Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GABA(B) agonists inhibit excitatory transmission to hippocampal CA3 neurons during low frequency stimulation. We examined whether GABA(B) receptor activation can also enhance synaptic efficacy, when investigated at an input with high initial release probability. Short-term depression of field excitatory postsynaptic potential (EPSP) amplitude was observed during trains of stimuli applied to associational/commissural inputs (10-50 Hz; 22 degrees C). Baclofen (10 microM) reduced the amplitude of initial EPSPs in a train, and also reduced the degree of short-term depression. EPSPs recorded late in a train were significantly larger in baclofen than those recorded in control solution. These dual effects were mimicked by another selective GABA(B) agonist (SKF 97541, 10 microM), and abolished by a GABA(B)-selective antagonist (SCH 50911, 20 microM). The effects of baclofen were similar at a higher recording temperature (32 degrees C), where short-term depression was observed at higher stimulation frequencies. These results are consistent with the idea that a reduction of transmitter release probability could increase the fidelity of high-frequency transmission at this input, an effect that could help account for excitatory effects of GABA(B) agonists in some seizure models.
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PMID:GABA(B)-receptor modulation of short-term synaptic depression at an excitatory input to murine hippocampal CA3 pyramidal neurons. 1523 71

GABA(B) receptors are believed to play a role in rhythmic activity in the mammalian brain. The aim of our study was to examine the presynaptic and postsynaptic locations of these receptors in the medial septal diagonal band area (MS/DB), an area known to pace the hippocampus theta rhythm. Whole-cell patch recordings were made from parasagittal MS/DB slices obtained from the 16-25 day rat. Neurons were classified into GABAergic and cholinergic subtypes according to previous electrophysiological criteria. Bath application of the GABA(B) receptor agonist baclofen in the presence of tetrodotoxin, and brief tetanic fiber stimulation in the presence of ionotropic receptor antagonists, provided evidence for the presence of postsynaptic GABA(B) receptor transmission to GABAergic but not cholinergic neurons. Bath application of baclofen, at concentrations too low to elicit postsynaptic activity in MS/DB neurons, significantly reduced the amplitudes of stimulus-evoked ionotropic receptor inhibitory postsynaptic potentials (IPSPs) and excitatory postsynaptic potentials (EPSPs) and the paired pulse depression of these evoked potentials. Baclofen also significantly reduced the frequencies but not the amplitudes of miniature inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs), indicating the presence of presynaptic GABA(B) receptors on GABAergic and glutamatergic terminals in the MS/DB. Baclofen, also at a concentration too low to elicit postsynaptic activity, reduced the frequencies and amplitudes of spontaneous IPSCs and EPSCs recorded in the presence of 200-400 nM kainate. Rhythmic compound IPSCs at theta frequencies were recorded under these conditions in some neurons, and these rhythmic compound IPSCs were disrupted by the activation but not by the inhibition of GABA(B) receptors. These results suggest that GABA(B) receptors modulate rather than generate rhythmic activity in the MS/DB, and that this modulatory effect occurs via receptors located on presynaptic terminals.
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PMID:GABAB receptors in the medial septum/diagonal band slice from 16-25 day rat. 1583 39

A 79-year-old man with end-stage renal disease treated by automated peritoneal dialysis was referred to the emergency department for altered consciousness. The first investigations, including toxicology screening, failed to reveal the precise etiology. The patient was treated for a possible seizure. After the progression of central nervous system depression with bradypnea, the patient was intubated and mechanically ventilated. It appeared later on that he had ingested by mistake one of his wife's medications, baclofen. Baclofen was detected in the blood sampled on admission at a level above the therapeutic range. Baclofen is mainly excreted by the kidney. A short-term administration of low-dose of baclofen is not effectively removed by peritoneal dialysis and may result in prolonged but reversible coma.
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PMID:Prolonged unconsciousness in a patient on automated peritoneal dialysis. 1709 Oct 61

Long-term depression (LTD) of excitatory transmission at cerebellar parallel fibre-Purkinje cell synapses is a form of synaptic plasticity crucial for cerebellar motor learning. Around the postsynaptic membrane of these synapses, B-type gamma-aminobutyric acid receptor (GABABR), a Gi/o protein-coupled receptor for the inhibitory transmitter GABA is concentrated and closely associated with type-1 metabotropic glutamate receptors (mGluR1) whose signalling is a key factor for inducing LTD. We found that in cultured Purkinje cells, GABABR activation enhanced LTD of a glutamate-evoked current (LTDglu), increasing the magnitude of depression. It has been reported that parallel fibre-Purkinje cell synapses receive a micromolar level of GABA spilled over from the synaptic terminals of the neighbouring GABAergic interneurons. This level of GABA was able to enhance LTDglu. Our pharmacological analyses revealed that the betagamma subunits but not the alpha subunit of Gi/o protein mediated GABABR-mediated LTDglu enhancement. Gi/o protein activation was sufficient to enhance LTDglu. In this respect, LTDglu enhancement is clearly distinguished from the previously reported GABABR-mediated augmentation of an mGluR1-coupled slow excitatory postsynaptic potential. Baclofen application for only the induction period of LTDglu was sufficient to enhance LTDglu, suggesting that GABABR signalling may modulate mechanisms underlying LTDglu induction. Baclofen augmented mGluR1-coupled Ca2+ release from the intracellular stores in a Gi/o protein-dependent manner. Therefore, GABABR-mediated LTDglu enhancement is likely to result from augmentation of mGluR1 signalling. Furthermore, pharmacological inhibition of GABABR reduced the magnitude of LTD at parallel fibre-Purkinje cell synapses in cerebellar slices. These findings demonstrate a novel mechanism that would facilitate cerebellar motor learning.
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PMID:Postsynaptic GABAB receptor signalling enhances LTD in mouse cerebellar Purkinje cells. 1805 14

Gamma-aminobutyric acid (GABA) dysfunction is a known feature of alcoholism. We investigated GABA-B receptor activity in 3-week abstinent alcoholics using the growth hormone (GH) response to baclofen, a GABA-B receptor agonist. The study aimed to investigate the relationship between GABA-B receptor activity and alcohol withdrawal. GH response to baclofen was measured in alcohol-dependent males without depression (n = 22) who were on day 21 of alcohol abstinence and in healthy control male subjects (n = 23). After 20mg baclofen was given orally to the subjects, blood samples for GH assay were obtained every 30 min for the subsequent 150 min. The patients were divided into two subgroups (continuing withdrawal and recovered withdrawal subgroups) according to their withdrawal symptom severity scores on day 21 of alcohol cessation. Baclofen administration significantly altered GH secretion in the controls, but not in the patients. When GH response to baclofen was assessed as DeltaGH, it was lower in the patients with continuing withdrawal symptoms than in the controls and in the recovered withdrawal group. Impaired GH response to baclofen in all patients mainly pertained to the patients whose withdrawal symptoms partly continued. Our results suggest that reduced GABA-B receptor activity might be associated with longer-term alcohol withdrawal symptoms in alcoholic patients.
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PMID:Growth hormone response to the GABA-B agonist baclofen in 3-week abstinent alcoholics. 1804 8

The mammalian dorsal cochlear nucleus (DCN) is considered to contribute to the localization of the sound sources. Fusiform cells (FCs), principal projection neurons in the DCN, integrate two excitatory inputs from auditory nerve fibers (ANFs) and parallel fibers (PFs). Although an immunohistochemical study suggested presence of GABA(B) receptors at excitatory presynaptic terminals in the DCN, it has not been elucidated how GABA(B) receptors modulate the synaptic transmission to FCs. Here, we examined effects of baclofen on the transmission in vitro. Baclofen reduced both PF-EPSC and ANF-EPSC by reducing transmitter releases, and it enhanced the facilitation in PF-FC synapses and prevented the depression in ANF-FC synapses. The enhancement and prevention were prominent during high-frequency (50Hz) synaptic input, suggesting the activation of presynaptic GABA(B) receptors may optimize both PF-FC and ANF-FC synapses for high-frequency transmission. Postsynaptic GABA(B) receptors activated GIRK current and would further modulate the activity of FCs.
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PMID:Presynaptic GABA(B) receptors modulate synaptic facilitation and depression at distinct synapses in fusiform cells of mouse dorsal cochlear nucleus. 1819 Jul 80

Inhibition mediated by GABA-B receptors can play a role in epilepsy. We therefore studied its involvement in cortical epileptic afterdischarges in adult rats by means of a GABA-B receptor agonist baclofen. Three different experiments were performed with cortical epileptic afterdischarges and an additional experiment studied possible effect of baclofen on cortical interhemispheric (transcallosal) evoked potentials. Baclofen was administered intraperitoneally in doses of 3 or 6 mg/kg. In contrast to a marked proconvulsant action of a GABA-B receptor antagonist baclofen did not exhibit clear anticonvulsant action against EEG afterdischarges but a moderate effect on motor phenomena was observed. On the contrary, it tended to decrease threshold intensities for individual epileptic phenomena. Augmentation of postictal refractoriness by baclofen was found only with a short poststimulation interval (2 min). Cortical interhemispheric responses induced by single pulses were influenced only moderately by baclofen; paired-pulse potentiation induced by short intervals between stimuli was not changed but there was a depression of the second response induced 200 and 250 ms after the first one with the 6 mg/kg dose of baclofen. Failure of baclofen to exhibit an expected anticonvulsant activity might be due to a complexity of GABA-B inhibitory system (pre- as well as postsynaptic localization of GABA-B receptors).
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PMID:Effects of a GABA-B receptor agonist baclofen on cortical epileptic afterdischarges in rats. 1831

Adjuvant analgesics are drugs that are not primarily used as analgesics but can produce analgesia in certain types of pain. Adjuvant analgesics can be administered together with non-opioid and opioid analgesics on each step of the WHO analgesic ladder. They should be given when an additional or specific indication exists, but should not be used as a substitute for a thorough treatment with opioids and nonopioids. Adjuvant analgesics can be classified into groups according to the type of pain to be treated: continuous neuropathic pain or lancinating neuropathic pain, sympathetically maintained pain, bone pain and those for multipurpose use. Adjuvant drugs used for continuous neuropathic pain include local anaesthetics, clonidine, capsaicin, and antidepressants. Tricyclic antidepressants are the group that have been best investigated, and are therefore the drugs of choice. An analgesic effect is probably produced via enhancement of transmitter concentrations in pain-modulating pathways. This occurs at lower doses than those necessary to treat depression. Anticholinergic actions, acute glaucoma, constipation, orthostatic hypotension and cardiac arrhythmias are adverse effects that are seen predominantly with teritiary amine drugs and less often with secondary amine compounds. Initial doses should be small to avoid these adverse effects. Local anaesthetics are used less often, because of the high incidence of side effects (especially with tocainide, flecainide). An analgesic effect has been described in neuropathic pain, however, probably due to membrane stabilization and reduction of aberrant signal conduction. Mexiletine is considered to be the safest local anaesthetic, and should be used initially in small doses (100-150 mg/d). If side effects do not occur, doses can be increased step-wise up to 900 mg/d. Local anaesthetics are indicated for the treatment of severe neuropathic pain; this treatment is contraindicated in patients with cardiac arrhythmias. Systemic or intrathecal clonidine can be tried in neuropathic pain refractory to opioid therapy. The same stands for the topical application of capsaicin in certain types of pain. Lancinating neuropathic pain is an indication for anticonvulsant drugs. Carbamazepine, clonazepam, valproate and phenytoin seem to reduce aberrant signal conduction in damaged nerves in a manner similar to the supression of epileptiform activities in the brain. Common side effects include sedation, dizziness and nausea. Of greater concern are the more severe side effects, such as bone marrow depression (carbamazepine) and hepatotoxicity (phenytoin, valproate). Low initial doses and stepwise increases in dosage, repeated blood counts, and monitoring of plasma levels are helpful in recognizing and avoiding these adverse effects. Baclofen, a GABA agonist primarily used for spasticity, is effective in the treatment of trigeminal neuralgia and is often used in the management of lancinating pain of unspecific origin. The initial dosage is 10-15 mg/d, increasing to 30-90 mg/d, or higher. If neural blockade fails to reduce sympathetically maintained pain sufficiently specific adjuvants can be used. Sympatholytic drugs, e.g. phenoxybenzamine (60-120 mg/d) or prazosin, can be administered to patients without major cardiovascular dysfunction. There is experimental evidence of the involvement of calcium channels in nociception, and a beneficial clinical effect of nifidepine in reflex sympathetic dystrophy (RDS) has been demonstrated. Bone pain is common in tumor patients and can often be treated effectively with non-steroidal anti-inflammatory drugs. Biphosphonates (etidronate, clodronate, pamidronate derivates) also produce analgesic effects in patients with bone metastases. However, differences among the various compounds have not been clearly evaluated yet. Potent and specific radioisotopes are still under development and the use of calcitonin in bone pain is considered controversial.
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PMID:[Pharmacotherapy of cancer pain. 3. Adjuvant drugs.]. 1841 35

Many studies have demonstrated that GABAergic inhibition within the basolateral amygdala (BLA) plays an integral role in the regulation of anxiety, an important behavioral component in the etiology of alcoholism. Although ethanol has recently been shown to enhance BLA GABAergic inhibition via two distinct populations of inhibitory cells, local and lateral paracapsular (lpcs) interneurons, little is known about the mechanisms underlying ethanol potentiation of these two inhibitory pathways. Ethanol is known to enhance GABAergic inhibition in many brain regions via a complex array of pre- and postsynaptic mechanisms. In addition, ethanol's presynaptic effects are often subject to GABA(B) autoreceptor (GABA(B)-R) modulation. Therefore, in this study, we characterized GABA(B)-R function and modulation of ethanol actions at local and lpcs GABAergic synapses. At local synapses, we found significant paired-pulse depression (PPD, 250 ms inter-pulse interval) which was abated by SCH-50911 (GABA(B)-R antagonist). No significant PPD was detected at lpcs synapses, but SCH-50911 significantly potentiated lpcs-evoked IPSCs. Baclofen (GABA(B)-R agonist) had similar depressant effects on local- and lpcs-evoked IPSCs, however baclofen pretreatment only reduced ethanol potentiation at local synapses. Ethanol also significantly enhanced the frequency of spontaneous and miniature IPSCs, and these effects were also sensitive to GABA(B)-R modulators. Collectively, these data suggest that stimulus-independent inhibitory responses recorded from BLA principal neurons primarily reflect the activity of local GABAergic interneurons and provide additional evidence that ethanol potentiates local BLA inhibitory synapses primarily via a presynaptic enhancement of GABA release that is tightly regulated by GABA(B)-Rs. In contrast, ethanol potentiation of lpcs GABAergic synapses is not sensitive to GABA(B)-R activation and does not appear to involve increased presynaptic GABA release.
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PMID:Differential effects of GABAB autoreceptor activation on ethanol potentiation of local and lateral paracapsular GABAergic synapses in the rat basolateral amygdala. 1937 78

Light-induced phase shifts of hamster circadian activity rhythms are modulated by GABA(B) receptors. Recently, positive allosteric modulators (PAM)s at GABA(B) receptors were described, but it is not known whether they affect light-induced entrainment of circadian rhythms. Therefore, we studied the effects of two GABA(B) PAMs, GS39783 and RacBHFF, upon light-induced phase advances and delays of hamster circadian wheel-running activity rhythms. Wheel running activity was recorded for Syrian hamsters maintained in constant darkness. Drugs administered intraperitoneally were evaluated for their ability to modulate a light-induced shift of the circadian activity rhythm. Baclofen (3.75-15 mg/kg) dose-dependently inhibited both light-induced phase advances and delays of hamster wheel running rhythms, and its actions were blocked by the selective GABA(B) antagonist, SCH50911 (5mg/kg). Neither GS39783 (3-30 mg/kg) nor RacBHFF (0.63-10mg/kg) affected phase advances when injected alone, but both GS39783 (3mg/kg) and RacBHFF (10mg/kg) augmented the inhibitory effect of baclofen (5mg/kg). At doses above 3mg/kg, GS39783 and RacBHFF significantly inhibited phase delays alone, consistent with the notion of "agonist-allosteric" properties. GS39783 (0.5mg/kg), but not RacBHFF (10mg/kg), augmented the inhibitory action of baclofen on phase delays. These data are consistent with the possibility that GS39783 and RacBHFF act as PAMs at GABA(B) receptors inhibiting light-induced phase advances, yet that they also posses "allosteric agonist" actions at the (presumably separate) population of GABA(B) receptors modulating light-induced phase delays. GABA(B) receptors clearly warrant further investigation as agents for modulation of circadian dysfunction associated with CNS disorders such as depression.
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PMID:Positive allosteric modulators at GABAB receptors exert intrinsic actions and enhance the influence of baclofen on light-induced phase shifts of hamster circadian activity rhythms. 2175 29


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