but not GDP-beta-S reduced both GABA-gated chloride currents and cell surface GFP fluorescence in oocytes expressing the GABAAR-GFP chimera indicating that the chimera undergoes internalization upon stimulation of oocyte GTP-binding proteins. The results of the present study show that the GABAAR-GFP chimera is functionally similar to the wild-type GABAA receptor and can be used to study receptor trafficking in living cells. This is the first demonstration of a ligand-gated ion channel-GFP chimera for an ion channel belonging to this superfamily and also is the first example of the fusion of GFP to an extracellular domain of an integral membrane protein.

Anesthetics↗

PubMed2003

GABAB receptor-mediated presynaptic potentiation of ATP ionotropic receptors in rat midbrain synaptosomes.

Nucleotides can activate ionotropic P2X receptors that induce calcium-responses in rat midbrain synaptosomes. In this report, we show that ATP elicits Ca(2+) responses producing a monophasic dose-response curve with an EC(50) value of 24.24+/-1.42 micro M. In the presence of gamma-aminobutyric acid (GABA), the ATP dose-response curve becomes biphasic with EC(50) values of 3.69+/-0.44 nM and 59.65+/-8.32 micro M. Moreover, the maximal calcium response induced by ATP is 52.1% higher than the control. This effect is mimicked or blocked by the specific GABA(B) receptor agonist and antagonist, baclofen and saclofen, respectively. Presynaptic GABA(B) receptors, identified by immunocytochemistry are present in 62% of the total synaptosomal population. Adenylate cyclase and protein kinase A cascades are involved in the potentiatory effects mediated by baclofen and their activation or inhibition modifies calcium signalling and synaptosomal cAMP levels. The potentiatory action of baclofen was confirmed by microfluorimetry performed on single synaptic terminals. In its presence, 86% of the terminals responding to 100 micro M ATP, are also able to respond to nanomolar concentrations (100 nM) of this nucleotide. This potentiatory effect is reduced to 32% in the presence of pertussis toxin. Our data suggest that the activity of P2X receptors is modulated by GABA(B) receptors in midbrain synaptosomes.

Adenosine Triphosphate↗

PubMed2003

Investigations into the potential neurotoxicity induced by diselenides in mice and rats.

It is well known that selenium is highly toxic to several species of mammals. Here we report the potential neurotoxicity of diselenides, as measured by the manifestation of seizures. The modulation of various neurotransmitter systems potentially involved in seizure episodes and death was also evaluated. The results of the present investigation suggest that toxicity of diselenides depends on the route of administration as well the species (rats or mice). These data show that modulation of more than one neuronal system can account for diselenide-induced seizures in mice. Additionally, changes in structure of diselenides, such as to introduce a functional group, influence the appearance of seizure episode. Conversely, all allosteric modulators tested did not protect dipropyl diselenide-induced seizures, indicating that aliphatic is more toxic than aromatic diselenides. Acute treatment with dipropyl diselenide inhibited [3H]-glutamate uptake to the crude synaptosomes. In contrast animals injected with diphenyl diselenide did not inhibit [3H]-glutamate uptake.

Animals↗

PubMed1996

5-HT1A and benzodiazepine receptors in the basolateral amygdala modulate anxiety in the social interaction test, but not in the elevated plus-maze.

In order to investigate the role of the 5-HT1A receptors of the amygdala in modulating anxiety, rats were implanted with bilateral cannulae aimed at the basolateral nucleus of the amygdala complex and infused with either artificial cerebrospinal fluid (aCSF) or the selective 5-HT1A receptor agonist 8-OH-DPAT (50-200 ng) and tested in two animal models of anxiety. In the elevated plus-maze test, no significant effects were detected in this dose range. In contrast, 8-OH-DPAT caused an overall reduction in levels of social investigation, thus indicating anxiogenic actions in the social interaction test. At 50 ng, 8-OH-DPAT had a selective action on anxiety, while at 200 ng there was a concomitant reduction in locomotor activity and, in some animals, signs of the 5-HT1A syndrome. Evidence that the anxiogenic effect of 8-OH-DPAT (50 ng) was due to activation of 5-HT1A receptors came from the finding that (-)-tertatolol, a 5-HT1A receptor antagonist, reversed this effect at a dose (1.5 micrograms) which was silent when given alone. The benzodiazepine receptor agonist, midazolam (1 and 2 micrograms) was bilaterally administered into the basolateral nucleus of the amygdala and evoked clear-cut anxiolytic effects in the social interaction test. These data indicate that the agonist activation of post-synaptic 5-HT1A receptors in the basolateral nucleus of the amygdala may produce anxiogenic effects, while agonist activation of BDZ receptors in the same areas evokes anxiolytic effects. Our results from the social interaction test are similar to those previously reported from tests of anxiety using punished paradigms, but contrast with those found in the elevated plus-maze. Thus, it is concluded that either the two tests have different sensitivities to midazolam and 8-OH-DPAT or more intriguingly, the tests are evoking fundamentally different states of anxiety, with that evoked by the plus-maze being mediated via brain areas or receptors different from those studied here.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1988

Neuropeptide Y in the rat nucleus accumbens: ultrastructural localization in aspiny neurons receiving synaptic input from GABAergic terminals.

The ultrastructure, afferent input, and sites of termination of neurons containing neuropeptide Y-like immunoreactivity (NPY-LI) were examined in the adult rat nucleus accumbens by using the peroxidase-antiperoxidase (PAP) method. The NPY-LI was seen in sparsely distributed, spindle-shaped perikarya having cross-sectional diameters of 15-20 microns. These perikarya exhibited highly invaginated nuclear membranes and thin rims of cytoplasm containing Golgi lamellae, dense-core vesicles, and other organelles. A few large, principally aspiny, dendrites also showed NPY-LI. The dendrites received synaptic input from unlabeled terminals forming both symmetric and asymmetric junctions. Immunolabeling for NPY was evident in other processes that were not clearly differentiated as dendrites or axons. These were seen primarily near glial processes and the basal laminae of blood vessels. A few myelinated and many unmyelinated axons and axon terminals also were labeled for NPY. These terminals contained numerous, small (40-60 nm), clear and one or more large (80-100 nm) dense core vesicles. Forty-seven percent (27 out of 57) of the terminals containing NPY-LI formed symmetric junctions with unlabeled dendrites or dendritic spines. The remainder lacked recognizable densities within single planes of section. The neurons exhibiting NPY-LI in the nucleus accumbens were characterized further with respect to their afferent input from terminals labeled for the GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD). Immunogold labeling of a rabbit antiserum against NPY and PAP labeling for a sheep antiserum to GAD were sequentially applied to the same sections. The GAD-labeled terminals formed symmetric junctions primarily with the more numerous unlabeled dendrites. However, a few synaptic junctions also were detected between the GAD-labeled terminals and dendrites showing immunogold labeling for NPY. We conclude (1) that in the rat nucleus accumbens, NPY-LI is found principally in neurons of the aspiny type and (2) that the output from these presumably intrinsic neurons to other neighboring neurons or blood vessels is at least partially modulated by GABA.

Animals↗

PubMed1983

Benzodiazepine receptor mediated discriminative cues: effects of GABA-ergic drugs and inverse agonists.

Rats were exposed to a two-lever drug discrimination procedure using the benzodiazepine (BZ) receptor inverse agonists N'-methyl-beta-carboline-3-carboxamide (FG 7142) or methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). FG 7142 (30 mg/kg) failed to acquire discriminative stimulus control, although it did suppress responding. The same group of animals was trained successfully to discriminate diazepam (DZP, 2.5 mg/kg) from vehicle. The DZP cue was potentiated by the GABA agonist 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol (THIP, 1,3 mg/kg); THIP alone produced vehicle-appropriate responding. In addition, clonazepam (0.2 mg/kg) and chlordiazepoxide (5 mg/kg) substituted for DZP (with potencies of 7.5 and 0.25 times that of DZP, respectively). In antagonism tests, FG 7142 (5-17.5 mg/kg), methyl-beta-carboline-3-carboxylate (beta-CCM, 2.5 mg/kg) did not effect, bicuculline (2 mg/kg) and DMCM (1 mg/kg) partially blocked, and the BZ receptor antagonist Ro 15-1788 (40 mg/kg) completely blocked the discriminative stimulus effects of DZP. In animals trained to discriminate DMCM (0.2 mg/kg) from vehicle, 95.2% substitution occurred with bicuculline (2 mg/kg); DZP (1-5 mg/kg) completely antagonized DMCM. These results indicate that the DZP cue is mediated by GABA-coupled BZ receptors and that GABA may modulate the efficacy of a BZ at its receptor site. However, since inverse BZ receptor agonists (FG 7142, DMCM and beta-CCM) were, at best, only marginally effective in antagonizing DZP, the DZP cue may be mediated by a distinct subclass of BZ receptors.

Animals↗

PubMed2004

The gamma-aminobutyric acidergic effects of valerian and valerenic acid on rat brainstem neuronal activity.

UNLABELLED: Valerian is a medicinal herb that produces anxiolytic and sedative effects. It was suggested that valerian acts via gamma-aminobutyric acid (GABA)ergic mechanisms. Previous studies showed binding of valerian extract to GABA receptors, but the functional effect of the binding has not been demonstrated. In this study we evaluated the GABAergic effect of valerian extract and one of its major constituents, valerenic acid, on brainstem neuronal activity in an in vitro neonatal rat brainstem preparation. We first observed that muscimol, a GABA(A) receptor agonist, decreased the firing rate in most brainstem neurons in a concentration-related fashion; 30 micro M produced a 38.9% +/- 3.0% (mean +/- SE) inhibition compared with control values (P < 0.01; 50% inhibitory concentration [IC(50)], 2.0 +/- 0.1 microM). This effect was antagonized by bicuculline (10 microM), a GABA(A) antagonist. Then we showed that valerian extract 3 mg/mL induced a 29.6% +/- 5.1% inhibition with an IC(50) of 240 +/- 18.7 microg/mL, whereas 100 microM valerenic acid induced a 22.2% +/- 3.4% inhibition with an IC(50) of 23 +/- 2.6 microM (both P < 0.01). Bicuculline antagonized the inhibitory effects of both the valerian extract and valerenic acid. In addition, pretreatment with valerian extract or valerenic acid decreased the brainstem inhibitory effects produced by muscimol (both P < 0.05), suggesting that these compounds play an important role in the regulation of GABAergic activity. Data from this study suggest that the pharmacological effects of valerian extract and valerenic acid are mediated through modulation of GABA(A) receptor function. Thus, valerian may potentiate the sedative effects of anesthetics and other medications that act on GABA receptors, and presurgical valerian use may cause a valerian-anesthetic interaction. IMPLICATIONS: Valerian is an herb used in treating anxiety and insomnia. We observed that the valerian effects are mediated through brain gamma-aminobutyric acid (GABA) receptors in a rat brainstem preparation. Thus, valerian may potentiate the effects of anesthetics that act on GABA receptors, and presurgical valerian use may cause a valerian-anesthetic interaction.

Animals↗

PubMed1999

Subunit dependent modulation of GABAA receptor function by neuroactive steroids.

Neurosteroids are potent, endogenous modulators of GABAA receptor function in the central nervous system. The endogenous progesterone metabolite allopregnanolone (ALP) and the synthetic steroid compound alphaxalone (AFX) have been shown to both directly activate and potentiate GABAA receptor-activated membrane current (IGABA). The role of different alpha and gamma subunit subtypes in modulation of IGABA by ALP and AFX was investigated using recombinant GABAA receptor isoforms expressed in Xenopus oocytes. Changing or removal of the alpha subunit subtype altered the efficacy of both ALP and AFX (alpha2beta1gamma2L>alpha1beta1gamma2L>>beta1gamma2L) to potentiate IGABA, but did not alter the potency of the neuroactive steroids at these receptor isoforms. The efficacy of ALP to enhance IGABA was also dependent on the gamma subunit subtype (alpha1beta1gamma3>alpha1beta1gamma2L = alpha1beta1gamma1). AFX also had higher efficacy in the alpha1beta1gamma3 receptor isoform compared to alpha1beta1gamma1. In contrast to ALP, the potency of AFX was greater in the alpha1beta1gamma3 and alpha1beta1gamma1 receptor isoforms compared to alpha1beta1gamma2L. This study provides evidence that the alpha subunit subtype determines the efficacy, but not the potency, of these neuroactive steroids to potentiate IGABA. The gamma3 subunit subtype increases the maximal efficacy of neuroactive steroids compared to other gamma subunit subtypes. These results suggest that the heteromeric assembly of different GABAA receptor isoforms containing different subunit subtypes results in multiple steroid recognition sites on GABAA receptors that in turn produce distinctly different modulatory interactions between neuroactive steroids acting at the GABAA receptor.

Animals↗

PubMed2001

Effects of CRH and ACTH administration on plasma and brain neurosteroid levels.

The 3alpha-hydroxy ring A-reduced metabolite of progesterone, 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) is among the most potent known ligands of the gamma aminobutyric acid (GABA) receptor, designated GABA-A, in the central nervous system. We determined by RIA serum levels of progesterone (PROG), 5-alpha-dihidroprogesterone (DHP) and allopregnanolone in male and female rats after corticotropin releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) administration. Allopregnanolone was undetectable in plasma and brain of control males but detectable in plasma and brain of males injected with CRH and ACTH and of control and similarly treated females. Allopregnanolone increased in the plasma and brain after CRH and ACTH administration in all cases. The data demonstrate that the administration of CRH plus ACTH results in a rapid increase of the neuroactive steroid allopregnanolone in the brain of males and females to levels known to modulate GABA-A receptor function. Thus, stress could regulate neurosteroid biosynthesis via the hormones ACTH and CRH.

20-alpha-Dihydroprogesterone↗

PubMed2001

Homeostatic plasticity induced by chronic block of AMPA/kainate receptors modulates the generation of rhythmic bursting in rat spinal cord organotypic cultures.

Generation of spontaneous rhythmic activity is a distinct feature of developing spinal networks. We report that rat embryo organotypic spinal cultures contain the basic circuits responsible for pattern generation. In this preparation rhythmic activity can be recorded from ventral interneurons and is developmentally regulated. When chronically grown in the presence of an AMPA/kainate receptor blocker, this circuit expresses long-term plasticity consisting largely of increased frequency of fast synaptic activity and reduction in slow GABAergic events. We examined whether, once this form of homeostatic plasticity is established, the network could still exhibit rhythmicity with properties similar to controls. Control or chronically treated ventral interneurons spontaneously generated (with similar probability) irregular, network-driven bursts over a background of ongoing synaptic activity. In control cultures increasing network excitability by strychnine plus bicuculline, or by raising [K(+)](o), induced rapid-onset, regular rhythmic bursts. In treated cultures the same pharmacological block of Cl(-)-mediated transmission or high-K(+) application also induced regular patterned activity, although significantly faster and, in the case of high K(+), characterized by slow onset due to postsynaptic current summation. Enhancing GABAergic transmission by pentobarbital surprisingly accelerated the high-K(+) rhythm of control cells (though depressing background activity), whereas it slowed it down in chronically treated cells. This contrasting effect of pentobarbital suggests that, to preserve bursting ability, chronic slices developed a distinct GABAergic inhibitory control on over-expressed bursting circuits. Conversely, in control slices GABAergic transmission depressed spontaneous activity but it facilitated bursting frequency. Thus, even after homeostatic rearrangement, developing mammalian spinal networks still generate rhythmic activity.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMedDate not supplied

Cholecystokinin-B (CCK-B) receptor antagonists improve "aged" sleep: a new class of sleep modulators?

Sleep disorders are a major, although often minimized and underdiagnosed, medical problem. Current therapy is based on the use of hypnotics, mainly benzodiazepines, which disrupt the sleep pattern often suppressing rapid-eye-movement (REM) sleep. Here, new types of pharmacological tools such as cholecystokinin (CCK) receptor antagonists are examined. In particular, since the awake-sleep rhythm is mainly altered in old age in humans, the influence of these compounds over REM and non-REM sleep has been studied in aged rats (21 months) vs. young rats (5 months) prepared for electroencephalographic (EEG) recordings. Basal EEG data indicated that REM and non-REM sleep was reduced in aged rats vs. young rats. GV-150013, a selective CCK-B receptor antagonist, was found to increase REM sleep, as well as non-REM sleep, and therefore total sleep (non-REM + REM) mainly in aged rats. The dose-range of activity (0.5-60 micrograms/kg) together with the evidence that another CCK-B receptor antagonist, L-365,260 (5 micrograms/kg) increased, while devazepide (a CCK-A receptor antagonist; 20 micrograms/kg) decreased non-REM sleep and total sleep time, support the original hypothesis that the activity of GV-150013 on sleep progress through CCK-B receptors. Furthermore, no tolerance was detected after chronic treatments with GV-150013. In contrast, typical EEG modifications (decrease of REM) and the development of tolerance towards benzodiazepines were monitored following chronic treatment with triazolam (400 micrograms/kg). These results suggest that the CCKergic compounds studied are involved via a different mechanism of action than benzodiazepines in the modulation of the awake-sleep rhythm. A further observation is that the total sleep time recorded in aged rats after treatment with GV-150013 reached the value of the total sleep time of young untreated rats also prepared for EEG. Finally, this work suggests that CCK receptor antagonists, GV-150013 in particular, are more effective in aged resulting in an improvement of sleep quality towards that of young rats.

Adamantane↗

PubMed1983

Benzodiazepine receptors: differential ligand interactions and purification of the receptor protein.

The benzodiazepine receptor can be considered as a regulatory unit for GABA receptor function. Receptor agonists such as the classical benzodiazepines induce a conformational change of the receptor which results in an enhancement of GABAergic transmission, leading to therapeutically useful effects. Inverse agonists such as several beta-carboline derivatives induce a different conformational change of the receptor resulting in a reduction of GABAergic transmission with concomitant anxiogenic and convulsant effects. Antagonists like Ro 15-1788 largely lack drug efficacy per se but antagonize the action of agonists and inverse agonists by competitive interaction at the receptor. Highly purified benzodiazepine receptor fractions showed properties similar to those in intact neuronal membranes. The receptor fractions contained high affinity binding sites for benzodiazepine agonists, antagonists and inverse agonists which were amenable to modulation by GABA. In addition, high affinity sites for GABA were present. The progress made in the isolation of the GABA receptor complex raises hopes to determine the molecular details of receptor function and of drug efficacy in the near future.

Affinity Labels↗

PubMed2001

Amphetamine-stimulated cortical acetylcholine release: role of the basal forebrain.

Systemic administration of amphetamine results in increases in the release of acetylcholine in the cortex. Basal forebrain mediation of this effect was examined in three experiments using microdialysis in freely-moving rats. Experiment 1 examined whether dopamine receptor activity within the basal forebrain was necessary for amphetamine-induced increase in cortical acetylcholine by examining whether intra-basalis perfusion of dopamine antagonists attenuates this increase. Systemic administration of 2.0 mg/kg amphetamine increased dopamine efflux within the basal forebrain nearly 700% above basal levels. However, the increase in cortical acetylcholine efflux following amphetamine administration was unaffected by intra-basalis perfusions of high concentrations of D1- (100 microM SCH 23390) or D2-like (100 microM sulpiride) dopamine receptor antagonists. Experiments 2 and 3 determined whether glutamatergic or GABAergic local modulation of the excitability of the basal forebrain cholinergic neurons influences the ability of systemic amphetamine to increase cortical acetylcholine efflux. In Experiment 2, perfusion of kynurenate (1.0 mM), a non-selective glutamate receptor antagonist, into the basal forebrain attenuated the increase in cortical acetylcholine produced by amphetamine. Experiment 3 revealed that positive modulation of GABAergic transmission by bilateral intra-basalis infusion of the benzodiazepine receptor agonist chlordiazepoxide (40 microg/hemisphere) also attenuated the amphetamine-stimulated increase in cortical acetylcholine efflux. These data suggest that amphetamine increases cortical acetylcholine release via a complex neuronal network rather than simply increasing basal forebrain D1 or D2 receptor activity.

Acetylcholine↗