The effects of chronic morphine administration (dependence) and naloxone-induced withdrawal on cerebral GABAB receptor and its signal transduction system were examined. Alterations in receptor affinity and number and in the amount of Gi protein were determined by radioligand binding assay and immunoblotting with Gi protein antibody, respectively. [3H]GABA binding to GABAB receptors in the brain of morphine-dependent and -withdrawn mice showed no significant change in either high or low affinity sites. Similarly, no alterations were noted in the coupling between GABAB receptor and Gi protein or in the amount of protein. However, the suppressive effect of baclofen, a GABAB agonist, on forskolin-stimulated cAMP formation in cerebral cortical slices of these animals was abolished. These results indicate that chronic morphine administration may induce functional deterioration in the coupling between Gi protein and the adenylate cyclase system.
All-or-none electrographic seizures (EGSs) were studied in hippocampal slices from young (21- to 38-day-old) rats in medium containing low (0 mM) or physiological (0.9 mM) levels of magnesium, with and without the GABAB agonist baclofen. Extracellular recording and stimulation were performed in stratum pyramidale and stratum radiatum of CA3, respectively. EGS activity was induced by exposure to low-Mg medium or by delivering repetitive stimulus trains in physiological Mg medium. After EGS activity had stabilized, the EGSs were tested for all-or-none behavior by varying the number of pulses in a train. An EGS was considered all-or-none if subthreshold stimulation produced no afterdischarge bursts, and if the EGS duration was largely independent of the number of suprathreshold stimulus pulses. According to this measure, EGSs in Mg-free + baclofen medium were all-or-none. EGSs evoked in physiological Mg medium were also all-or-none, although the threshold was higher, and the EGS duration lower, than in Mg-free medium. This all-or-none characteristic was observed whether the EGSs were induced by prior exposure to Mg-free medium or by repetitive stimulation, and in the presence and absence of baclofen. The all-or-none characteristic suggests that while the triggering mechanism for EGSs is strongly dependent on stimulus intensity, regenerative mechanisms--independent of stimulus intensity--are responsible for the maintenance of EGSs. EGSs are also terminated by mechanisms not dependent on stimulus intensity.
We examined synaptic plasticity at intrasuprachiasmatic nucleus (SCN) gamma-aminobutyric acid (GABA)ergic synapses by measuring the paired-pulse ratio between pairs of evoked inhibitory postsynaptic currents (IPSCs). Interstimulus intervals were chosen to represent the range of spontaneous action potential firing frequencies found in SCN neurons. A majority of synapses studied during the day exhibited paired-pulse depression (PPD), whereas a majority of synapses studied during the night showed no PPD. Two types of PPD were found. Type 1 PPD expresses the greatest inhibition at shorter interstimulus intervals, is predominant in the early morning and is likely to be a result of vesicle depletion. Type 2 showed the greatest inhibition at interstimulus intervals between 175 and 225 ms, is found throughout the day yet rarely at night and is likely to be a result of a Ca(2+)-dependent mechanism that is independent of pertussis toxin-sensitive G-proteins. Thus, multiple mechanisms of synaptic plasticity modulate intra-SCN communication throughout the diurnal cycle.
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Alcohol abuse and dependence represents a very serious health problem worldwide with major social, interpersonal and legal interpolations. Pharmacological treatments presently used are of uncertain effectiveness and there is even more doubt on the comparative effects and value for money.
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We used fura-2 microfluorometry and the gramicidin-perforated patch clamp technique in an attempt to clarify the mechanisms underlying the GABA- and glycine-induced increases in the cytosolic Ca2+ concentration ([Ca]in) in acutely isolated chick embryo ciliary ganglion neurons. GABA, glycine, and isoguvacine, but not baclofen, increased [Ca]in in a dose- and a Ca2+-dependent manner. The GABA-induced [Ca]in increase was inhibited by bicuculline and picrotoxin, and potentiated by pentobarbital, flunitrazepam, and alphaxalone, whereas the glycine-induced [Ca]in increase was inhibited by strychnine but not by bicuculline or picrotoxin. L- and N-type Ca2+ channel blockers inhibited the GABA- and glycine-induced [Ca]in increases, whereas Bay K-8644 potentiated these responses. These responses were also substantially potentiated by blockers of various K+ channels and by lowering the external Cl- concentrations. The high KCI- and nicotine-induced [Ca]in increases were substantially reduced during continuous stimulation with either 2 microM GABA or 1 mM glycine. Electrophysiological studies indicated that the reversal potential of the GABA-induced current exhibited a more depolarized value than the resting membrane potential in 17 of the 25 cells examined. Taken together, these results suggest that both GABA and glycine depolarize the membrane potentials by increasing Cl- conductance via respective receptors and thus increase the Ca2+ influxes through L- and N-type voltage-dependent Ca2+ channels.
Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. As D2 receptors are mostly expressed in postsynaptic neurons, pharmacological and genetic approaches have been unable to definitively address the in vivo contribution of D2 autoreceptors to DA-mediated behaviors. We found that midbrain DA neurons from mice deficient in D2 autoreceptors (Drd2(loxP/loxP); Dat(+/IRES-cre), referred to as autoDrd2KO mice) lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release. AutoDrd2KO mice displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine. The mice also exhibited increased place preference for cocaine and enhanced motivation for food reward. Our results highlight the importance of D2 autoreceptors in the regulation of DA neurotransmission and demonstrate that D2 autoreceptors are important for normal motor function, food-seeking behavior, and sensitivity to the locomotor and rewarding properties of cocaine.
To identify dogs and cats with baclofen toxicosis and characterize the patient population, clinical signs, and outcome.
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The lateral amygdala nucleus (LA) receives auditory inputs from both the auditory thalamus (medial geniculate nucleus, MGN) and auditory association cortex (AAC). These auditory inputs are closely linked with glutamate and GABA(B) receptors in the LA. The LA has intra-amygdaloid connections with the central amygdala nucleus, which mediates auditory fear potentiation of startle (AFPS) via pathways to the startle circuits. The purpose of the present study was to establish an electromyographic (EMG) model for studying AFPS-related neural transmissions in the LA. Hind-limb startle-like EMG responses to single-pulse electrical stimulation of the trigeminal nucleus (TN) were recorded in anesthetized rats. These EMG responses were enhanced by single-pulse sub-threshold electrical stimulation of the MGN when the MGN stimulus led the TN stimulus at short inter-stimulus intervals (ISI). However, the EMG responses were not affected by single-pulse sub-threshold electrical stimulation of the AAC. Bilateral injection of the glutamate antagonist, kynurenic acid, into the LA decreased both the EMG enhancement caused by MGN stimulation at short ISIs and EMG responses to combined TN and AAC stimulation across various ISIs. Moreover, bilateral injection of the GABA(B) antagonist, phaclofen, into the LA increased both EMG responses to combined TN and MGN stimulation across various ISIs, and EMG responses to combined TN and AAC stimulation at short ISIs. These results suggest that the auditory inputs to the LA from the MGN and those from the AAC are affected differently by glutamate and GABA(B) receptors in the LA, and play differential roles in modulating startle responses.
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Intrathecal baclofen (ITB) pump catheter placement is traditionally performed through entry into the spinal sac at the lumbar spine. A minority of children with cerebral palsy have severe concomitant neuromuscular scoliosis. In these children, whether surgically treated or not, access to the intradural space via the lumbar spine may prove technically challenging. The authors report on a series of children in whom, for various reasons, an ITB catheter was implanted using a posterior cervical spine approach.
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Baclofen has been shown to be a selective agonist for a subclass of GABA receptors (GABAB) in many regions of the vertebrate nervous system. On the intraspinal terminals of dorsal roots (DRT), it evokes a pure hyperpolarizing response. We have previously shown that the response of DRT to GABA and some of its analogs (e.g. kojic amine) in isolated frog spinal cord is dual in nature, consisting of a bicuculline-sensitive depolarizing component and a bicuculline-resistant hyperpolarizing component. Under the working hypothesis that the hyperpolarizing component of the GABA-evoked response is mediated by the activation of GABAB receptors, we have examined, using the sucrose gap technique, some characteristics of the response of DRT to baclofen. We have found that this response is stereospecific (L-baclofen being about 100 times more potent than D-baclofen), dependent on [K]o (response amplitude inversely related to [K]o), blocked by barium (0.5 mM causing a reduction of the response amplitude to 37% of control), and is not significantly affected by 4-aminopyridine, nor by inorganic calcium channel blockers (manganese, cobalt, cadmium). Some proposed GABAB antagonists (delta-aminovaleric acid, delta-aminolaevulinic acid, phaclofen) are also rather ineffective at blocking it. These results are therefore consistent with the notion that the baclofen-evoked response of DRT is mediated by an increase in conductance to potassium ions.
45/138 (32.6%) patients showed pathological pH/MII despite ongoing therapy with 40 mg esomeprazole. In these, a significant reduction in liquid/mixed reflux events was observed after administering 2 x 40 mg (mean: 118.3 vs. mean: 66.6; p < 0.001), and pH/MII turned to normal in 32/45 (71.1%). Baclofen was additionally administered to 7/13 patients, which did not lead to a remarkable reduction in reflux events.
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Rat cerebral cortex synaptosomes prelabeled with [3H]gamma-aminobutyric acid [( 3H]GABA) were exposed in superfusion to various concentrations of KCl (9-50 mM). The evoked release of [3H]GABA reached a plateau at about 35 mM KCl. The K+-induced release was Ca2+-dependent, particularly at the lowest K+ concentrations. The GABAB agonist (-)-baclofen concentration dependently inhibited the release of [3H]GABA evoked by K+; this effect decreased with increasing K+ concentration and disappeared at 35 mM KCl. The GABAA agonist muscimol (1-100 microM) was totally ineffective to inhibit the release of [3H]GABA. Veratrine (1-30 microM) induced the release of [3H]GABA and the effect was tetrodotoxin-sensitive. (-)-Baclofen, but not muscimol, decreased the veratrine-induced [3H]GABA release; the GABAB agonist was particularly effective in presence of low concentrations of veratrine (1-3 microM) but the effect disappeared when 30 microM of the alkaloid was used. The inhibitory effect of (-)-baclofen on the release of [3H]GABA evoked by 15 mM KCl was dependent on the concentration of Ca2+: the effect increased as the concentration of Ca2+ was raised, reaching a plateau at 0.6 mM Ca2+. Exogenous GABA, in presence of the GABA uptake blocker SK & F 89976A, inhibited the release of [3H]GABA evoked by K+; this effect was antagonized by phaclofen. The data support the idea that terminal GABA autoreceptors in the rat cerebral cortex are of the GABAB type.
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Glutamate and γ-aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitter systems, respectively in the central nervous system (CNS). Dysregulation, in any of these or both, has been implicated in various CNS disorders. GABA acts via ionotropic (GABA(A) and GABA(C) receptor) and metabotropic (GABA(B)) receptor. Dysregulation of GABAergic signaling and alteration in GABA(B) receptor expression has been implicated in various CNS disorders. Clinically, baclofen-a GABA(B) receptor agonist is available for the treatment of spasticity, dystonia etc., associated with various neurological disorders. Moreover, GABAB receptor ligands has also been suggested to be beneficial in various neuropsychiatric and neurodegenerative disorders. The present review is aimed to discuss the role of GABA(B) receptors and the possible outcomes of GABA(B) receptor modulation in CNS disorders.
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GABAB receptors (GABABRs) are considered promising drug targets for the treatment of mental health disorders. GABABRs are obligate heteromers of principal GABAB1 and GABAB2 subunits. GABABRs can additionally associate with auxiliary KCTD8, 12, 12b and 16 subunits, which also bind the G-protein and differentially regulate G-protein signaling. It is unknown whether the KCTDs allosterically influence pharmacological properties of GABABRs. Here we show that KCTD8 and KCTD16 slightly but significantly increase GABA affinity at recombinant receptors. However, KCTDs clearly do not account for the 10-fold higher GABA affinity of native compared to recombinant GABABRs. The positive allosteric modulator (PAM) GS39783, which binds to GABAB2, increases both potency and efficacy of GABA-mediated G-protein activation ([(35)S]GTPγS binding, BRET between G-protein subunits), irrespective of whether KCTDs are present or not. Of note, the increase in efficacy was significantly larger in the presence of KCTD8, which likely is the consequence of a reduced tonic G-protein activation in the combined presence of KCTD8 and GABABRs. We recorded Kir3 currents to study the effects of GS39783 on receptor-activated G-protein βγ-signaling. In transfected CHO cells and cultured hippocampal neurons GS39783 increased Kir3 current amplitudes activated by 1 μM of baclofen in the absence and presence of KCTDs. Our data show that auxiliary KCTD subunits exert marginal allosteric influences on principal GABABR subunits. PAMs at principal subunits will therefore not be selective for receptor subtypes owing to KCTD subunits. However, PAMs can differentially modulate the responses of receptor subtypes because the KCTDs differentially regulate G-protein signaling.
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This review emphasises the paucity of research into this important field especially the lack of rigorous human trials.
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In order to explore the nature of the facilitatory GABAergic control of cerebral noradrenergic neurons, we have studied the effect of a variety of GABA mimetics (given systemically or injected locally into brain areas containing noradrenergic cell bodies or terminals) on several indices of noradrenaline turnover in the rat brain. Systemic administration of both direct and indirect acting GABA mimetics enhanced; 1) the pargyline induced accumulation of normetanephrine in the hypothalamus; 2) total DOPEG levels in a number of brain regions innervated by noradrenergic neurons; 3) both DOPAC and MOPEG levels in noradrenergic cell body areas (A1, A2 and A6). These effects are probably mediated by GABAA receptors as specific GABAA or mixed GABAA/GABAB agonists but not the GABAB agonist baclofen enhanced noradrenaline turnover. Interruption of noradrenergic impulse flow (by local injection of tetrodotoxin or by hemitransection) blocked the ability of progabide to increase DOPEG concentrations in the hypothalamus and cerebral cortex. Similarly, the co-administration of clonidine with progabide antagonized the progabide-induced increase in hypothalamic total DOPEG levels. Co-administration of yohimbine with progabide provoked an additive effect on hypothalamic DOPEG levels at moderate but not at high doses of yohimbine. Thus, the acceleration of noradrenaline turnover induced by GABA mimetics appears to depend on ongoing activity in noradrenergic neurons and occurs via an increase in neuronal discharges. Local injection of muscimol into the nucleus accumbens or hypothalamus failed to affect DOPEG levels in these structures; similarly, local injection of muscimol into the locus coeruleus failed to modify DOPEG levels in corresponding noradrenergic projection areas. These data indicate that the GABAergic influence is not exerted via GABA receptors located on noradrenergic cell bodies or nerve endings. Furthermore, since systemically administered progabide still increased hypothalamic DOPEG levels after ibotenate-induced destruction of the hypothalamic neuronal cell bodies, a presynaptic modulation of noradrenergic neurons by local GABAergic interneurons is excluded. Chemical destruction of serotoninergic pathways or enhancement of 5-HT transmission by quipazine failed to alter the ability of progabide to increase cerebral DOPEG levels. Moreover, scopolamine or naloxone also failed to affect the progabide-induced increase in cerebral DOPEG levels.(ABSTRACT TRUNCATED AT 400 WORDS)
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Spasticity is a common complication of CNS injury and a cause of considerable discomfort and disability for the patient and difficulty for caregivers. It is estimated that over half a million people in the USA are affected by spasticity. In recent years, advances in the treatment of spasticity include the use of intrathecal baclofen, addition of tizanidine to oral medication and the introduction of intramuscular botulinum toxin injections. This review aims to give an overview of one of those advances, the use of botulinum toxin. The term spasticity refers only to a type of increased muscle tone due to overactive stretch reflexes, but there are other forms of muscle overactivity that follow brain or spinal cord injury which cause problems. Generally, however, the clinical picture is dominated by the neurological deficits that result from CNS injury. A useful concept in understanding the motor consequences of injury to the CNS is that of the upper motor neuron syndrome.
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The observational fear (OF) paradigm in rodents, in which the subject is exposed to a distressed conspecific, elicits contextual fear learning and enhances future passive avoidance learning, which may model certain behavioral traits resulting from traumatic experiences in humans. As these behaviors affected by the OF require dorso-medial prefrontal cortex (dmPFC), we searched for synaptic adaptations in dmPFC resulting from OF in mice by recording synaptic responses in dmPFC layer V pyramidal neurons elicited by repeated 5 Hz electrical stimulation of dmPFC layer I or by optogenetic stimulation of specific interneurons ex vivo 1 day after OF. OF increased depression of inhibitory postsynaptic currents (IPSCs) along IPSC trains evoked by the 5 Hz electrical stimulation, but, surprisingly, decreased depression of dendritic IPSCs isolated after blocking GABAa receptor on the soma. Subsequent optogenetic analyses revealed increased depression of IPSCs originating from perisomatically projecting parvalbumin interneurons (PV-IPSCs), but decreased depression of IPSCs from dendritically projecting somatostatin cells (SOM-IPSCs). These changes were no longer detectable in the presence of a GABAb receptor antagonist CGP52432. Meanwhile, OF decreased the sensitivity of SOM-IPSCs, but not PV-IPSCs to a GABAb receptor agonist baclofen. Thus, OF causes opposing changes in GABAb receptor mediated suppression of GABA release from PV-positive and SOM-positive interneurons. Such adaptations may alter dmPFC connectivity with brain areas that target its deep vs superficial layers and thereby contribute to the behavioral consequences of the aversive experiences.Neuropsychopharmacology advance online publication, 4 January 2017; doi:10.1038/npp.2016.273.
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Inpatient multidisciplinary rehabilitation unit in France.
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Stiff-person syndrome is a rare disease characterized by muscle rigidity and painful spasms in the axial and limb muscles. The authors reported here a case of an axilally lymphadenectomy in a 46-year-old woman with stiff-person syndrome. With train of four ratio (TOFR) monitoring at the ulnar nerve, general anesthesia was induced and maintained with fentanyl, vecuronium and propofol with target controlled infusion. A TOFR, BIS monitor and invasive arterial pressure monitoring were employed. During the operation, there was no muscle rigidity and spasm. Ten minutes after the operation, she was fully awake and train of four ratio recovered to 95%, and extubated uneventfully. We chose propofol, because of previous reports about prolonged hypotonicity by interaction of baclofen and isoflurane. Preoperative good symptom control, choice of total intravenous anesthesia (TIVA), and application of the electrical nerve stimulator prevented postoperative hypotonia and resulted in safe anesthetic management.
The sensitivity of Purkinje cells (PCs) and neurons of the cerebellar nuclei (NCNs) to iontophoretic application of gamma-aminobutyric acid (GABA), 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) and baclofen, i.e., GABAA and GABAB agonists respectively, have been studied in anesthetized rats. All the agonists produced dose-dependent firing rate depression of the PCs but with different potencies. The inhibitory actions of both GABA and THIP were specifically antagonized by bicuculline (Bic) and the baclofen-induced responses by 2-hydroxysaclofen. GABA and THIP also depressed the spontaneous activity of NCNs while baclofen was ineffective. The present results therefore suggest that GABAA receptors are involved in the GABA-induced inhibition in the cerebellar cortex and in the cerebellar nuclei and GABAB receptors are involved only in the cerebellar cortex.
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The pre- and postsynaptic effects of baclofen, a broad-spectrum gamma-aminobutyric acid (GABA)B receptor agonist, and gabapentin, a selective agonist at GABA(B) receptors composed of GABA(B)(1a,2) heterodimers, were examined in CA1 pyramidal cells using whole-cell patch-clamp recordings in hippocampal slices from different strains of mice. In slices from C57BL/6 mice, by means of GABA(B) receptors, gabapentin and baclofen activated outward K+ currents at resting membrane potential. In weaver mice with a Kir3.2 channel mutation, baclofen and gabapentin failed to activate postsynaptic K+ currents. However, in littermate controls of weaver mice, gabapentin failed to evoke K+ currents, whereas baclofen activated currents in the same cells. Thus, postsynaptic actions of gabapentin and baclofen on K+ currents are different in this mouse strain. Via presynaptic GABA(B) receptors, baclofen significantly reduced GABA(A) inhibitory postsynaptic currents (IPSCs) in slices from C57BL/6 mice, as well as weaver and control mice. In contrast, gabapentin did not affect IPSCs significantly in any group of mice. These results indicate that although baclofen and gabapentin are agonists at postsynaptic GABA(B) receptors positively coupled to K+ channels, their mechanism of action differs in certain strains of mice, including the weaver wild-type mice, suggesting a dissociation in their signaling mechanism and coupling to K+ channels.
The reviewers extracted the data independently and the odds ratio (OR) and its 95% confidence interval (CI) or the weighted mean difference with 95% CI were estimated. The reviewers assumed that people who dropped out had no improvement.