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PubMed1977

Rotational behaviour and cGMP responses following manipulation of nigral mechanisms with chlordiazepoxide. Evidence for enhancement of GABA transmission by benzodiazepines.

Unilateral stereotaxic injections of 1 microgram of the soluble benzodiazepine chlordiazepoxide hydrochloride into the predominantly GABA-containing zona reticulata of the substantia nigra of amphetamine-pretreated rats induced rotational behaviour similar to that seen following unilateral elevation of nigral GABA levels and amphetamine treatment; this effect was not seen following injections into the vicinity of the predominantly dopamine-containing zona compacta. Chlordiazepoxide-induced rotations were abolished by the GABA-antagonist picrotoxin. Both chlordiazepoxide and GABA depressed production of cyclic 3',5'-guanosine monophosphate in samples of nigral tissue in vitro as estimated by radioimmunoassay. It is concluded that chlordiazepoxide may enhance GABA transmission within the substantia nigra, by some as yet unidentified mechanism, to create asymmetric activity in GABA-modulated neurones and hence induce rotation.

Aminobutyrates↗
PubMed1981

Nigral output neurons are engaged in regulation of static fusimotor action onto flexors in cat.

Picrotoxin and muscimol were unilaterally injected into the postero-lateral part of the reticular zone of substantia nigra (plSNR) through chronically implanted guide cannulae in ketamine-anesthetized cats. Afferent activity of pretibial flexor muscle spindle primary and secondary endings was recorded before and after drug administration, and spindle sensitivity monitored during both sinusoidal and ramp stretch of the receptor-bearing muscle. From changes in spindle sensitivity after drug injection it is deduced that unilateral block by picrotoxin of the action of GABA on postsynaptic receptors in plSNR removes tonic static fusimotor action from flexor muscle spindle primary endings. Secondary endings seemed largely unaffected. The effect on primary endings is reversed by a subsequent injection of muscimol. It is concluded that the central nervous system, through GABA-modulated nigral output neurons, can control static fusimotor action onto flexor muscle spindle primary and secondary endings separately to some extent.

Animals↗
PubMed1994

Quantitative autoradiographic characterization of the binding of [3H]tiagabine (NNC 05-328) to the GABA uptake carrier.

The kinetic properties and regional distribution of [3H]tiagabine ([3,4-3H]N-[4,4-bis(3-methyl-2-thienyl)but-3-en-1-yl]nipecotic acid) binding to the central GABA uptake carrier was examined in the rat brain using quantitative receptor autoradiography. In slide mounted sections of frontal cortex, the binding of [3H]tiagabine was saturable, reversible and sodium dependent. The kinetics of association and dissociation of [3H]tiagabine were monophasic, and Scatchard transformation of saturation isotherms resulted in a linear plot with a Kd = 58 +/- 7 nM and a Bmax = 58.9 +/- 0.9 pmol/mg protein. The autoradiographic distribution of [3H]tiagabine binding sites in rat brain was heterogeneously distributed. The highest density of [3H]tiagabine binding sites was present in the cerebral cortex, mammillary body, globus pallidus, substantia nigra pars reticulata, hippocampus, dorsal raphé, superior colliculus (outer layer), and cerebellum. The distribution of GABA uptake sites, as measured by [3H]tiagabine binding, in the rat brain is highly consistent with the organization of GABAergic terminals and cell bodies. The present investigation characterized the use of [3H]tiagabine as a novel radioligand for the GABA uptake carrier using quantitative receptor autoradiography. [3H]Tiagabine has several major advantages over the currently utilized radioligand for the GABA uptake carrier [3H]nipecotic acid, in that [3H]tiagabine has an increased affinity, specificity, and is not transported intracellularly via the GABA uptake carrier. These data suggest that [3H]tiagabine represents a novel and highly useful ligand for studying the GABA uptake carrier using quantitative receptor autoradiography.

Animals↗
PubMed1990

Modulation of GABA-stimulated Cl- flux by a benzodiazepine agonist and an 'inverse agonist' after chronic flurazepam treatment.

Rats treated one week with flurazepam were killed while still on the drug or 48 h after termination of drug treatment. The brain 'microsac' preparation derived from the cerebral cortices was used for studying the GABA-stimulated chloride influx. There was no significant change in the basal or GABA-stimulated influx between control and treated groups. However, the effect of flunitrazepam to enhance 10 microM GABA-stimulated influx was significantly reduced, indicating tolerance. Methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3- carboxylate (DMCM), an 'inverse agonist' at benzodiazepine receptors, dose dependently inhibited 50 microM GABA-stimulated influx; chronic treatment did not alter the effect of DMCM. This study demonstrates that one week treatment with flurazepam produces tolerance to benzodiazepines without any change in the effect of GABA or DMCM. This indicates that GABA and benzodiazepine sites are differently modulated after chronic treatment with benzodiazepines. However, since both benzodiazepine and DMCM act on the same receptors it appears that the different 'domains' on the benzodiazepine receptor are differently altered during chronic treatment.

Animals↗
PubMed1990

Pentobarbital attenuates stress-induced increases in noradrenaline release in specific brain regions of rats.

To examine whether anxiolytic action of drugs acting at the GABA/BZD-chloride channel complex may be related to the brain noradrenergic system, we investigated the effect of pentobarbital, a typical barbiturate which has potent GABA modulating properties, on increased NA release in nine brain regions of stressed rats. Pentobarbital (10 and 25 mg/kg) was injected IP 65 min before sacrifice (5 min before one-hour immobilization stress). Levels of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), the major metabolite of brain noradrenaline (NA), and of plasma corticosterone, were fluorometrically determined. Pentobarbital treatment by itself increased MHPG-SO4 levels in the thalamus, locus coeruleus (LC) region, midbrain and basal ganglia of nonstressed rats. Stress produced increases in MHPG-SO4 levels in all brain regions examined and elevation of plasma corticosterone levels. Pentobarbital attenuated, in a dose-dependent manner, stress-induced increases in MHPG-SO4 levels in the hypothalamus, thalamus, anterior cerebral cortex, LC region and basal ganglia and also attenuated the stress-induced elevation of plasma corticosterone levels. These data suggest that pentobarbital can attenuate both stress-induced increases in NA release in specific brain regions as well as activation of the hypothalamo-pituitary-adrenocortical system. These attenuating effects may be related to the anxiolytic action of barbiturates.

Animals↗
PubMed1993

Inhibitory effect of GABA (gamma-aminobutyric acid) on the induction of long-term potentiation in guinea pig superior colliculus slices.

Superior colliculus (SC) slices were prepared from guinea pigs and postsynaptic potentials (PSPs) were recorded in the superficial grey layer of the SC after electrical stimulation to the optic layer (OL). Tetanic stimulation of 50 Hz frequency and 20 s duration to the OL induced long-term potentiation (LTP) in the PSP increasing the amplitude to 140% of the original level in 30 min. Tetanic stimulation failed to induce LTP after application of gamma-aminobutyric acid (GABA) (300 microM, 1 or 3 mM) to the perfusion medium. On the other hand, tetanic stimulation to the OL after application of bicuculline methiodide (1 microM), a GABAA receptor antagonist, facilitated the formation of LTP. These results indicate that GABA modulates the formation of LTP in the SC.

Animals↗
PubMed1996

A benzodiazepine, chlordiazepoxide, blocks vasopressin and oxytocin release after footshocks but not osmotic stimulus in the rat.

Noxious as well as hypertonic stimuli potentiate vasopressin and oxytocin secretion in rats. Neurohypophysial vasopressin- and oxytocin-secreting neurons receive inhibitory synaptic inputs mediated by gamma-aminobutyric acid (GABA). Benzodiazepines modulate GABA-A receptor activity in a facilitatory fashion. It is thus possible that benzodiazepines suppress vasopressin and oxytocin release after noxious stimuli. To test this hypothesis, we investigated whether chlordiazepoxide impairs the enhanced release of vasopressin and oxytocin after noxious or hypertonic stimuli in male rats. Chlordiazepoxide (5-20 mg/kg, i.p.) blocked dose-dependently the vasopressin and oxytocin responses to footshocks. Chlordiazepoxide, however, did not impair the hormonal responses to hypertonic stimulus. The results demonstrate that chlordiazepoxide selectively prevents vasopressin and oxytocin release after noxious stimuli and therefore suggest that the sites of chlordiazepoxide actions are not on the vasopressin or oxytocin neurons in rats.

Animals↗
PubMed2006

Anticonvulsant action of allopregnanolone in immature rats.

Anticonvulsant activity of allopregnanolone, a neurosteroid allosterically modulating GABA(A) receptor was tested in a model of motor seizures elicited by pentetrazol in immature rats. Rats 7, 12, 18, 25 or 90 days old were pretreated with allopregnanolone in doses from 5 to 40 mg/kg i.p. and 15 min later pentetrazol was injected subcutaneously in a dose of 100 mg/kg. Rats were observed in isolation for 30 min. Allopregnanolone dose-dependently suppressed both generalized tonic-clonic and minimal clonic seizures with the highest efficacy in 12-day-old rats. Anticonvulsant action was least expressed in adult animals. Duration of anticonvulsant action tested after a dose of 20 mg/kg in 12- and 90-day-old rats demonstrated markedly longer effects in young rats. Allopregnanolone compromised motor performance of rats but duration of this unwanted effect in 12-day-old rats was shorter than duration of anticonvulsant action. This difference can be important for possible clinical use of neurosteroids.

Age Factors↗
PubMed2005

Long-term effects of diazepam and phenobarbital treatment during development on GABA receptors, transporters and glutamic acid decarboxylase.

Diazepam (DZ) and phenobarbital (PH) are commonly used to treat early-life seizures and act on GABAA receptors (GABAR). The developing GABAergic system is highly plastic, and the long-term effects of postnatal treatment with these drugs on the GABAergic system has not been extensively examined. In the present study, we investigated the effects of prolonged DZ and PH treatment during postnatal development and then discontinuation on expression of a variety of genes involved in GABAergic neurotransmission during adulthood. Rat pups were treated with DZ, PH or vehicle from postnatal day (P) 10-P40 and then the dose was tapered for 2 weeks and terminated at P55. Expression of GABAR subunits, GABAB receptor subunits, GABA transporters (GAT) and GABA synthesizing enzymes (glutamic acid decarboxylase: GAD) mRNAs in hippocampal dentate granule neurons (DGNs) were analyzed using antisense RNA amplification at P90. Protein levels for the alpha1 subunit of GABAR, GAD67, GAT1 and 3 were also assessed using Western blotting. At P90, mRNA expression for GAT-1, 3, 4, GABAR subunits alpha4, alpha6, beta3, delta and theta and GABAB receptor subunit R1 was increased and mRNA expression for GAD65, GAD67 and GABAR subunits alpha1 and alpha3 were decreased in DGNs of rats treated with DZ and PH. The current data suggest that prolonged DZ and PH treatment during postnatal development causes permanent alterations in the expression of hippocampal GABA receptor subunits, GATs and GAD long after therapy has ended.

Age Factors↗
PubMed2006

Sulfated steroids as endogenous neuromodulators.

Central nervous system function is critically dependent upon an exquisitely tuned balance between excitatory synaptic transmission, mediated primarily by glutamate, and inhibitory synaptic transmission, mediated primarily by GABA. Modulation of either excitation or inhibition would be expected to result in altered functionality of finely tuned synaptic pathways and global neural systems, leading to altered nervous system function. Administration of positive or negative modulators of ligand-gated ion channels has been used extensively and successfully in CNS therapeutics, particularly for the induction of sedation and treatment of anxiety, seizures, insomnia, and pain. Excessive activation of excitatory glutamate receptors, such as in cerebral ischemia, can result in neuronal damage via excitotoxic mechanisms. The discovery that neuroactive steroids exert rapid, direct effects upon the function of both excitatory and inhibitory neurotransmitter receptors has raised the possibility that endogenous neurosteroids may play a regulatory role in synaptic transmission by modulating the balance between excitatory and inhibitory neurotransmission. The sites to which neuroactive steroids bind may also serve as targets for the discovery of therapeutic neuromodulators.

Animals↗
PubMed1997

Co-localization of carnosine and glutamate in photoreceptors and bipolar cells of the frog retina.

Immunocytochemical methods were used to visualize carnosine (beta-alanyl-L-histidine)-like immunoreactivity (-LI) in the frog retina and to compare its localization with that of glutamate. Carnosine-LI was conspicuous in photoreceptors and bipolar cells. The axon terminals of labelled bipolar cells formed five bands in the inner plexiform layer. A few presumed amacrine and ganglion cells, as well as Müller cell endfeet, were also labelled. Post-embedding immunocytochemistry revealed particularly high levels of glutamate-LI in the synaptic axon terminals of bipolar cells, with a mean gold particle density 5 x higher than that of amacrine cells. Photoreceptor terminals were also labelled, but with a labelling intensity about half that of bipolar cells. Labelling of serial semithin sections showed co-localization of carnosine and glutamate in photoreceptors and bipolar cells. These findings are consistent with the notion that glutamate is the neurotransmitter of neuronal elements that transfer information vertically through the retina. We propose that carnosine may modulate GABA and/or glutamate receptors by virtue of its ability to chelate Zn2+ and other ions.

Animals↗
PubMed2000

Neuronal nicotinic receptors in synaptic functions in humans and rats: physiological and clinical relevance.

The present report describes the participation of nicotinic receptors (nAChRs) in controlling the excitability of local neuronal circuitries in the rat hippocampus and in the human cerebral cortex. The patch-clamp technique was used to record responses triggered by the non-selective agonist ACh and the alpha7-nAChR-selective agonist choline in interneurons of human cerebral cortical and rat hippocampal slices. Evidence is provided that functional alpha7- and alpha4beta2-like nAChRs are present on somatodendritic and/or preterminal/terminal regions of interneurons in the CA1 field of the rat hippocampus and in the human cerebral cortex and that activation of the different nAChR subtypes present in the preterminal/terminal areas of the interneurons triggers the tetrodotoxin-sensitive release of GABA. Modulation by nAChRs of GABAergic transmission, which can result either in inhibition or disinhibition of pyramidal neurons, depends both on the receptor subtype present in the interneurons and on the agonist acting upon these receptors. Not only do alpha7 nAChRs desensitize faster than alpha4beta2 nAChRs, but also alpha7 nAChR desensitization induced by ACh lasts longer than that induced by choline. These mechanisms, which appear to be retained across species, might explain the involvement of nAChRs in cognitive functions and in such neurological disorders as Alzheimer's disease and schizophrenia.

Alzheimer Disease↗
PubMed1997

GABA augments basal and electrically stimulated 3H-norepinephrine release in hypothalamic, preoptic area and cortical slices of female rats.

These studies examined the regulation by GABA of norepinephrine release from hypothalamus, preoptic area and frontal cortex. Using superfused brain slices from female rats, we show that 100 microM GABA enhances both basal and electrically stimulated release of 3H-norepinephrine in all three brain regions. The GABAA agonist muscimol (100 microM) significantly augments 3H-norepinephrine release, but it is somewhat less effective than GABA. The GABAB agonist baclofen has little or no effect on basal 3H-norepinephrine efflux. GABA also augments both the magnitude and duration of electrically evoked 3H-norepinephrine release in slices from all three brain regions. GABA facilitation of electrically stimulated 3H-norepinephrine release is mediated through GABAA receptors as evidenced by its blockade by 10 microM bicuculline, a GABAA antagonist, but not by 200 microM 2-OH-saclofen, a GABAB antagonist. These data show that the inhibitory amino acid neurotransmitter GABA enhances both basal and evoked release of 3H-norepinephrine in brain slices from female rats. These effects are predominantly mediated by GABAA receptors. GABA modulation of hypothalamic norepinephrine release may play a role in the regulation of gonadotropin secretion and reproductive behaviors such as lordosis.

Animals↗
PubMed2001

Mechanisms influencing stimulus-response properties of the human corticospinal system.

BACKGROUND: Stimulus-response (S-R) properties of the corticospinal system in humans depend on the interactions that take place at different sites along the corticospinal pathway. The mechanisms influencing stimulus-response curves elicited by transcranial magnetic stimulation (TMS) and their operation site along the human neuraxis are poorly understood. In this study, we investigated the effects of CNS-active drugs with distinct mechanisms of action on S-R curves. Effects of each of these drugs on S-R curves would point to the involvement of specific mechanisms. Additionally, relative sensitivity of S-R curves compared with other measures of corticospinal excitability was studied. METHODS: We studied the effects of lorazepam, which is a positive allosteric modulator of GABA(A) receptors; lamotrigine, an inhibitor of voltage-gated Na(+) and Ca(2+) channels; and D-amphetamine, an indirect agonist of the dopaminergic-adrenergic system on S-R curves, motor thresholds (MT), and intracortical inhibition (ICI) and facilitation (ICF) with a double-pulse technique. Maximum peripheral M responses and F waves were investigated as measures of the total alpha-motoneuron pool and its excitability. RESULTS: F and M waves were unaffected by either the drugs or placebo. S-R curves were significantly depressed by lorazepam and lamotrigine without changes in ICI and ICF. Both S-R curves and ICF were enhanced by D-amphetamine. MT increased only with lamotrigine. CONCLUSIONS: S-R curves were influenced by changes in the GABAergic and monoaminergic system and Na(+) and Ca(2+) channel properties. Our results indicate that, out of different parameters of motor system excitability, S-R curves were the most sensitive.

Adult↗
PubMed1996

Localization of dopamine D4 receptors in GABAergic neurons of the primate brain.

Dopamine receptors are the principal targets of drugs used in the treatment of schizophrenia. Among the five mammalian dopamine-receptor subtypes, the D4 subtype is of particular interest because of its high affinity for the atypical neuroleptic clozapine. Interest in clozapine stems from its effectiveness in reducing positive and negative symptoms in acutely psychotic and treatment-resistant schizophrenic patients without eliciting extrapyramidal side effects. We have produced a subtype-specific antibody against the D4 receptor and localized it within specific cellular elements and synaptic circuits of the central nervous system. The D4-receptor antibody labelled GABAergic neurons in the cerebral cortex, hippocampus, thalamic reticular nucleus, globus pallidus and the substantia nigra (pars reticulata). Labelling was also observed in a subset of cortical pyramidal cells. Our findings suggest that clozapine's beneficial effects in schizophrenia may be achieved, in part, through D4-mediated GABA modulation, possibly implicating disinhibition of excitatory transmission in intrinsic cortical, thalamocortical and extrapyramidal pathways.

Animals↗
PubMed2005

Identification of candidate drugs for the treatment of ALS.

A consortium of investigators interested in neurodegenerative diseases collaborated to screen 1040 drugs in multiple neurodegenerative disease assays. One model of amyotrophic lateral sclerosis (ALS) pathogenesis in particular incorporated glutamate exposure in enriched primary rat motor neuron cultures. In this model 78 compounds decreased motor neuron death caused by 100 microM glutamate. Almost all these pharmacological agents act at one or more of the following cellular targets: 1) protein synthesis inhibition; 2) Cox inhibition; 3) regulation of anion flux; 4) modulation of GABA receptors; 5) antioxidant, and 6) cell cycle inhibition. The most prevalent mode of action was the regulation of intracellular calcium. These data extend the understanding of motor neuron degeneration and identify a number of cellular targets for the improvement of combined therapies for neurodegenerative disease.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Multiple types of GABAA receptors mediate inhibition in brain stem parasympathetic cardiac neurons in the nucleus ambiguus.

Recent work suggests neurons can have different types of gamma-aminobutyric acid type A (GABA(A)) receptors that mediate phasic inhibitory postsynaptic currents (IPSCs) and tonic currents. This study examines the diversity of GABAergic synaptic currents in parasympathetic cardioinhibitory neurons that receive rhythmic bursts of GABAergic neurotransmission. Focal application of gabazine (25 microM) to cardiac vagal neurons in vitro did not change the frequency of firing in spontaneously active neurons or the resting membrane potential; however, picrotoxin (100 microM) significantly depolarized cardiac vagal neurons and increased their firing. Similarly, gabazine (25 microM) selectively blocked GABAergic IPSCs but did not change holding current in cardiac vagal neurons, whereas picrotoxin (100 microM) not only blocked GABAergic IPSCs but also rapidly decreased the tonic current. Because the tonic current could be attributable to activation of GABA receptors by ambient GABA or, alternatively, spontaneous opening of constitutively active GABA channels, an antagonist for the GAT-1 GABA transporter NO-711 (10 microM) was applied to distinguish between these possibilities. NO-711 did not significantly alter the holding current in these neurons. The benzodiazepine flunitrazepam (1 microM) significantly increased the tonic current and GABAergic IPSC decay time; surprisingly, however, in the presence of gabazine flunitrazepam failed to elicit any change. These results suggest cardiac vagal neurons possess gabazine-sensitive GABA(A) receptors that mediate phasic synaptic currents, a gabazine-insensitive but picrotoxin-sensitive extrasynaptic tonic current that when blocked depolarizes and increases the firing rate of cardiac vagal neurons, and benzodiazepines recruit a third type of GABA(A) receptor that is sensitive to gabazine and augments the extrasynaptic tonic current.

Animals↗
PubMed1999

Neurosteroid modulation of synaptic and GABA-evoked currents in neurons from the rat medial preoptic nucleus.

The effects of the neurosteroid 3alpha-hydroxy-5alpha-pregnane-20-one (allopregnanolone) on synaptic and GABA-evoked currents in acutely dissociated neurons from the medial preoptic nucleus of rat were investigated by perforated-patch recordings under voltage-clamp conditions. The effect of 2.0 microM allopregnanolone on GABA-evoked currents depended strongly on the GABA concentration: the currents evoked by 100 microM GABA were markedly depressed and the desensitization was faster, but the decay after GABA application was prolonged. In contrast, the currents evoked by 1.0 microM GABA were markedly potentiated, the activation was faster, a prominent desensitization was induced, and the decay after GABA application was prolonged. In the absence of externally applied GABA, 2.0 microM allopregnanolone induced a slow current that could be attributed to Cl-. Allopregnanolone did not significantly affect the amplitude of spontaneous tetrodotoxin-insensitive (miniature) synaptic currents (mIPSCs) originating from synaptic terminals releasing GABA onto the dissociated neurons. However, the mIPSC decay phase was dramatically prolonged, with half-maximal effect at approximately 50 nM allopregnanolone. A qualitatively similar effect of allopregnanolone was seen when KCl was used to evoke synchronous GABA release. The frequency of mIPSCs was also affected, on average increased 3.5-fold, by 2.0 microM allopregnanolone, suggesting a presynaptic steroid action.

Animals↗