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Non-antiepileptic drugs have been used in trigeminal neuralgia management since the 1970s.
Recent evidence suggests that an excitant amino acid may be a neurotransmitter at acoustic nerve synapses in cochlear nucleus (CN). Release of excitant amino acids is reportedly reduced by baclofen, a lipophilic GABA-mimetic used to treat the spasticity of multiple sclerosis and spinal injury. Microiontophoresis of (-)baclofen suppressed spontaneous and tone-evoked activity in CN neurons. GABA inhibited the responses of most neurons responsive to (-)baclofen. However, iontophoresis of these two substances onto the same CN neuron resulted in dramatic differences in time course to maximum effect and to recovery. Onset and offset of (-)baclofen-induced firing reduction were gradual at all doses (currents), but even the highest doses rarely caused total suppression of firing. Inhibition of firing by GABA was abrupt, and total suppression was frequently observed over the range of doses used. GABA desensitization (fading) commonly occurred while the (-)baclofen response never faded. The same CN neurons were also suppressed by D-alpha-aminoadipate, which blocks certain excitatory amino acid receptors, while the GABA antagonist bicuculline had no effect on the (-)baclofen response. These findings support the hypothesis that an excitant amino acid may be a transmitter at acoustic nerve synapses in CN.
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The effect of gamma-aminobutyric acid (GABA) on the release of [3H]acetylcholine [( 3H]ACh) from human cerebral cortex nerve terminals was investigated using synaptosomes prepared from neurosurgical specimens (which had to be removed to reach deeply located tumors) prelabeled with [3H]choline and exposed in superfusion to varying concentrations of GABA. The amino acid (3-100 microM) increased in a concentration-dependent manner (maximal effect: 40%; EC50 = 14.7 microM) the release of [3H]ACh but not that of [3H]choline. The GABAA receptor agonist muscimol (up to 100 microM) did not increase significantly the release of [3H]ACh. Accordingly, the effect of GABA was insensitive to the GABAA receptor antagonist bicuculline. The release of [3H]ACh was not affected by the GABAB receptor agonist (-)-baclofen (100-300 microM). The GABA-induced [3H]ACh release was counteracted by two inhibitors of GABA uptake, N-(4,4-diphenyl-3-butenyl)nipecotic acid (SKF 89976A) and nipecotic acid. Moreover, the enhancing effect of GABA on [3H]ACh release was clearly Na+-dependent and was reduced by almost 90% in presence of 23 mM NaCl. The data indicate that, similarly to what had been observed in the rat, cholinergic nerve terminals in the human cerebral cortex possess a GABA transporter. Activation of this carrier brings about release of newly synthesized ACh. GABA and ACh might co-exist in some cerebrocortical nerve endings in the vertebrate brain, including man.
We identified eight small poorly reported studies for inclusion. For the outcome of 'no clinically important improvement in tardive dyskinesia' GABA agonist drugs were not clearly better than placebo (n = 108, RR 0.83 CI 0.6 to 1.1). Deterioration in mental state was more likely to occur in people receiving GABA medication (n = 95, RR 2.47 CI 1.1 to 5.4), but this effect was influenced by the decision to assign a negative outcome to those who dropped out before the end of the study. A greater proportion of people allocated GABA medication may fail to complete the trial compared with those allocated placebo (20% versus 9%), but this difference was not statistically significant (n = 136, RR 1.99 CI 0.8 to 4.7). There is a suggestion of an increase in ataxia (loss of power of muscular coordination) for both baclofen and sodium valproate (n = 95, RR 3.26 CI 0.4 to 30.2), and in sedation (n = 113, RR 2.12 CI 0.8 to 5.4) compared with placebo, but this was not significant. Withdrawal of tetrahydroisoxazolopyridine (THIP) may cause seizures.
The N-methyl-D-aspartate (NMDA) receptor antagonist, AP7, was evaluated in two animal test procedures known to be sensitive to the effects of diazepam. In rats trained to discriminate diazepam from vehicle, AP7 produced dose-dependent generalization to the diazepam interoceptive stimuli. This NMDA antagonist also increased the rates of conflict responding in a chronic test procedure used to identify compounds with potential anxiolytic effects. A comparison of AP7 with diazepam and two muscle relaxants (methocarbamol and baclofen) showed that excitatory amino acid antagonists (of the receptor site stimulated by NMDA) produce a muscle relaxant effect (drug discrimination) and may represent a new class of compounds for the treatment of anxiety-related disorders (conflict test).
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Experimental data has shown that sodium valproate has analgesic properties in animals, probably by way of the increase in cerebral and spinal gamma amino-butyric acid (GABA) it induces. A study was therefore designed to assess this analgesia in man in the postoperative period. A first open study was carried out on 12 consenting patients, who were each given 15 mg.kg-1 sodium valproate intravenously over 20 min. A significant decrease in pain intensity, measured by an analogic visual scale, was seen from the 20th min up to the 140th min. A controlled double-blind study was then carried out; it included three groups of 13 patients each. Patients in group 1 were given placebo (5% dextrose); group 2 patients were given 15 mg.kg-1 sodium valproate intravenously over 20 min, and group 3 patients 2 mg.kg-1 ketoprofen intravenously over 20 min also. There was no difference in the pain intensity profile of groups 1 and 2: sodium valproate was no more efficient than placebo in relieving postoperative pain. However, ketoprofen gave a prompt and effective analgesic effect. The clinical data obtained with sodium valproate in man during the postoperative period stand in contrast with the promising animal results. Sodium valproate cannot be recommended for the treatment of postoperative pain.
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GABA(B) receptors mediate inhibition of neurotransmitter exocytosis from nerve endings. Unexpectedly, the well known GABA(B) receptor antagonist CGP35348 and, in part, the compound CGP52432, are now found to inhibit on their own the K(+)-evoked exocytosis of glycine when added at low micromolar concentrations to superfused mouse glycinergic nerve endings prelabelled with [(3)H]glycine through GLYT2 transporters. CGP35348 inhibited [(3)H]glycine release both in spinal cord and in hippocampus, but was also able to prevent the inhibitory effect of (-)-baclofen; CGP52432 exhibited intrinsic activity only in the hippocampus; in spinal cord, it behaved exclusively as a silent orthosteric antagonist by blocking the release inhibition brought about by (-)-baclofen. The intrinsic activity of CGP35348 in spinal cord was not prevented by CGP52432, indicating that CGP35348 is not a partial GABA(B) agonist in this experimental system. CGP54626, an extremely potent antagonist, exhibited only a minimal intrinsic activity. SCH50911, a GABA(B) antagonist belonging to a different chemical class, was devoid of significant activity, while phaclofen was effective only at 100-300 microM. In synaptosomes purified from the spinal cord or the hippocampus of mice lacking either the GABA(B1) (GABA(B1-/-) mice) or the GABA(B2) (GABA(B2-/-) mice) subunit, the evoked exocytosis of [(3)H]glycine was no longer inhibited by (-)-baclofen, whereas the intrinsic activity of CGP35348 and CGP52432 was not decreased. Activation of unknown sites on glycinergic terminals is likely to be involved. These unexpected effects should not be ignored when interpreting results obtained with the above GABA(B) receptor antagonists.
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The purpose of this study is to examine the interaction between drugs acting on GABA receptors in the DRN and alcohol in their effects on aggressive behaviors.
Frazier Rehab Institute, Louisville, Kentucky and University of Louisville.
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The nature of the coupling mechanism of presynaptic calcium channels involved in the release of neurotransmitters in the mammalian central nervous system is unknown. Using intracellular recordings from CA1 neurons in the rat hippocampal slice preparation, we show that the N-type calcium channels antagonist omega-conotoxin GVIA (omega-CgTx) blocks partially the excitatory (EPSP) and totally the inhibitory (IPSP) synaptic transmission in CA1 hippocampal pyramidal neurons. In addition, the inhibitory effect of omega-CgTx on IPSPs is strongly depressed by intrahippocampal injection of PTX, while the effect on EPSP is not. The results suggest that the nature or the regulation of calcium channels might be different, depending on the location of these channels on excitatory or inhibitory terminals.
There is compelling evidence that excessive GABA-mediated inhibition may underlie the abnormal electrical activity, initiated in the thalamus, associated with epileptic absence seizures. In particular, the GABAB receptor subtype seems to play a critical role, because its antagonists are potent inhibitors of absence seizures, whereas its agonists exacerbate seizure activity. Using a validated rat model of absence epilepsy, we have previously found no evidence of abnormal GABAB receptor density or affinity in thalamic tissue. In the present study, we have used in vivo microdialysis to monitor changes in levels of extracellular GABA and other amino acids in this brain region. We have shown that basal extracellular levels of GABA and, to a lesser extent, taurine are increased when compared with values in nonepileptic controls. However, modifying GABAergic transmission with the GABAB agonist (-)-baclofen (2 mg/kg i.p.), the GABAB antagonist CGP-35348 (200 mg/kg i.p.), or the GABA uptake inhibitor tiagabine (100 microM) did not produce any further alteration in extracellular GABA levels, despite the ability of these compounds to increase (baclofen and tiagabine) or decrease (CGP-35348) seizure activity. These findings suggest that the increased basal GABA levels observed in this animal model are not simply a consequence of seizure activity but may contribute to the initiation of absence seizures.
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A previous study from our laboratory showed that baclofen (BAC, GABAB receptor agonist) was able to prevent the behavioral expression of nicotine (NIC) withdrawal syndrome. To further investigate the mechanisms underlying this effect, we conducted this study, with the aims of analyzing α4β2 nicotinic receptor density during NIC withdrawal and, in case we found any changes, of determining whether they could be prevented by pretreatment with BAC. Swiss Webster albino mice received NIC (2.5 mg/kg, s.c.) 4 times daily, for 7 days. On the 8th day, NIC-treated mice received the nicotinic antagonist mecamylamine (MEC; 2 mg/kg, i.p.) 1 h after the last dose of NIC. A second group of NIC-treated mice received BAC (2 mg/kg, i.p.) prior to MEC administration. Thirty minutes after MEC, mice were sacrificed and brain autoradiography with [(3)H]epibatidine was carried out at five different anatomical levels. Autoradiographic mapping showed a significant increase of α4β2 nicotinic receptor labeling during NIC withdrawal in the nucleus accumbens shell (AcbSh), medial habenular nucleus (HbM), thalamic nuclei, dorsal lateral geniculate (DLG) nucleus, fasciculus retroflexus (fr), ventral tegmental area, interpeduncular nucleus and superior colliculus. BAC pretreatment prevented the increased α4β2 nicotinic receptor binding sites in the AcbSh, MHb, thalamic nuclei, DLG nucleus and fr. The present results suggest a relationship between BAC's preventive effect of the expression of NIC withdrawal signs, and its ability to restore the changes in α4β2 nicotinic receptor labeling, evidenced in specific brain areas in NIC withdrawn animals.
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Oral and intrathecal baclofen (ITB) have been associated with epileptic seizures. The authors observed a higher incidence of epileptic seizures in 99 patients with multiple sclerosis (MS) treated with ITB vs a matched control group (7% vs 1%, p < 0.05). Three patients with MS on ITB developed status epilepticus. Seizures were often associated with additional triggering factors.
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SDR resulted in early and lasting reduction in spasticity in all 20 children operated upon. Improved muscular function, however, required training and time. Not until 60 months after operation were functional measures significantly better than the preoperative values.
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We report a case of a 12-year-old girl with spastic quadriplegia who gained 20 lbs after pump implantation. It was necessary to identify the access port of her pump by ultrasonography during drug refilling so as to avoid multiple needle punctures.
lioresal intrathecal dose
Basar's view that the larger the number of synchronized and coupled participating neural generators, i.e., the lower the entropy of the neural systems, the lower the responsiveness of the system, and vice versa, was reconsidered experimentally and theoretically, in the light of current knowledge about the relationship between EEG states and evoked potentials. It was found that the morphology as well as the magnitude of the somatosensory evoked potentials was the same during synchronized (low entropy) and desynchronized (high entropy) EEG states in normal human subjects. Baclofen caused an increase in the somatosensory evoked potentials without affecting the EEG in unanaesthetized dogs. In the less complicated and more limited systems such as the skeletal muscle and monosynaptic reflex paradigms, an inverse relationship was established between the entropy state and responsiveness. This relationship can be simply explained by the neurophysiological facts such as Na-inactivation process at the excitable membranes and the refractory states of the neural generators. These results are consistent with those from the literature; the evoked potentials are usually large when recorded during synchronized EEG states and vice versa. It is suggested that, at least, the well established neurophysiological facts should not be ignored in physical approaches to neural mechanisms, especially when it concerns highly complex systems such as the brain.
Trace amines (TAs) are present in the central nervous system in which they up-regulate catecholamine release and are implicated in the pathogenesis of addiction, attention-deficit/hyper-activity disorder, Parkinson's disease, and schizophrenia. By using intracellular and patch-clamp recordings from dopaminergic cells in the rat midbrain slices, we report a depressant postsynaptic action of two TAs, beta-phenylethylamine (beta-PEA) and tyramine (TYR) on the GABA(B)-mediated slow inhibitory postsynaptic potential and baclofen-activated outward currents. beta-PEA and TYR activated G-proteins, interfering with the coupling between GABA(B) receptors and G-betagamma-gated inwardly rectifying potassium channels. This is the first demonstration that beta-PEA and TYR depress inhibitory synaptic potentials in neurons of the central nervous system, supporting their emerging role as neuromodulators.
The pharmacodynamics of baclofen on the bladder and urethral sphincters in acute and chronic spinal cord injury male patients were evaluated. A total of 100 supine and sitting urodynamic profiles was done in 25 patients. Baclofen decreased external urethral sphincter resistance by depressing pudendal-to-pudendal nerve reflex through spinal cord presynaptic hyperpolarization. This new centrally acting antispastic drug produced a significant reduction of residual urine in 73 per cent of the cases within an average of 4.98 weeks. Baclofen is a new alternative in the medical treatment of postural non-electrically induced detrusor striated sphincter dyssynergia in spinal cord injury patients. Indications for external sphincterotomy are discussed.
In this research data of 161 children were analyzed with spastic tetraparesis (GMFCS V). Evaluation was based on an analysis of the quantity of additional surgical procedures before and after ITB implantation. Subjective assessment was made using questionnaires addressed to parents on fundamental aspects of everyday activities and quality of life after implantation of ITB. RESULTS. The average age AT the time of surgery was 12 year and 2 months (SD 4.7). The average follow up was 3 years and 2 months (SD 2.4). During ITB implantation additional surgical procedure were performed in 43% of Children. During the next scheduled ITB pump exchange indication to addictional surgical procedure was reduced to 20%. The average questionnaire score was 13 points (0-16 max.). Fifty eight percents of caregivers of children who had any kind of device related complication scored with average score 13.5.
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The prevalence of tetanus reflects a failure of immunization. Prompt diagnosis and prediction of severity are crucial for the prevention of early life threatening complications and the institution of appropriate management. The current symptomatic treatment of heavy sedation, paralysis and artificial ventilation for 3-5 weeks for moderate and severe tetanus, is, even in the best centers, still associated with unacceptably high mortality, due to the disease and complications of the therapy itself. It is especially inappropriate for the developing world where intensive care resources are minimal. New options reported to avoid artificial ventilation and sedation are dantrolene (Dantrium, Procter and Gamble Pharmaceuticals), baclofen (Lioresal, Novartis) and magnesium. Magnesium therapy has the advantages of controlling spasms and sympathetic over activity without sedation. This simplifies nursing care and minimizes the need for ventilatory support except in the very severe disease and the elderly. Magnesium is recommended as the first-line therapy in tetanus.
In June 1997 a questionnaire was sent to 598 German and Austrian anaesthesiologists specialized in pain therapy. Questions concerning the use of medicaments for epidural and intrathecal treatment of chronic pain were asked.
lioresal intrathecal dosage
After discovering that binding to GABAB receptors in rat neocortex varied as a function of the estrous cycle of the rat, we asked whether either or both of the major ovarian steroids could affect binding to GABAB receptors in the same way, namely, by regulating the apparent density (Bmax) of GABAB receptors. We report here that in ovariectomized rats, subcutaneous injection of progesterone alone, without the necessity of estrogen priming, increased the Bmax of baclofen binding to GABAB receptors in the neocortex. Radioimmunoassay of plasma progesterone before and after progesterone injections revealed that plasma progesterone levels similar to those reached during the progesterone surge in proestrus were associated with increased baclofen binding. The effect of progesterone upon baclofen binding was evident 4 h but not 1 h following progesterone treatment. There was some specificity with respect to the cortical receptors affected by progesterone in that under our conditions, progesterone did not increase agonist binding to 5-HT1A or GABAA receptors. We interpret our results to indicate that progesterone variation during the estrous cycle could be responsible for a component of the regulation of GABAB receptors that occurs in neocortex during the estrous cycle of the rat.
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Effects of baclofen and gamma-aminobutyric acid on medullary respiratory neurons were investigated. Medullary inspiratory neurons of the dorsal and ventral respiratory groups were stimulated by baclofen, 0.5-2 mg/kg, and depressed by doses greater than 4-6 mg/kg. Expiratory neurons were depressed by doses of baclofen which increased phrenic nerve activity. Microelectrophoresis of baclofen (5 mM, pH 3) depressed medullary inspiratory neurons. It is suggested that low i.v. doses of baclofen increase inspiratory activity by disinhibition of medullary neurons whereas higher doses directly depress medullary inspiratory neurons.
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Using whole cell patch-clamp recordings, we investigated the effects of the GABA(B) receptor agonist baclofen in thin slices of rat brain stem containing identified gastric- or intestinal-projecting dorsal motor nucleus of the vagus (DMV) neurons. Perfusion with baclofen (0.1-100 microM) induced a concentration-dependent outward current (EC(50), 3 microM) in 54% of DMV neurons with no apparent differences between gastric- and intestinal-projecting neurons. The outward current was attenuated by pretreatment with the selective GABA(B) antagonists saclofen and 2-hydroxysaclofen, but not by the synaptic blocker TTX, indicating a direct effect at GABA(B) receptors on DMV neurons. Using the selective ion channel blockers barium, nifedipine, and apamin, we showed that the outward current was due to effects on potassium and calcium currents as well as calcium-dependent potassium currents. The calcium-mediated components of the outward current were more prominent in intestinal-projecting neurons than in gastric-projecting neurons. These data indicate that although baclofen inhibits both intestinal- and gastric-projecting neurons in the rat DMV, its mechanism of action differs among the neuronal subpopulations.
Dystonia in complex regional pain syndrome (CRPS) responds poorly to treatment. Intrathecal baclofen (ITB) may improve this type of dystonia, but information on its efficacy and safety is limited. A single-blind, placebo-run-in, dose-escalation study was carried out in 42 CRPS patients to evaluate whether dystonia responds to ITB. Thirty-six of the 38 patients, who met the responder criteria received a pump for continuous ITB administration, and were followed up for 12 months to assess long-term efficacy and safety (open-label study). Primary outcome measures were global dystonia severity (both studies) and dystonia-related functional limitations (open-label study). The dose-escalation study showed a dose-effect of baclofen on dystonia severity in 31 patients in doses up to 450 microg/day. One patient did not respond to treatment in the dose-escalation study and three patients dropped out. Thirty-six patients entered the open-label study. Intention-to-treat analysis revealed a substantial improvement in patient and assessor-rated dystonia scores, pain, disability and quality-of-life (Qol) at 12 months. The response in the dose-escalation study did not predict the response to ITB in the open-label study. Eighty-nine adverse events occurred in 26 patients and were related to baclofen (n=19), pump/catheter system defects (n=52), or could not be specified (n=18). The pump was explanted in six patients during the follow-up phase. Dystonia, pain, disability and Qol all improved on ITB and remained efficacious over a period of one year. However, ITB is associated with a high complication rate in this patient group, and methods to improve patient selection and catheter-pump integrity are warranted.
In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. This effect is attenuated by inhibition of glutamate or dopamine transmission in nucleus accumbens shell, or inactivation of ventral medial prefrontal cortex (mPFC). Here, we used an anatomical asymmetrical disconnection procedure to demonstrate that an interaction between glutamatergic projections from ventral mPFC to accumbens shell and local dopamine D(1) postsynaptic receptors contributes to context-induced reinstatement of heroin seeking. We also combined the marker of neuronal activity, Fos, with the retrograde tracer Fluoro-Gold to assess activation in this pathway during context-induced reinstatement. Rats were trained to self-administer heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a nondrug-associated context in the presence of the discrete cue. Rats were then tested in the heroin- or extinction-associated contexts under extinction conditions. Injections of muscimol + baclofen into ventral mPFC in one hemisphere and D(1)-family receptor antagonist SCH 23390 into the contralateral or ipsilateral accumbens shell decreased context-induced reinstatement. Unilateral injections of muscimol + baclofen into ventral mPFC or SCH 23390 into the accumbens shell had no effect. Context-induced reinstatement was associated with increased Fos expression in ventral mPFC neurons, including those projecting to accumbens shell, with higher double-labeling in the ipsilateral projection than in the contralateral projection. Our results demonstrate that activation of glutamatergic projections from ventral mPFC to accumbens shell, previously implicated in inhibition of cocaine relapse, promotes heroin relapse.
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A 2-year follow-up study of an incomplete T12 paraplegic patient, who was reluctant to undergo intrathecal baclofen therapy, presenting severe painful spasms in his lower limbs treated with intramuscular injections of botulinum toxin type A.
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Patients that do not respond satisfactorily to standard proton pump inhibitor (PPI) treatment have become the most common presentation of gastro-esophageal reflux disease (GERD) in third referral gastrointestinal practices. The causes of refractory GERD include lack of compliance with treatment, residual acid reflux and weakly acidic reflux, esophageal hypersensitivity and persistent symptoms not associated with reflux. A role for weakly acidic reflux in symptom generation has been proposed since the availability of impedance-pH monitoring. The possible mechanisms by which persistent weakly acidic reflux might contribute to persistent symptoms in patients under PPI treatment may include esophageal distension by increased reflux volume, persistent impaired mucosal integrity (ie, dilation of intercellular spaces) and/or esophageal hypersensitivity to weakly acidic reflux events. To establish a definite role of weakly acidic reflux in refractory GERD, outcome studies targeting this type of reflux are still lacking. Treatment strategies to reduce the number or effect of weakly acidic reflux could involve drugs that decrease transient lower esophageal sphincter relaxations (ie, baclofen or similar), improve oesophageal mucosa resistance or visceral pain modulators. Finally, anti-reflux surgery can be considered, only if a clear symptom-weakly acidic reflux association was demonstrated.
In the 1980s, Bowery and colleagues discovered the presence of a novel, bicuculline-resistant and baclofen-sensitive type of GABA receptor on peripheral nerve terminals, the GABA(B) receptor. Since this pioneering work, GABA(B) receptors have been identified in the Central Nervous System (CNS), where they provide an important inhibitory control of postsynaptic excitability and presynaptic transmitter release. GABA(B) receptors have been implicated in a number of important processes in the adult brain such as the regulation of synaptic plasticity and modulation of rhythmic activity. As a result of these studies, several potential therapeutic applications of GABA(B) receptor ligands have been identified. Recent advances have further shown that GABA(B) receptors play more than a classical inhibitory role in adult neurotransmission, and can in fact function as an important developmental signal early in life. Here we summarize current knowledge on the contribution of GABA(B) receptors to the construction and function of developing neuronal networks.