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Under vehicle conditions, DS and NS presentation elicited dopamine release within the NAc core. The DS evoked significantly more dopamine than the NS. Inactivation of the BLA selectively attenuated the magnitude of DS-evoked dopamine release, concurrent with an attenuation of DS-evoked conditioned approaches. Other behavioral responses (e.g., lever pressing) and dopamine release concomitant with those events were unaltered by BLA inactivation. Furthermore, neither ventral tegmental area electrically stimulated dopamine release nor the probability of high concentration dopamine release events was altered following BLA inactivation.
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Experiments on rats and mice were made to study the antianamnestic and antihypoxic effects of some GABA derivatives. Cetyl GABA, sodium and lithium hydroxybutyrates and phenibut were shown to be able to decrease the retrograde amnesia caused by electroshock in passive avoidance performance. As regards the degree of the antianamnestic effect, the above-mentioned non-cyclic derivatives of GABA are not inferior to the standard nootropic drug piracetam, a derivative of cyclic GABA. Antihypoxic activity of sodium hydroxybutyrate, cetyl GABA, phenibut and lioresal studied in experimental hypoxic hypoxia compares very favourably with that of piracetam. The compounds under consideration manifest their protective action against damaging factors in doses which do not provoke muscle relaxation or any types of central depression. According to the data obtained one may conclude that the nootropic effect is exhibited by not only piracetam, a derivative of cyclic GABA, but also by some of its non-cyclic derivatives.
The effect of gamma-butyrolactone (GBL) on inhibition by baclofen of gastric carcinogenesis was investigated in Wistar rats. In week 52, baclofen significantly decreased the incidence of gastric cancers. Concomitant treatment with GBL significantly increased gastric acid secretion but had no influence on the inhibition by baclofen of gastric carcinogenesis. This finding suggest that GBL significantly increased the sensitivity of gamma-aminobutyric acid (GABA) receptor to GABA mimetics in gastric acid secretion but not in the inhibitory effect of gastric carcinogenesis.
Inferior colliculus (IC) slices from guinea pigs were prepared by cutting the IC parasagittally and incubating the obtained slices in the standard medium. Postsynaptic field potentials (PSFP) were recorded in the superficial layer of the pericentral nucleus (PN) by stimulating the deep layer of the PN. GABA (gamma-aminobutyric acid) and its agonists (muscimol and baclofen) and antagonist (bicuculline) were applied in the perfusion medium. GABA (1-12.5 mM), muscimol (1-200 microM) and (-)-baclofen (0.1-20 microM) reduced the amplitude of the PSFP in a dose-dependent manner. Bicuculline (1-10 microM) enhanced the amplitude of the PSFP and evoked the epileptiform burst discharge (EBD). The incubation of IC slices with methoxypyridoxin (100 microM) and 3-mercaptopropionic acid (100 microM) for 2 h reduced the GABA level of the slice to about 50% of the initial value, at which point a distinct EBD appeared. The application of GABA (5 mM) to the medium in this condition blocked the EBD completely. The removal of chloride from the medium as well as the application of furosemide (100 microM) enhanced the amplitude of the PSFP and also elicited the EBD; GABA application in this case did not block the EBD. These results indicate that GABA plays an inhibitory role in the IC, and that the reduction of GABA and the blockade of GABA function cause the appearance of EBD in the IC.
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Patients underwent placement of a temporary intrathecal catheter that was connected to an external pump. A successful trial was defined as a one-level reduction in lower limb modified Ashworth scores in key spastic lower limb muscles identified for each individual patient. Subjective improvement in function or ease of performing functional tasks also were monitored.
Herein we report a case of baclofen-induced encephalopathy in a patient with pre-end-stage renal disease and review the literature regarding the magnitude of baclofen toxicity in patients with renal insufficiency. A Medline search for studies in English was performed. Twenty-one case reports involving 41 patients (including our patient) were identified.
The involvement of GABAergic mechanisms in shock-induced defensive fighting in rats was investigated in a series of three experiments. In Experiment 1, sodium n-dipropylacetate (100-200 mg/kg) failed to produce significant behavioural change whilst gamma-vinyl-GABA (100-200 mg/kg) induced a selective and dose-dependent reduction in fighting. In Experiment 2, although inconsistent behavioural effects were obtained with (+)-bicuculline (0.25-4 mg/kg), a biphasic influence on defensive fighting was observed with picrotoxin (0.125-2 mg/kg). The inhibitory effect on fighting, induced by the highest dose of picrotoxin, was related to motor impairment. In Experiment 3, muscimol reduced fighting at doses above 0.25 mg/kg with motor disruption evident only at the highest dose used (1 mg/kg). A dose-dependent inhibition of defensive fighting was observed with 1-baclofen (0.15-1.2 mg/kg) which, at the highest dose tested, also impaired motor coordination. None of the compounds tested significantly altered shock thresholds. Results are discussed in relation to the hypothesized inhibitory role of GABA in the mediation of aggressive behaviours.
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Drosophila melanogaster, the "fruit fly," is being increasingly used as an experimental model in neurosciences, including neuropharmacology. The advantages of Drosophila over typical mammalian models in neuropharmacology include better access to genetic manipulation and the availability of almost unlimited numbers of experimental subjects at relatively low cost and with minimal regulatory restrictions. Nevertheless, one should remain cognizant of the substantial differences between insects and mammals. Insects, including Drosophila, utilize gamma-aminobutyric acid (GABA) as a neurotransmitter and express both ionotropic GABA receptors and metabotropic GABA-B receptors. Before cloning of the Drosophila GABA-B receptors (subunits 1-3), it had been assumed that flies did not express these receptors since baclofen, a typical agonist for mammalian GABA-B receptors, does not produce any effects in insects. Subsequently, it was confirmed that cloned Drosophila GABA-B receptors exhibit a unique pharmacology. Using Drosophila as a model, it has been shown that GABA-B receptors are involved in the behavioral actions of alcohol and gamma-hydroxybutyric acid, and possibly in pain. Furthermore, recent research suggests that in flies these receptors may play an important developmental role and that they participate in olfaction and in regulation of circadian rhythms.
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The main aim of this study is to determine a set of suitable and effective therapeutic steps that can be used to improve patients' spasticity and to prevent the complications that stem from them, such as contractures, deformities, surgery, etc. Multiple treatments were used, including physiotherapy, rehabilitation and oral pharmacotherapy, with few satisfactory results. At present there are two very promising therapeutic alternatives for patients with infantile cerebral palsy: Botulinum toxin, which we already have a great deal of experience with, and intrathecal treatment with baclofen. We report on a series of 10 patients aged between 8 and 15 years who had had an intrathecal baclofen infusion pump implanted. To date (maximum follow-up: 12 months), their clinical course has been satisfactory in most cases, with no severe complications related to the surgical technique, except in one individual who presented a fistula that resolved spontaneously.
The effects of the GABAergic drugs nipecotic acid, Gabrene, baclofen and metatolylcarbamide (MTC), when given alone or in combination at subthreshold doses with AT II also at a subthreshold dose effective on PTZ-kindling in mice were studied. PTZ-kindling was provoked by intraperitoneal (i.p.) injections of PTZ (40 mg/kg) every other day in male albino mice until clonic seizures appeared. Nipecotic acid (100 and 200 micrograms/mouse intracerebroventricularly [i.c.v.]) tended to decrease seizure intensity. Gabrene (25, 50, 100 and 250 mg/kg i.p.) inhibited PTZ-kindled seizures. Baclofen at a doses of 2.5 and 5 mg/kg i.p. tended to decrease seizure intensity and at a dose of 10 mg/kg was ineffective at all. MTC (50 and 75 mg/kg i.p.) tended to decrease and at a dose of 100 mg/kg significantly decreased seizure intensity. Combinations of subthreshold dose of AT II (0.05 micrograms/mouse i.c.v.) and subthreshold doses of nipecotic acid (100 micrograms/mouse) or Gabrene (10 mg/kg) or baclofen (10 mg/kg) or MTC (50 mg/kg) significantly decreased the intensity of PTZ-kindled seizures in mice. The observed potentiation of the anticonvulsive activity on PTZ-kindling suggests interactions of AT II receptors with GABA receptors (GABAA, GABAB or both), effected through allosteric mechanisms.
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Rats, assigned to three experimental groups (Bac/isch, saline/isch, or Bac/sham), were injected twice daily for 10 consecutive days with Bac or saline, starting 24 h after induction of stroke. The sleep-wake cycle was assessed by EEG recordings and functional motor recovery by single pellet reaching test (SPR). In order to identify potential neuroplasticity mechanisms, axonal sprouting and neurogenesis were evaluated. Brain damage was assessed by Nissl staining.
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Baclofen, a centrally acting muscle relaxant, is used in the treatment of spasticity. Its pharmacokinetics has been derived from plasma and urine data in four healthy subjects, whose renal function was simultaneously measured. After oral administration of a single 40 mg dose, baclofen was mainly excreted unchanged by the kidney, 69 (14)%. The half-life, calculated from extended least squares modelling (ELSMOS) both of plasma and urine data was 6.80 (0.68) h, which is longer than reported in most studies based solely on plasma data. The renal excretion rate constant had the high mean value of 0.35 (0.24) h-1, and the apparent renal clearance of baclofen equalled the creatinine clearance. Passive tubular reabsorption is relatively unimportant, since no dependence was observed on variables urine flow or pH. Although active tubular secretion may contribute to its renal clearance, as shown by the effect of co-administration of probenecid, glomerular filtration appears to be the dominant transport mechanism.
We recorded extracellular responses from rat amygdaloid neurons in vivo after electrical stimulation of the basal forebrain and hippocampal formation. Iontophoretic application of the GABAA receptor antagonist, bicuculline, lead to the appearance of short latency evoked bursts after stimulation of either region. This occurred whether the baseline response was inhibitory or excitatory. Bicuculline only affected an early phase of inhibition, leaving a longer latency, longer duration phase unchanged or even increased. By contrast, the GABAB receptor antagonist, phaclofen, never produced such short latency evoked bursts. Both bicuculline and phaclofen increased the spontaneous rate of firing of amygdaloid neurons. The excitatory burst response to hippocampal formation stimulation of an amygdaloid candidate inhibitory neuron was blocked by CNQX (an antagonist of the AMPA subtype of glutamate receptor). Based on these and prior studies, it seems likely that the effects of hippocampal formation stimulation are mediated by feed-forward inhibition, in which GABAergic amygdaloid inhibitory neurons are excited by glutamatergic projections from the hippocampal formation. The effects of basal forebrain stimulation may be mediated by both feed-forward inhibition and direct, GABAergic inhibition.
The effect of the GABAB agonist, (+/-)-baclofen, on the N-methyl-D-aspartate (NMDA)-mediated stimulation of tyrosine hydroxylase activity was investigated in slices of rat striatum. Tyrosine hydroxylase activity was stimulated by NMDA in a concentration-dependent manner (EC50, 1.3 +/- 0.3 microM; maximum stimulation 194 +/- 7% of basal activity). The action of NMDA was reversed by the NMDA antagonist, 2-amino-5-phosphonovalerate (AP-5). (+/-)-Baclofen (100 microM) decreased the maximum effect of NMDA by 24 +/- 2% without significantly modifying its EC50. The IC50 for the inhibitory action of (+/-)-baclofen was 4.2 +/- 1.2 microM. These results show that GABAB receptor activation modulates NMDA-stimulated tyrosine hydroxylase activity, further supporting the possibility of a role of GABA in the regulation of striatal dopaminergic neurotransmission.
Low concentrations of ethanol (10-30 mM) in the presence of a GABAB receptor agonist, baclofen, promoted 36Cl- uptake into membrane vesicles (microsacs) prepared from mouse cortex. Neither ethanol nor baclofen alone altered chloride influx. The GABAB antagonists, phaclofen and 2-hydroxy-saclofen, completely blocked the increase in chloride flux produced by ethanol in the presence of either baclofen or GABA. Ethanol increased the chloride conductance produced by the GABAA agonists muscimol, isoguvacine, imidazolacetic acid and amino-propane sulfonic acid and this action of ethanol was blocked by phaclofen. The specific GABAA antagonist, bicuculline, blocked ethanol-induced increase in chloride flux in the presence of either baclofen or GABA. GABA-activated chloride channels were also studied in Xenopus oocytes expressing mouse brain mRNA. In this preparation, GABA action was enhanced by ethanol, pentobarbital, and diazepam, and 2-hydroxy-saclofen partially antagonized the action of ethanol without altering the effects of pentobarbital or diazepam. These results suggest that ethanol enhancement of GABAA receptor-chloride channel function also requires activation of GABAB receptors.
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Transmission at the end-bulb synapse formed by auditory nerve terminals onto the soma of neurons in the avian nucleus magnocellularis is characterized by high transmitter release probability and strong synaptic depression. Activation of presynaptic GABA(B) receptors minimizes depression at this synapse and significantly enhances synaptic strength during high-frequency activity. Here we investigate synaptic mechanisms underlying this phenomenon. EPSC amplitudes evoked by 200 Hz trains increased more than twofold when release probability was reduced with Cd(2+) or baclofen. This effect was not exhibited by a transmitter depletion model of presynaptic depression, which predicts that EPSC amplitudes reach a common steady-state amplitude during high-frequency trains, despite alterations of initial release probability. However, an additional source of postsynaptic depression was sufficient to explain our findings. Aniracetam, a modulator of AMPA receptors that reduces desensitization, decreased the amount of synaptic depression during trains, indicating that desensitization occurred during trains of stimuli. However, this effect of aniracetam was absent when release probability was lowered with baclofen or Cd(2+). No effect of aniracetam on the NMDA component of the EPSC was seen, confirming a postsynaptic site of action of aniracetam. When desensitization was reduced with aniracetam, steady-state EPSC amplitudes during trains were found to converge over a wide range of release probabilities, as predicted by the depletion model. Additional evidence of AMPA receptor desensitization was provided by direct measurement of quantal amplitudes immediately after stimulus trains. Thus, presynaptic modulation by GABA(B) receptors regulates the extent of AMPA receptor desensitization and controls synaptic strength, thereby modulating the flow of information at an auditory synapse.
Several spider neurotoxins are known to show highly selective effects on nervous tissues. Intracerebral injection into rats of spider venom from Scaptocosa raptoria, prevents seizures induced by convulsant agents. Injection of phenytoin (390 pmol/200 nl), muscimol (90 pmol/200 nl), baclofen (500 pmol/200 nl) into the substantia nigra (SN) pars reticulata, protected rats from convulsions evoked by unilateral focal injection of bicuculline into the area tempestas by 50, 80, and 100%, respectively. Denatured S. raptoria crude venom (4.6 microg, 2.3 microg, and 920 ng/200 nl), when administered into the SN, prevented seizures elicited by bicuculline in the area tempestas by 100, 100, and 87.5%, respectively. The injection into the SN of 160 ng/200 nl of fraction SrTx1 isolated from S. raptoria venom, reduced the magnitude of seizures. This fraction was rechromatographed affording fractions SrTx1.1, SrTx1.2 and SrTx1.3, and they were administered into the SN at doses of 100, 200, and 400 ng/200 nl respectively. Fraction SrTx1.3 protected 50, 85.7, and 100% of the animals against the seizures elicited by bicuculline injected into the area tempestas. This suggests that S. raptoria venom as well as its SrTx1.3 fraction, might be potential sources of new anticonvulsant drugs.
Ethanol inhibits the excitability of histaminergic neurons in mouse TMN slices, possibly via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites.
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Using mouse xenografts from the gemcitabine--sensitive pancreatic cancer cell line BXPC-3, we tested the effects of GABA and baclofen on nicotine-induced gemcitabine resistance. The levels of cAMP, p-SRC, p-ERK, p-AKT, p-CREB and cleaved caspase-3 in xenograft tissues were determined by ELISA assays. Expression of the two GABA-B receptors, metalloproteinase-2 and 9 and EGR-1 in xenograft tissues was monitored by Western blotting. Mechanistic studies were conducted in vitro, using cell lines BXPC-3 and PANC-1 and included analyses of cAMP production by ELISA assay and Western blots to determine protein expression of GABA-B receptors, metalloproteinase-2 and 9 and EGR-1.
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These results suggest that baclofen might be a novel therapeutic agent for opiate withdrawal syndrome. However, a larger study to confirm our results is warranted.
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This article is a review of the evidence for complementary and alternate systems of medicine in substance use disorders. Articles were searched using the Medical Subject Headings (MeSH) database of the PubMed search engine and further non-indexed information was obtained from the Google search engine. The article is organised in parts, each reviewing a different system of medicine in the following order--alternate medical systems, biologically based therapies, energy-based interventions and mind-body interventions; as classified by the National Center for Complementary and Alternative Medicine, National Institutes of Health, USA.