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Various drugs known to affect synaptic transmission were tested for their effects on extracellular field potentials evoked in the dentate granule cell layer of guinea pig hippocampal slices. Presumptive commissural (CF) and perforant path (PP) fibers were stimulated electrically by two separate pairs of stimulating electrodes. CF stimulation elicited a field potential with a current sink and PP stimulation with a current source in the cell layer. Bath-applied carbachol (0.5-10 microM), in an atropine sensitive manner, depressed the CF-evoked field potential, but left the PP-evoked field potential unchanged. Further pharmacological testing revealed that this effect is likely to be mediated by inhibitory neurons in the dentate hilus.
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We review the latest literature on the neuropharmacological treatments for acquired nystagmus.Nystagmus may have a significant [corrected] impact on health, yet there is little scientific evidence on which to make firm recommendations for treatment. Acquired pendular nystagmus may respond to gabapentin or memantine; downbeat and upbeat nystagmus to aminopyridines; and periodic alternating nystagmus to baclofen. To improve treatment we need multi-centre, randomised controlled trials using standardised techniques in reporting objective outcomes, with good follow-up duration and careful reporting of side effects.
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There were 63 males (56%) and 49 females (44%). Seventy-four (66%) had a quadriparesis, 34 (30.4%) had a paraparesis and 4 (3.6%) were hemiplegic. Among these patients 77 (68.7%) were non ambulatory, while 35 (31.3%) were ambulatory. These patients suffered from spasticity due to many different diseases. Mean follow-up was 55 months. The mean Modified Ashworth score decreased from 4.5±0.5 preoperatively to 1.2±0.4 on chronic intrathecal baclofen. Daily baclofen dose varied between 23 and 500 mcg. Drug-induced complications and catheter related problems occurred, respectively in 7 (6.3%) and 10 patients (8.9%).
A 61-year-old woman was admitted to the medical ICU for severe withdrawal symptoms from chronic GHB use. This manifested as delirium, tremor, and seizures despite only small decreases in GHB dose and treatment with benzodiazepines. The addition of baclofen allowed the rapid sequential decreases in the GHB dose without seizure or delirium and resulted in long-term improvement of her tremor.
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Many children with cerebral palsy have chronic ventriculomegaly as a consequence of perinatal intraventricular hemorrhage or periventricular leukomalacia, without symptoms of hydrocephalus. Children with cerebral palsy who are treated with intrathecal baclofen have a higher rate of cerebrospinal fluid (CSF) leaks along the baclofen catheter than do adults treated with intrathecal baclofen. We postulated that the cause of the increased frequency of CSF leaks was increased CSF pressure, that is, occult hydrocephalus.
Our previous study showed the local production of gamma-aminobutyrate (GABA) in hypertrophic-zone chondrocytes of the rat tibial growth plate, an important long bone growth site. The aim of this study was to identify the presence of GABA receptors in growth plate chondrocytes by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Chondrocytes expressed both GABA(A) and GABA(B) receptor subunit mRNAs as well as the corresponding proteins necessary for the assembly of functional receptors. The GABA(A) receptor subunits detected included alpha1-alpha4, alpha6, beta1-beta3, and delta, and both R1 and R2 subunits of GABA(B) receptors were detected. All receptor subunits were expressed in chondrocytes of the proliferative and hypertrophic zones. These results suggest that GABA is an autocrine/paracrine factor that regulates the physiological state of the growth plate. Subsequent studies with the mouse chondrogenic cell line ATDC5 showed the presence of mRNAs and the corresponding proteins for GABA(A) receptor alpha1, beta2, and beta3 subunits and GABA(B) receptor R1 and R2 subunits. GABA, muscimol (a GABA(A) receptor agonist), and baclofen (a GABA(B) receptor agonist) increased 5-bromodeoxyuridine (BrdU) incorporation into ATDC5 cells. The effect of muscimol was blocked by bicuculline (a GABA(A) receptor antagonist), and the effect of baclofen was blocked by CGP 35348 (a GABA(B) receptor antagonist). These results suggest that GABA contributes to the ATDC5 cell proliferation via GABA(A) and GABA(B) receptors and these mechanisms may be involved in cartilaginous cell growth.
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A neurological rehabilitation department of a university hospital. Pump implantation was realized in neurosurgery; follow-up was carried out mostly on an outpatient basis.
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Effects of selective gamma-aminobutyric acidA (GABAA) and GABAB receptor agonists on noradrenaline (NA)-induced and N-methyl-D-aspartate (NMDA)-induced luteinizing-hormone (LH) secretion were examined in ovariectomized estrogen-primed rats. Experiments were performed in unanesthetized animals bearing chronic intracerebroventricular (i.c.v.) cannulae. I.c.v. injections of NA or NMDA stimulated LH secretion in animals that had received prior i.c.v. injections of saline. The effects of NA and NMDA were significantly attenuated by a prior i.c.v. injection of phentolamine (a selective alpha-adrenergic-receptor blocker) and 2-amino-5-phosphonovaleric acid (a selective NMDA receptor antagonist), respectively. NA-induced LH release was also inhibited by i.c.v. injections of either muscimol (a selective GABAA receptor agonist) or baclofen (a selective GABAB receptor agonist). On the other hand, although muscimol inhibited the effect of NMDA, baclofen did not inhibit but slightly augmented the NMDA-induced release of LH. These results support the hypothesis that both GABAA and GABAB receptors are involved in the GABAergic inhibition of LH secretion, and further suggest that they are probably located at different sites in the neural mechanism regulating LH secretion in the female rat.
Patients receiving ITB for the management of spasticity.
N-methyl-D-aspartic acid (NMDA; 40 mg/kg, i.p.) did not elicit catalepsy, but it potentiated the cataleptic effect of haloperidol and GABAB receptor agonist, baclofen. MK-801 (0.2 mg/kg, i.p.), NMDA-receptor antagonist, reversed haloperidol- but not baclofen-induced catalepsy. MK-801 also potentiated the anticataleptic effect of scopolamine and bromocriptine against haloperidol-induced catalepsy. Dihydropyridine (DHP) calcium-channel antagonists such as nimodipine and nitrendipine (10 mg/kg, i.p.), reversed the anticataleptic effect of MK-801, and potentiated the cataleptic effect of haloperidol, as well as baclofen. These observations indicate the involvement of NMDA receptors in catalepsy, and suggest a potential clinical implication of NMDA-receptor antagonists in Parkinson's disease.
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In a Dutch national study, we recently established the effectiveness and safety of continuous intrathecal baclofen infusion (CITB) in children with intractable spastic cerebral palsy (CP). Because prospective studies on the cost-effectiveness of CITB in children with spastic CP are lacking, we conducted a cost-effectiveness analysis alongside our prospective national study. We compared the costs and health effects of CITB with those of standard treatment only, from the health care perspective for a 1-year period. Health effects were expressed in terms of a visual analogue scale for individual problems and quality-adjusted life years (QALYs). We included eight females and seven males, aged between 7 and 17 years (mean age 13y 8mo [SD 3y]). Eleven children had spastic CP and four had spastic-dyskinetic CP. One child was clsssified on the Gross Motor Function Classification System at Level III, two at Level IV, and 12 at Level V. CITB was more effective and more costly than standard treatment only. Gaining one QALY cost on average 32,737 euros. We conclude that based on the threshold-willingness to pay for one QALY in the Netherlands (80,000 euros), our results confirm the cost-effectiveness of CITB for carefully selected children with intractable spastic CP.
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We have examined the action of GABA on the electrical, secretory and synthetic activities of rat and porcine intermediate lobe (IL) cells in primary culture. Chloride and calcium currents were investigated using patch-clamp techniques. A chloride current activated by 1-100 microM isoguvacine, a specific GABA-A agonist, and antagonised by bicuculline and SR 95103 was recorded at the whole cell and single channel level current. Whole cell calcium currents were investigated and shown to be reduced by 40 microM cadmium, zero external calcium and 10 microM baclofen, a specific GABA-B receptor agonist. Both GABA-B receptor activation and use of calcium deficient medium inhibited peptide release from IL cells. Finally, pro-opiomelanocortin (POMC) mRNA levels were measured using a hybridization technique. Removal of calcium from the culture medium or long-term (48 hr) incubation with 10 microM GABA or muscimol (a mixed GABA-A and GABA-B agonist) significantly reduced POMC mRNA levels.
Intracellular recordings were used to characterize the inhibitory synapses formed by Purkinje cells on neurons in the deep cerebellar nuclei of the rat. This work was performed on organotypic cerebellar cultures where functional connections between Purkinje cells and deep cerebellar neurons are formed de novo. After blocking ionotropic excitatory amino acid, and GABAA receptors with 6-cyano-7-nitro-quinoxaline-2,3-dione,D-2-amino-5-phosphonovalerate and bicuculline, respectively, the majority of deep cerebellar neurons fired spontaneously without accommodation. This tonic firing was linearly dependent on membrane potential and was abolished with hyperpolarization. Bath application of muscimol and baclofen reversibly hyperpolarized deep cerebellar nuclei cells. In the presence of excitatory amino acid receptor antagonists, field stimulation within the Purkinje cell layer induced monosynaptic inhibitory potentials in deep cerebellar neurons that were graded and completely blocked by bicuculline. Inhibitory potential amplitudes were not markedly reduced during fast repetitive stimulation of Purkinje cells, and the resulting hyperpolarization was not affected by the competitive GABAB receptor antagonist CGP 35348. A single inhibitory potential temporarily interrupted trains of action potentials induced in deep cerebellar cells by short depolarizing pulses. Trains of five inhibitory postsynaptic potentials, evoked at 20 Hz, induced a hyperpolarization which transiently blocked the spontaneous firing of deep cerebellar cells. The efficiency to block action potential discharges depended on the frequency of evoked inhibitory potentials. Bath application of bicuculline induced burst discharges in the control solution. When the excitatory amino acid receptors were pharmacologically blocked, bicuculline depolarized deep cerebellar neurons inducing sustained action potential discharges. In the presence of tetrodotoxin, bicuculline abolished miniature inhibitory postsynaptic potentials and resulted in a membrane depolarization of deep cerebellar cells. We conclude that deep cerebellar neurons isolated from synaptic inputs display a pacemaker-like activity. Although these neurons possess GABAA and GABAB receptors, we confirm that only GABAA receptors were involved in the generation of inhibitory postsynaptic potentials, even with high frequency stimulation. The amplitude of evoked inhibitory potentials was weakly frequency-dependent, thus allowing a powerful inhibition of the pacemaker-like activity by trains of evoked inhibitory postsynaptic potentials. Additionally, spontaneous and miniature inhibitory potentials control the excitability of deep cerebellar neurons by exerting a continuous hyperpolarizing tone.
1. The gamma-aminobutyric acid (GABA) receptors on the somatic muscle cells of Ascaris, which mediate muscle cell hyperpolarization and relaxation, have been characterized by use of intracellular recording techniques. 2. These receptors are like mammalian GABAA-receptors in that the response is mediated by an increase conductance to chloride ions. The GABAA-mimetic, muscimol, has a relative potency of 0.40 +/- 0.02 (n = 3) compared to GABA. 3. The stereoselectivity of the GABA receptor on Ascaris is identical to that for the mammalian GABAA-receptor, as determined from the relative potency of three pairs of enantiomers of structural analogues of GABA. 4. The most potent agonist is (S)-(+)-dihydromuscimol which is 7.53 +/- 0.98 (n = 5) times more potent than GABA. 5. The Ascaris GABA receptor is not significantly blocked, at concentrations below 100 microM by the potent, competitive GABAA-receptor antagonist, SR95531. 6. The Ascaris GABA receptor does not recognise agents that are known to block the GABA gated chloride channel in mammalian preparations such as t-butylbicyclophosphorothionate (TBPS, 10 microM, n = 2) or the insecticide dieldrin (100 microM, n = 3). 7. GABAergic responses in Ascaris are not potentiated by pentobarbitone (100 microM, n = 3) or flurazepam (100 microM, n = 3). 8. The potencies of various GABA-mimetics in the Ascaris preparation have been compared with their potency at displacing GABAA-receptor binding in mammalian brain. Excluding the sulphonic acid derivatives of GABA, the correlation coefficient (r) between the potencies of compounds in the two systems is 0.74 (P less than 0.01). The significance of this correlation is discussed. 9. The pharmacology of the Ascaris GABA receptor is discussed in relation to other invertebrate systems and the mammalian subclassification of GABA receptors.
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Preapplication of baclofen 1-100 mumol.L-1 induced a concentration-dependent inhibition of the inward NMDA-activated current markedly. NMDA (100 mumol.L-1)-activated current was inhibited by 52% +/- 14% (n = 11, P < 0.01) by preapplication of baclofen 100 mumol.L-1. The inhibitory effect of baclofen was reversible, and was removed by saclofen 100 mumol.L-1, which was a selective antagonist of GABAB receptor.
The strain Achromobacter sp. JA81, which produced enoate reductase, was applied in the asymmetric reduction of activated alkenes. The strain could catalyze the bioreduction of alkenes to form enantiopure (R)-β-aryl-β-cyano-propanoic acids, a precursor of (R)-γ-amino butyric acids, including the pharmaceutically active enantiomer of the chiral drug (R)-baclofen with excellent enantioselectivity. It could catalyze as well the stereoselective bioreduction of other activated alkenes such as cyclic imides, β-nitro acrylates, and nitro-alkenes with up to >99 % ee and >99 % conversion. The draft genome sequencing of JA81 revealed six putative old yellow enzyme homologies, and the transcription of one of them, Achr-OYE3, was detected using reverse transcription polymerase chain reaction. The recombinant Escherichia coli expressing Achr-OYE3 displayed enoate reductase activity toward (Z)-3-cyano-3-phenyl-propenoic acid (2a).
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The major breakthrough in the treatment of mental diseases was the introduction of neuroleptics in the early 50's. Soon after this an increasing number of patients under the use of these drugs presented involuntary abnormal orofacial movements which have been considered directly dependent on the drug action. The term "tardive dyskinesia" (TD) was coined for these movements. Many theories have been put forward to explain the pathophysiology of TD. The most prominent theory concerns with the possibility of denervation hypersensitivity occurring in striatal post-synaptic dopamine neurons. The authors review the most important theories and offer a new possibility based on the assumption that the post-synaptic dopamine receptors under chronic neuroleptic action develop a shift in its affinity towards the direction of agonist action. This means that the post-synaptic receptor increase its affinity, and possibly its number, to agonist drugs and dopamine. The paper includes a review of the main drugs used in this condition, attempting to explain the specific sites where they act, either in the dopaminergic, cholinergic or GABA--ergic systems.
The effects of various psychotropic drugs (benzodiazepines, antidepressants, neuroleptics and nootropic drugs, a family of cognition activator agents) on firing rates of septohippocampal neurons, identified by electrical antidromic stimulation, were studied in the medial septum-nucleus of the diagonal band of Broca of rats anaesthetized with urethan. Extracellular potentials from single septohippocampal neurons were recorded using glass pipettes. Drugs were applied by either microiontophoresis or intravenous injections (i.v.). Benzodiazepines produced a marked depression of spontaneous firing rates of septohippocampal neurons whether applied i.v. (diazepam) or iontophoretically (flurazepam, midazolam). In addition, diazepam had a potent depressant effect on the rhythmically bursting activity of the septohippocampal neurons. Baclofen also had an inhibitory effect. Antidepressant drugs (applied by iontophoresis) as well as amphetamine, had a depressant effect on spontaneous firing rates. Neuroleptics (i.v.) had less significant or consistent effects on septohippocampal neurons, although the effects of haloperidol were usually inhibitory. Nootropic drugs were generally ineffective. These data indicate that most psychotropic drugs tested (with the exception of nootropic drugs) have an inhibitory effect on the spontaneous activity of septohippocampal neurons. However, benzodiazepines seem to be more active than antidepressants or neuroleptics. Oxotremorine (i.v.) had a potent excitatory effect on septohippocampal neurons. Atropine (i.v.) increased the septohippocampal neurons' firing rate in some cases. These results are discussed in view of the possible implication of the involvement of septohippocampal neurons in the mediation of the effects of psychotropic drugs on the central nervous system and, more specifically, on the cholinergic systems.
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The role of intrathalamic GABAB neurotransmission in the control of absence seizures was investigated. In rats with genetic absence epilepsy, bilateral injections of R-baclofen (50, 100 and 200 ng/side), a selective GABAB receptor agonist, into the specific relay nuclei and the reticular nuclei of the thalamus increased spontaneous spike and wave discharges in a dose-dependent fashion, whereas injections of a GABAB antagonist CGP 35,348 (1, 2.5 and 5 micrograms/side) into the same sites decreased these seizures dose-dependently. The effect of R-baclofen (200 ng/side) on spike and wave discharges could be blocked by a subsequent injection of CGP 35,348 (1 microgram/side) at the same site. Injections of R-baclofen (200 ng) or CGP 35,348 (5 micrograms) into the midline thalamus had no effect on these seizures. In non-epileptic rats, bilateral injections of R-baclofen (1 microgram/side) into the specific relay nuclei induced synchronized rhythmic oscillations on the cortical electroencephalogram. The results suggest that GABAB receptors in the ventrolateral thalamus and in the reticular nuclei are involved in an oscillatory activity which underlies the rhythmic spike and wave discharges recorded during spontaneous generalized non-convulsive seizures.
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To conduct an evidence-based analysis of the effectiveness and cost-effectiveness of intrathecal baclofen for spasticity.
Twelve patients perceived a definite reduction in symptoms of spasticity with pregabalin, and 9 continued to take it. Eight patients experienced significant side-effects which limited its use, 5 experienced no beneficial or adverse effects.