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PubMed1996

The anaesthetic action and modulation of GABAA receptor activity by the novel water-soluble aminosteroid Org 20599.

The anaesthetic profile of a novel water-soluble aminosteroid, Org 20599 [(2 beta, 3 alpha, 5 alpha)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one methanesulphonate], and the ability of the compound to allosterically regulate the activity of the GABAA receptor, have been studied in comparison to the properties of established intravenous general-anaesthetic agents. Intravenously administered Org 20599 produced a rapid onset, short duration loss of the righting reflex in mice. The anaesthetic potency of Org 20599 was comparable to that of the steroids 5 alpha-pregnan-3 alpha-ol-20-one or alphaxalone, and exceeded that of propofol, thiopentone or pentobarbitone. Org 20599 and the reference anaesthetic agents allosterically displaced the binding of [35S]-t-butylbicyclophosphorothionate (TBPS) from GABAA receptors of rat-brain membranes with the order of potency: 5 alpha-pregnan-3 alpha-ol-20-one > Org 20599 > alphaxalone > propofol > thiopentone > pentobarbitone. At human recombinant alpha 1, beta 2, gamma 2L subunit-containing GABAA receptors expressed in Xenopus laevis oocytes, the anaesthetic agents produced a concentration-dependent and reversible potentiation of the peak amplitude of GABA-evoked currents. A similar positive allosteric action of Org 20599 was observed for the GABAA receptors expressed by bovine adrenal chromaffin cells maintained in culture. The rank order of potency in the aforementioned assays was identical to that determined from the displacement of TBPS binding. At concentrations greater than those required for potentiation of GABA, the anaesthetics exhibited GABA-mimetic effects with a rank order of potency that paralleled their modulatory activity. Such direct agonism varied greatly in maximal effect between compounds. The modulatory and direct agonist actions of Org 20599 were additionally confirmed utilizing rat hippocampal neurones in culture. The results indicate Org 20599 to be a potent and short-acting intravenous anaesthetic agent in mice and suggest positive allosteric regulation of GABAA receptor function to be a plausible molecular mechanism of action for the drug.

Anesthetics↗
PubMed2006

Neurosteroid analogues. 11. Alternative ring system scaffolds: gamma-aminobutyric acid receptor modulation and anesthetic actions of benz[f]indenes.

Benz[f]indenes are tricyclic compounds with a linear 6-6-5 fused carbocyclic ring system. When properly substituted, benz[f]indenes can satisfy the pharmacophore requirements of the critical hydrogen-bond donor and acceptor groups found in neuroactive steroids that modulate gamma-aminobutyric acidA (GABAA) receptor function. Thus, the benz[f]indene ring system provides an opportunity to extend the previously well-studied GABAA receptor structure-activity relationships (SAR) of neuroactive steroids to a different ring system. Depending on whether the stereochemistry of the 6-6-5 ring fusions are trans-trans or cis-trans, either planar or nonplanar benz[f]indenes are obtained. We found that the planar trans-trans benz[f]indenes are active, but less active than the steroids they were designed to mimic, whereas the nonplanar cis-trans compounds have little, if any, activity. The results provide new insight into the importance of the steroid framework for the actions of neuroactive steroids at GABAA receptors.

Animals↗
PubMed1987

Benzodiazepine ([3H]flunitrazepam) binding in cat visual cortex: ontogenesis of normal characteristics and the effects of dark rearing.

[3H]Flunitrazepam (FNZ) binding sites were characterized in homogenates of cat visual cortex during normal postnatal development and following dark rearing from birth. In parallel experiments, the distribution and density of [3H]FNZ binding sites were examined by in vitro autoradiographic or 'scrape' methods. In homogenates, Bmax measurements showed low early values, rising to a peak in receptor density at about 60 days postnatal, followed by a decline in adulthood. At all ages, gamma-aminobutyric acid (GABA) altered the Kd, but not the Bmax of [3H]FNZ binding sites. Kd values showed a general increase with age, parallelled by an increased sensitivity to GABA. Receptor autoradiography revealed that the highest density of [3H]FNZ binding sites was in layer IV of cats of all ages. Deafferentation of extrinsic inputs to the visual cortex by surgical undercutting did not alter this pattern of laminar distribution, indicating that the receptors were associated with intrinsic cortical elements rather than subcortical inputs. Dark rearing had no effect on [3H]FNZ laminar distribution in the visual cortex. The Bmax was higher at 30 days postnatal, but did not differ significantly thereafter. Modulation by GABA was concomitantly higher at 30 days, but lower than normal in dark-reared animals at ages greater than 30 days postnatal. The results are discussed in relation to the normal and abnormal development of GABA receptors in the cat visual cortex.

Animals↗
PubMed2000

Characterization of the anxiolytic properties of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3alpha, 21-dihydroxy-3beta-trifluoromethyl-19-nor-5beta-pregnan-20-one), a selective modulator of gamma-aminobutyric acid(A) receptors.

The purpose of this study was to evaluate the effects of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3alpha, 21-dihydroxy-3beta-trifluoromethyl-19-nor-5beta-pregnan-20-one), on gamma-aminobutyric acid(A) receptors in vitro and to define its anxiolytic-like effects and side effect profile in vivo. Co 2-6749 fully inhibited [(35)S]t-butylbicyclophosphorothionate binding in rat brain cortical membranes with an IC(50) value of 230 nM and in human gamma-aminobutyric acid(A) receptor subunit combinations of alpha1beta2gamma2L, alpha2beta2gamma2L, alpha3beta2gamma2L, alpha4beta3gamma2L, alpha5beta2gamma2L, and alpha6beta3gamma2L receptors (IC(50) values of 200, 200, 96, 2300, 210, and 2000 nM). Rats were trained in a Geller-Seifter operant conflict paradigm. Co 2-6749 caused a dose-related increase in punished responding with a minimum effective dose of 1.6 mg/kg, p.o., a wide therapeutic index relative to a decrease in unpunished responding and relative to ataxia, and no tolerance. Additionally, ethanol caused less than a 2-fold shift to the left in the dose-response function of Co 2-6749 in the rotorod procedure in rats. In a pigeon conflict paradigm, punished responding was maximally increased to 784% of vehicle control by 30 mg/kg, p.o., with a 2-h duration and no effect on unpunished responding at this dose. Similarly, punished responding in squirrel monkeys was maximally increased to 1774% of control by 10 mg/kg, p.o., with no effect on unpunished responding at this dose. With robust anxiolytic-like activity across species, a large separation between anxiolytic-like effects and sedation/ataxia, a minimal interaction with ethanol, a lack of tolerance, and apparent oral bioavailability, Co 2-6749 makes an ideal candidate for development as a novel anxiolytic drug.

Alprazolam↗
PubMed1996

Thiopentone induced enhancement of somatic motor responses to noxious stimulation: influence of GABAA receptor modulation.

PURPOSE: This study was conducted to determine whether hyperalgesic effects of subanaesthetic concentrations of thiopentone could be attributed to GABAA receptor effects. METHODS: All studies were performed on 50 rats in a prospective, randomized, blinded fashion using saline-injected animals as controls. Using a modified Randall-Selitto technique, the motor behavior stimulated by noxious stimulation was quantified by determining the lowest tail pressure required to provoke a withdrawal response (somatic motor response threshold, SMRT). In the first protocol (21 rats), we studied the effects of 0.5, 1.5 and 5 mg.kg-1 i.v. of the GABAA agonist, muscimol, on SMRT. In the second protocol (20 rats), the effects of administration of saline, muscimol 0.5 mg.kg-1, or the competitive GABAA antagonist, bicuculline 0.25 mg.kg-1, upon the SMRT-reducing effects of a standardized thiopentone infusion were observed. RESULTS: No dose of muscimol produced hyperalgesia. The highest dose of muscimol used (5 mg.kg-1) produced pronounced analgesic effects, raising the SMRT above 750 g. No change in SMRT was detected with the smaller doses of muscimol. Given in combination with muscimol (0.5 mg.kg-1), thiopentone produced analgesia, as shown by an increase in SMRT (P = 0.009). In the bicuculline treated animals, SMRT decreased linearly with increasing plasma thiopentone concentrations (P < 0.001). The slope of the relationship in the bicuculine group was not significantly different from that observed in the saline-treated group, indicating that bicuculline did not block the hyperalgesic effects of thiopentone. CONCLUSION: The results of these studies suggest that hyperalgesia associated with thiopentone is not mediated primarily by GABAA receptors.

Animals↗
PubMed2004

The Discriminative stimulus effects of gamma-hydroxybutyrate and related compounds in rats discriminating baclofen or diazepam: The role of GABA(B) and GABA(A) receptors.

The discriminative stimulus effects of gamma-hydroxybutyrate (GHB) can be mimicked by GABA(A) receptor-positive modulators (e.g., diazepam) and GABA(B) receptor agonists (e.g., baclofen). The purposes of this study were to see whether stimulus control could be established with baclofen and to further characterize the role of GABAergic mechanisms in the behavioral actions of GHB by evaluating GHB and related compounds in rats discriminating either diazepam or baclofen. Training criteria were satisfied with baclofen and diazepam after 69 and 44 sessions, respectively. GHB and its precursors gamma-butyrolactone and 1,4-butanediol occasioned >80% responding on the drug-associated lever in rats discriminating baclofen and <11% in rats discriminating diazepam. Diazepam and other GABA(A) receptor-positive modulators occasioned intermediate levels of responding on the baclofen lever, whereas baclofen occasioned less than 4% responding on the diazepam lever. The GABA(B) receptor antagonist CGP 35348 [(3-aminopropyl)(diethoxymethyl) phosphinic acid] partially antagonized the effects of baclofen as well as the baclofen-like effects of GHB, and flumazenil partially antagonized the effects of diazepam. This study established stimulus control with baclofen, and substitution data provided direct evidence for a role of GABAergic, especially GABA(B), mechanisms in the discriminative stimulus effects of GHB. The lack of substitution by GHB or its metabolic precursors for diazepam indicates a comparatively smaller role of GABA(A) mechanisms in these effects of GHB. The inability of CGP 35348 to completely attenuate the effects of baclofen and GHB suggests that multiple receptors could be involved in the discriminative stimulus effects of GHB.

Adjuvants, Anesthesia↗
PubMed1992

GABA receptors in Deiters nucleus modulate posturokinetic responses to cortical stimulation in the cat.

The early component of the postural responses which accompany the limb flexion during unilateral stimulation of the motor cortex in the cat is not of reflex origin, but results from a central command. These postural adjustments are characterized by a decreased force under the limb diagonally opposite to the moving one and an increased force under the other two. Since the lateral vestibular nucleus (LVN) exerts an excitatory influence on ipsilateral limb extensor motoneurons, experiments were performed in cats to establish whether the cortical-induced postural changes were mediated through the LVN. This structure is tonically inhibited by GABAergic synapses originating from Purkinje cells of the cerebellar vermis, so that local microinjection into the LVN of GABA agonists or antagonists should either decrease or increase the spontaneous discharge of their neurons. Unilateral microinjection of 0.25 microliters of the GABA-A agonist muscimol or the GABA-B agonist baclofen (at 2-4 micrograms/microliters saline) into the LVN produced a short-lasting episode of ipsilateral postural hypotonia and contralateral hypertonia, during which the cats were unable to stand on the measurement platform. When, shortly after, some recovery of the postural activity appeared, no changes in threshold, latency or amplitude of the cortical-induced flexion movement were observed; however, the early component of the postural responses decreased in the other three limbs. Moreover, the slope of the response curve of the moving limb remained unmodified, while that of the early component of the postural responses, which involved the remaining limbs, decreased following stimulation of the motor cortex at different stimulus intensities. These effects started a few min after the injection and lasted for about 2-3 h. The effects described above were dose-dependent. Moreover, histological controls indicated that the structure responsible for these postural changes corresponded to the middle part of the LVN. The specificity of the results was shown by the fact that unilateral microinjection of 0.25 microliters of the GABA-A antagonist bicuculline or the GABA-B antagonist phaclofen (at 5-8 micrograms/microliter saline) into the LVN produced a postural asymmetry opposite in sign to that elicited in the same experiments by the corresponding agonists. These injections did not modify the amplitude of the cortical-induced limb flexion, but rather enhanced the amplitude of the early component of the postural responses in the other three limbs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake.

It has recently become more clearly understood that in human brain pathophysiology, neurosteroids play a role in anxiety disorders, premenstrual syndrome, postpartum depression, posttraumatic stress disorder, and depression. In the treatment of major depression, recent clinical studies indicate that the pharmacological profiles of fluoxetine and fluvoxamine are correlated with the ability of these drugs to increase the brain and cerebrospinal fluid content of allopregnanolone (Allo), a potent positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors. Thus, the neurosteroid-induced positive allosteric modulation of GABA action at GABAA receptors is facilitated by fluoxetine or its congeners (i.e., paroxetine, fluvoxamine, sertraline), which may not block 5-HT reuptake at the doses currently prescribed in the clinic. However, these doses are effective in the treatment of premenstrual dysphoria, anxiety, and depression. In socially isolated mice, we tested the hypothesis that fluoxetine, norfluoxetine, and other specific serotonin reuptake inhibitor (SSRI) congeners stereoselectively upregulate neurosteroid content at doses insufficient to inhibit 5-HT reuptake; although they potentiate pentobarbital-induced sedation and exert antiaggressive action. Very importantly, the inhibition of 5-HT reuptake lacks stereospecificity and requires fluoxetine and norfluoxetine doses that are 50-fold greater than those required to increase brain Allo content, potentiate the action of pentobarbital, or antagonize isolation-induced aggression. Based on these findings, it could be inferred that the increase of brain Allo content elicited by fluoxetine and norfluoxetine, rather than the inhibition selective of 5-HT reuptake, may be operative in the fluoxetine-induced remission of the behavioral abnormalities associated with mood disorders. Therefore, the term "SSRI" may be misleading in defining the pharmacological profile of fluoxetine and its congeners. To this extent, the term "selective brain steroidogenic stimulants" (SBSSs) could be proposed.

Animals↗
PubMed1982

Intra-raphe muscimol induced hyperactivity depends on ascending serotonin projections.

Acute microinjections of the GABA agonist, muscimol (100 ng), into either the dorsal (DR) or the median (MR) raphe nucleus of etherized rats induced post-anesthesia hyperactivity as measured in photocell chambers. The increased activity counts seen after MR injections, furthermore, were 4 times greater than those following DR injections. In animals implanted with chronically indwelling cannulae, a muscimol (25-400 ng) dose-response analysis confirmed the greater sensitivity of the MR site. Subsequent experiments thus employed only MR cannulae. The benzodiazepine, chlordiazepoxide, in a subataxic dose (3.8 mg/kg, IP) by itself did not affect activity level, but enhanced the locomotor response to low doses (25-50 ng) of muscimol. Conversely, a sub-convulsant dose of the GABA antagonist, bicuculline (1.1 mg/kg, IP), completely blocked the hyperactivity produced by muscimol (50-100 ng). Bilateral electrolytic destruction of the ventral tegmental nuclei of Gudden produced hyperactivity, but failed to alter the effect of muscimol. Forebrain 5-hydroxytryptamine (5-HT, serotonin) depletion following administration of 5,7-dihydroxytryptamine did not affect baseline activity level, but markedly attenuated the locomotor response produced by intra-MR injections of muscimol. These data suggest that midbrain GABA neurons modulate activity level through a direct action on 5-HT neurons, and indicate that intra-MR muscimol induced hyperactivity depends on intact ascending 5-HT fibers.

Animals↗
PubMed2003

The effects of vigabatrin on type II spike wave discharges in rats.

The antiepileptic drug vigabatrin increases GABA concentrations by inhibiting GABA transaminase. The effects of vigabatrin on type II spike wave discharges (SWDs) in the electroencephalogram of ACI rats were studied in order to learn more about the effects of altering GABA concentration on SWDs. The incidence of type II SWDs increased after vigabatrin (60/h) as compared to saline treatment (3.7/h). This effect appeared with a halftime of 100 min. The duration of type II SWDs increased after vigabatrin (1.52 s) as compared to saline treatment (1.04 s), but the peak-frequency of the type II SWDs decreased after vigabatrin (5.6 Hz) as compared to saline treatment (7.5 Hz). Thus, vigabatrin alters the type II SWD morphology. These results are in agreement with predictions of Destexhe's theoretical model, modulating both GABA(A) and GABA(B) conductances.

Action Potentials↗
PubMed2004

Diazepam-induced adaptive plasticity revealed by alpha1 GABAA receptor-specific expression profiling.

Benzodiazepines are in wide clinical use for their sedative and tranquilizing actions, the former being mediated via alpha1-containing GABAA receptors. The signal transduction pathways elicited beyond the receptor are only poorly understood. Changes of transcript levels in cerebral cortex induced by acute diazepam administration were therefore compared by microarray analysis between wild-type and point mutated alpha1(H101R) mice, in which the alpha1 GABAA receptor subunit had been rendered insensitive to diazepam. In wild-type animals, diazepam reduced the expression levels of the alpha subunit of the calcium/calmodulin-dependent protein kinase II, as well as brain-derived neurotrophic factor, MAP kinase phosphatase, transcription factor GIF, c-fos and nerve growth factor induced gene-A. None of these transcripts was changed in the alpha1(H101R) mice after treatment with diazepam. Thus, the sedative action of diazepam is correlated with a selective down-regulation of transcripts involved in the regulation of neuronal plasticity and neurotrophic responses. Most transcript changes were transient except for the decrease of the CaMKIIalpha transcript which persisted even 40 h after the single dose of diazepam. This long-term alteration is likely to contribute to the resetting of the neuronal responsiveness, which may be involved in rebound phenomena and, under chronic treatment, in the development of tolerance and dependence.

Animals↗
PubMed1999

Activation of protein kinase C by phorbol dibutyrate modulates GABAA receptor binding in rat brain slices.

Effects of protein kinase C (PKC) activation on the function of the GABA/benzodiazepine receptor-chloride complex were analyzed by quantitative autoradiography using [3H]muscimol, [3H]flunitrazepam and [35S]TBPS in rat brain slices. The density of [3H]muscimol binding was highest in cerebellar granular layers and high in both the frontal cortex and thalamus, but binding levels in the hippocampus were low. After activation of PKC by 100 nM phorbol-12,13-dibutyrate (PDBu), [3H]muscimol binding was decreased in the frontal cortex, striatum and thalamus, but binding levels were not changed in the hippocampus or cerebellum. The density of [3H]flunitrazepam binding was high in the cortex, hippocampus and molecular layers of cerebellum but was low in thalamus. PDBu increased the [3H]flunitrazepam binding only in the striatum and in part of the cortex and thalamus after activation of PKC. After activation of PKC by PDBu [35S]TBPS binding was increased in most areas, but binding levels were not changed in the brainstem or cerebellum. The receptor binding was markedly decreased in almost all areas by the addition of 2.5 mM Mg2+. Elevated [35S]TBPS binding produced by PDBu was significantly inhibited by the addition of Mg2+. These results suggest that the activation of PKC potentiates benzodiazepine and TBPS binding, but decreases muscimol binding in a region-specific manner in the rat brain.

Animals↗
PubMed2000

GABAC receptor sensitivity is modulated by interaction with MAP1B.

GABA(C) receptors contain rho subunits and mediate feedback inhibition from retinal amacrine cells to bipolar cells. We previously identified the cytoskeletal protein MAP1B as a rho1 subunit anchoring protein. Here, we analyze the structural basis and functional significance of the MAP1B-rho1 interaction. Twelve amino acids at the C terminus of the large intracellular loop of rho1 (and also rho2) are sufficient for interaction with MAP1B. Disruption of the MAP1B-rho interaction in bipolar cells in retinal slices decreased the EC(50) of their GABA(C) receptors, doubling the receptors' current at low GABA concentrations without affecting their maximum current at high concentrations. Thus, anchoring to the cytoskeleton lowers the sensitivity of GABA(C) receptors and provides a likely site for functional modulation of GABA(C) receptor-mediated inhibition.

Amino Acid Transport Systems, Neutral↗
PubMed2004

Effects of positive allosteric modulators of the GABAB receptor on cocaine self-administration in rats.

RATIONALE: Previous studies have strongly implicated a role for GABA(B) receptors in modulating the reinforcing effects of cocaine. OBJECTIVE: The purpose of the present study was to examine the efficacy of two novel positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, to decrease cocaine self-administration in rats responding under various schedules of reinforcement. METHODS: Rats were trained to self-administer cocaine under progressive ratio (PR), fixed ratio (FR) and discrete trials (DT) schedules of reinforcement, and the ability of CGP7930 and GS39783 to decrease cocaine-maintained responding was examined. RESULTS: On a PR schedule, CGP7930 markedly decreased break points maintained by 1.5 mg/kg per injection cocaine in a dose-dependent manner. GS39783 produced only modest decreases in cocaine-reinforced break points, with only the highest dose decreasing break points relative to baseline. On an FR1 schedule of reinforcement, both drugs decreased responding for a threshold dose of cocaine, but did not alter responding for higher doses of cocaine. In a DT procedure, 1.5 mg/kg per injection cocaine was made available during three 10-min trials each hour during 24-h sessions (DT3), engendering a circadian pattern of responding characterized by high numbers of infusions during the dark phase and low numbers of infusions during the light phase. Doses of 30 mg/kg CGP7930, 3.0 mg/kg GS39783 and 2.5 mg/kg baclofen significantly decreased cocaine-maintained responding when administered at the beginning of the dark phase of the cycle. Across all schedules, CGP7930 was more effective at decreasing cocaine self-administration than GS39783, a finding that may be due to differences in bioavailability between the two drugs. CONCLUSIONS: These findings suggest that positive allosteric modulators of the GABA(B) receptor may hold promise as potential pharmacotherapies for cocaine abuse and dependence.

Analysis of Variance↗
PubMed1994

Imidazenil, a partial positive allosteric modulator of GABAA receptors, exhibits low tolerance and dependence liabilities in the rat.

Long-term treatment of rats with full (triazolam) or selective (diazepam) allosteric modulators of gamma-aminobutyric acid type A (GABAA) receptors rapidly induced tolerance to the protective effect of these drugs against bicuculline-induced convulsion. In contrast, long-term administration of partial allosteric modulators (imidazenil and bretazenil) of GABAA receptors, in doses equipotent to those of diazepam and triazolam that induce anticonvulsant tolerance, failed to elicit such a tolerance. Furthermore, no cross-tolerance was observed between diazepam and imidazenil. Discontinuation of long-term treatment with diazepam or triazolam, but not of long-term treatment with imidazenil or bretazenil, sensitized rats to behavioral inhibition by punishment (electric shock) in a manner that was potentiated by flumazenil. Administration of a single oral dose of [14C]diazepam or [3H] imidazenil to rats treated repeatedly with the corresponding unlabeled drug or vehicle revealed that the brain concentrations of drugs and their metabolites were similar in both groups of animals. This suggests that tolerance to the full or selective allosteric modulators of GABAA receptors may be associated with changes in the efficacy of the allosteric modulation rather than with changes in drug metabolism. Imidazenil has a longer half-life than an equipotent dose of diazepam and protects rats against bicuculline-induced convulsions for a significantly longer time than diazepam or bretazenil.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric Regulation↗
PubMed1992

GABAergic afferents modulate proenkephalin mRNA expression in the guinea pig hypothalamic magnocellular dorsal nucleus.

The proenkephalin (PE) gene expression within Met-enkephalin (ME) neurons of the guinea pig magnocellular dorsal nucleus (MDN) was measured following activation of GABAergic transmission by aminooxyacetic acid treatment (AOAA). A combination of preembedding ME immunocytochemistry and PE in situ hybridization was used to investigate PE mRNA and enkephalin immunoreactivity levels. In perikarya of the MDN, chronic AOAA-treatment resulted in an important decline in PE mRNA signal (-128%). In double-labeled neurons, the PE mRNA decrease was associated to an increase in ME immunoreactivity. These results indicate that the increase in ME immunoreactivity in the MDN following AOAA-treatment is not due to a rise in PE gene transcription. This study provides additional morphological evidence supporting a role for GABA in modulating the enkephalinergic hypothalamoseptal tract of the guinea pig.

Aminooxyacetic Acid↗
PubMed2005

Distinct roles of glycinergic and GABAergic inhibition in coordinating locomotor-like rhythms in the neonatal mouse spinal cord.

The primary objective of our study was to examine the role of the inhibitory neurotransmitters glycine and GABA in modulating spontaneous activity and coordinating neurochemically induced locomotor-like rhythms in the mouse spinal cord. Motor outputs were recorded in lumbar ventral roots of 1-4-day old neonatal mice, and the function of glycinergic and GABAergic synapses in regulating spontaneous and induced activities was examined by suppressing synaptic inhibition using selective glycine or GABAA receptor antagonists. Strychnine (0.5 microM), a glycine receptor antagonist, did not change the pattern of spontaneous activity that consisted of random single spikes and discharges of variable durations and intervals. In contrast, blocking GABAA receptors with either picrotoxin (10 microM) or bicuculline (5 microM) triggered bilaterally synchronous, non-rhythmic discharges. These findings suggested that GABAergic synapses suppressed excitatory synapses, and their disinhibition synchronized spontaneous discharges between the two sides of the spinal cord. Locomotor-like rhythms alternating between the two sides of the spinal cord were triggered by the neurotransmitter agonists 5-HT, N-methyl-D,L-aspartic acid and dopamine. Blocking glycine receptors increased tonic discharges, and in most preparations it reduced the phase correlation between the alternating rhythms. Inhibiting GABAA receptor-mediated synapses synchronized the onset and prolonged the duration of rhythmic discharges. Intraburst alternating peaks were evident and those were suppressed by strychnine, suggesting that they were mediated via glycinergic synapses. Our findings indicated that GABAergic and glycinergic synapses played different roles in modulating neurochemically induced locomotion rhythms. GABAergic inhibition regulated the onset and duration of neurochemically induced locomotor-like rhythms, and glycinergic inhibition stabilized the pattern of the alternating rhythms.

2-Amino-5-phosphonovalerate↗
PubMed1999

Developmental study of miniature IPSCs of CA3 hippocampal cells: modulation by midazolam.

Maturation of GABAA/benzodiazepine receptors is associated with changes in their subunit composition. We have investigated whether these changes are accompanied by a developmental modification in the kinetic properties of miniature IPSCs (mIPSCs) and sensitivity to midazolam, a benzodiazepine agonist. In the presence of TTX (10 microM) and excitatory amino acid antagonists, AP5 (50 microM) and CNQX (50 microM), we whole-cell recorded mIPSCs in CA3 cells of hippocampal slices of adult and young (4-8 days) rats. mIPSCs were mediated by GABAA receptors as they were suppressed by bicuculline (10 microM). In both the adult and young rats, mIPSCs were similar in amplitude and kinetic properties. However, the mIPSCs frequency markedly increased with age from 4+/-3 Hz in the young rats to 20+/-9 Hz in the adult rats. In both age groups, midazolam (0.01 microM(-10) microM) and pentobarbital (30 microM) did not affect the amplitude, frequency and rise time of the mIPSCs but they increased to a similar extent their decay time constant. The current responses to isoguvacine, a GABAA agonist, were potentiated by 0.1 microM midazolam in both age groups. It is concluded that in immature and adult rats, synaptic GABAA receptors of CA3 were not different in their kinetic properties and sensitivity to midazolam.

2-Amino-5-phosphonovalerate↗