scholarly journals Effect of GABAB Receptor Agonist SKF97541 on Cortical and Hippocampal Epileptic Afterdischarges

2014 ◽  
pp. 529-534 ◽  
Author(s):  
P. FÁBERA ◽  
P. MAREŠ
Keyword(s):  
Gabaa Receptors ◽  
Receptor Agonist ◽  
Gabab Receptor ◽  
Dorsal Hippocampus ◽  
Brain Structures ◽  
Gabab Receptors ◽  
Adult Rats ◽  
Inhibitory Postsynaptic Potentials ◽  
Male Wistar Rats ◽  
Epileptic Afterdischarges

Activation of GABAB receptors leads to longer inhibitory postsynaptic potentials than activation of GABAA receptors. Therefore GABAB receptors may be a target for anticonvulsant therapy. The present study examined possible effects of GABAB receptor agonist SKF97541 on cortical and hippocampal epileptic afterdischarges (ADs). Epileptic ADs elicited by electrical stimulation of sensorimotor cortex or dorsal hippocampus were studied in adult male Wistar rats. Stimulation series were applied 6 times with 10- or 20-min interval. Either interval was efficient for reliable elicitation of cortical ADs but stimulation at 10-min intervals did not reliably elicit hippocampal ADs, many stimulations were without effect. SKF97541 in dose 1 mg/kg significantly prolonged cortical ADs. Duration of hippocampal ADs was not significantly changed by either dose of SKF97541 in spite of a marked myorelaxant effect of the higher dose. Our present data demonstrated that neither cortical nor hippocampal ADs in adult rats were suppressed by GABAB receptor agonist SKF97541. Proconvulsant effect on cortical ADs indicates a different role in these two brain structures. In addition, duration of refractory period for electrically-induced ADs in these two structures in adult rats is different.

scholarly journals Effect of Short- and Long-Term Administration of Baclofen on Spatial Learning and Memory in Rats

2018 ◽  
pp. 133-141 ◽  
Author(s):  
M. HOLAJOVA ◽  
M. FRANEK
Keyword(s):  
Learning And Memory ◽  
Spatial Learning ◽  
Receptor Agonist ◽  
Gabab Receptor ◽  
Spatial Learning And Memory ◽  
Adult Rats ◽  
Treatment Groups ◽  
Term Administration ◽  
Short And Long Term

Baclofen is the only clinically available metabotropic GABAB receptor agonist. In our experiment, we tested the hypothesis that long-term baclofen administration can impair learning and memory in rats. The experiment consisted of three parts. In the first part of the study the drug was administered simultaneously with the beginning of the behavioral tests. In the second and third part of the experiment baclofen was administered daily for 14 days and for one month before the tests. In each part of the experiment, adult rats were randomly divided into four treatment groups. Three groups were given an injection of baclofen at doses of 1 mg/kg, 5 mg/kg, 10 mg/kg, while the fourth group was injected with saline. The injections were given after each session. Spatial learning and memory were tested using the Morris water maze, involving three types of tests: Acquisition, Probe, and Re-acquisition. This work reveals that baclofen did not affect spatial learning at any of the tested doses and regardless of the length of administration. Memory was observed to be affected, but only at the highest dose of baclofen and only temporarily. This conclusion is in line with previously published clinical cases.

scholarly journals What is the role of neurotransmitter systems in cortical seizures?

2008 ◽  
pp. S111-S120
Author(s):  
P Mareš ◽  
H Kubová
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Gabab Receptor ◽  
Age Groups ◽  
Gabab Receptors ◽  
Neurotransmitter Systems ◽  
Metabotropic Glutamate ◽  
Rat Pups ◽  
Epileptic Afterdischarges

Epileptic afterdischarges (ADs) elicited by electrical stimulation of sensorimotor cortical area were used as a model to study the role of neurotransmitter systems in cortical seizures in three age groups of developing rats. Drugs augmenting inhibition mediated by GABAA receptors were found to suppress ADs in all age groups, their activity was usually more marked in younger than in 25-day-old rat pups. Drugs potentiating GABAB receptors exhibit lower efficacy and more complicated developmental profile than GABAA-ergic drugs. Effects of an antagonist of GABAB receptor--marked prolongation of ADs in all three age groups--suggest an important role of GABAB receptors in arrest of cortical seizures. Drugs affecting glutamate receptors exhibit variable effects, usually better expressed in older animals than in 12-day-old ones. No specific role for ionotropic as well as metabotropic glutamate receptors could be predicted. Activation of adenosinergic inhibitory modulatory system also exhibited anticonvulsant action in the present model. All three neurotransmitter systems probably participate in mechanisms of generation, maintenance and arrest of cortical seizures.

scholarly journals Neonatal Clonazepam Administration Induced Long-Lasting Changes in GABAA and GABAB Receptors

2020 ◽  
Vol 21 (9) ◽  
pp. 3184
Author(s):  
Hana Kubová ◽  
Zdeňka Bendová ◽  
Simona Moravcová ◽  
Dominika Pačesová ◽  
Luisa Rocha ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Receptor Binding ◽  
Brain Structure ◽  
Gabab Receptor ◽  
Brain Structures ◽  
Emotional Behavior ◽  
Gabab Receptors ◽  
Behavioral Impairment ◽  
Almost All ◽  
The Brain

Benzodiazepines (BZDs) are widely used in patients of all ages. Unlike adults, neonatal animals treated with BZDs exhibit a variety of behavioral deficits later in life; however, the mechanisms underlying these deficits are poorly understood. This study aims to examine whether administration of clonazepam (CZP; 1 mg/kg/day) in 7–11-day-old rats affects Gama aminobutyric acid (GABA)ergic receptors in both the short and long terms. Using RT-PCR and quantitative autoradiography, we examined the expression of the selected GABAA receptor subunits (α1, α2, α4, γ2, and δ) and the GABAB B2 subunit, and GABAA, benzodiazepine, and GABAB receptor binding 48 h, 1 week, and 2 months after treatment discontinuation. Within one week after CZP cessation, the expression of the α2 subunit was upregulated, whereas that of the δ subunit was downregulated in both the hippocampus and cortex. In the hippocampus, the α4 subunit was downregulated after the 2-month interval. Changes in receptor binding were highly dependent on the receptor type, the interval after treatment cessation, and the brain structure. GABAA receptor binding was increased in almost all of the brain structures after the 48-h interval. BZD-binding was decreased in many brain structures involved in the neuronal networks associated with emotional behavior, anxiety, and cognitive functions after the 2-month interval. Binding of the GABAB receptors changed depending on the interval and brain structure. Overall, the described changes may affect both synaptic development and functioning and may potentially cause behavioral impairment.

Voltage-dependent calcium channels in rat midbrain dopamine neurons: modulation by dopamine and GABAB receptors

1995 ◽  
Vol 74 (3) ◽  
pp. 1137-1148 ◽  
Author(s):  
D. L. Cardozo ◽  
B. P. Bean
Keyword(s):  
Calcium Channels ◽  
Calcium Current ◽  
Receptor Agonist ◽  
Gabab Receptor ◽  
Calcium Currents ◽  
Dopamine Neurons ◽  
Gabab Receptors ◽  
High Threshold ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

1. Voltage-dependent calcium channels were studied with whole cell voltage-clamp recordings from neurons enzymatically dispersed from the ventral mesencephalon of rat brains (postnatal days 3-10) and identified as dopamine neurons by 5,7-dihydroxytryptamine autofluorescence. 2. Dopamine neurons had large high-threshold calcium currents activated by depolarizations positive to -50 mV. Different components of calcium channel current were not readily distinguishable by voltage dependence or kinetics, but pharmacological experiments showed the existence of different channel types. The overall current had significant components blocked by nimodipine (28%), by omega-conotoxin GVIA (22%), and by omega-agatoxin-IVA (omega-Aga-IVA) (37%), and there was a significant amount of current (16%) remaining in saturating concentrations of all three blockers. 3. High-threshold calcium current was reversibly reduced by the gamma-aminobutyric acid-B (GABAB) receptor agonist baclofen and by dopamine and the D2 receptor agonist quinpirole. Inhibition by GABAB or dopamine agonists developed and reversed within seconds. 4. Quinpirole reduced both omega-conotoxin-sensitive and omega-Aga-IVA-sensitive components of calcium current. 5. With physiological ionic conditions, inward calcium currents were outweighed by outward currents, in part through calcium-activated potassium channels activated by omega-conotoxin-sensitive and omega-Aga-IVA-sensitive calcium entry.

GABAB receptors presynaptically modulate excitatory synaptic transmission in the rat supraoptic nucleus in vitro

1996 ◽  
Vol 76 (2) ◽  
pp. 1166-1179 ◽  
Author(s):  
S. B. Kombian ◽  
J. A. Zidichouski ◽  
Q. J. Pittman
Keyword(s):  
Synaptic Transmission ◽  
Receptor Agonist ◽  
Supraoptic Nucleus ◽  
Gabab Receptor ◽  
Synaptic Depression ◽  
Receptor Activation ◽  
Excitatory Synaptic Transmission ◽  
Gabab Receptors ◽  
Dependent Manner

1. The effect of gamma-aminobutyric acid-B (GABAB)-receptor activation on excitatory synaptic transmission in the rat supraoptic nucleus (SON) was examined using the nystatin perforated-patch whole cell recording technique in coronal hypothalamic slices. 2. Stimulation of the hypothalamic region dorso-medial to the SON elicited glutamate and GABAA-receptor-mediated synaptic responses in electrophysiologically identified magnocellular neurosecretory cells. 3. Bath application of the GABAB-receptor agonist, +/- -baclofen reversibly reduced pharmacologically isolated, glutamate-mediated excitatory postsynaptic currents (EPSCs) in a concentration-dependent manner. At the concentrations used, baclofen altered neither the postsynaptic conductances of these cells nor their response to bath applied alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). 4. The baclofen-induced synaptic depression was accompanied by an increase in paired pulse facilitation (PPF). This increase in PPF, as well as the synaptic depression, was blocked by the GABAB-receptor antagonists CGP36742 and saclofen. 5. In addition to blocking the actions of baclofen in this nucleus, CGP36742 caused an increase in the evoked EPSC amplitude without altering postsynaptic cell conductances or responses induced by bath-applied AMPA. Contrary to the action of CGP36742, saclofen caused a baclofen-like depression of the evoked EPSC, suggesting that it may act as a partial GABAB receptor agonist. 6. These results indicate that the activation of presynaptic GABAB receptors reduces fast excitatory synaptic transmission in the SON. They further suggest that presynaptic GABAB receptors may be tonically activated in vitro. Thus GABAB receptors may influence the level of activity and excitation of SON neurons and hence modulate the secretion of the regulatory neuropeptides vasopressin and oxytocin.

Neuronal inhibition by a GABAB receptor agonist in the rostral ventrolateral medulla of the rat

1995 ◽  
Vol 268 (2) ◽  
pp. R428-R437 ◽  
Author(s):  
Y. W. Li ◽  
P. G. Guyenet
Keyword(s):  
Receptor Agonist ◽  
Gabab Receptor ◽  
Rostral Ventrolateral Medulla ◽  
Synaptic Activity ◽  
Gabab Receptors ◽  
Ventrolateral Medulla ◽  
Gamma Aminobutyric Acid ◽  
Neuronal Inhibition

We recorded the effects of the gamma-aminobutyric acid class B (GABAB) receptor agonist baclofen on neuronal activity in the rat rostral ventrolateral medulla (RVLM) in tissue slices and in vivo. In vitro, baclofen (3 microM) produced hyperpolarization (13 of 17), decrease in input resistance (12 of 16), and reduction of spontaneous synaptic activity (7 of 14). Baclofen inhibited 84 of 87 spontaneously active neurons recorded extracellularly in vitro. Inhibition was concentration dependent (0.1-3 microM, maximum inhibition: 94 +/- 4%, n = 16) and persisted in low-Ca2+/high-Mg2+ medium (n = 19). The GABAB receptor antagonists CGP-54626A (1 microM, n = 19), CGP-55845A (1 microM, n = 15), and 2-hydroxysaclofen (0.5 mM, n = 3) attenuated inhibition by baclofen (1-3 microM) but not by muscimol or GABA. In vivo, iontophoresis of baclofen inhibited 31 of 32 RVLM neurons, including bulbospinal barosensitive (15 of 16) and respiratory ones (7 of 7). CGP-55845A attenuated baclofen inhibition (6 of 9). Bicuculline attenuated the effect of GABA but not that of baclofen (4 of 4). In summary, RVLM presympathetic neurons have somatodendritic GABAB receptors that may contribute to baclofen-induced hypotension in humans.

Activity-dependent disinhibition. III. Desensitization and GABAB receptor-mediated presynaptic inhibition in the hippocampus in vitro

1989 ◽  
Vol 61 (3) ◽  
pp. 524-533 ◽  
Author(s):  
S. M. Thompson ◽  
B. H. Gahwiler
Keyword(s):  
Receptor Agonist ◽  
Gabab Receptor ◽  
Mossy Fiber ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Gabab Receptors ◽  
Initial Time ◽  
Dependent Manner ◽  
Iontophoretic Application ◽  
Activity Dependent

1. Single-electrode voltage-clamp recordings were made from CA3 pyramidal cells in organotypic hippocampal slice cultures for measurement of membrane currents underlying both the gamma-aminobutyric acid (GABA)-mediated, Cl- -dependent inhibitory postsynaptic potential (IPSC), evoked in response to stimulation of the mossy fiber pathway, and responses to iontophoretically applied GABA. Pre- and postsynaptic mechanisms mediating activity-dependent reductions in the conductance underlying the IPSC (gIPSC) were investigated. 2. During 99-s applications of GABA, the mean evoked conductance (gGABA) decreased 43% with an initial time constant of 51 s. Desensitization was never complete. 3. Ca2+-influx, activated with depolarizing voltage commands of 100-ms to 15-s duration in the presence of intracellular Cs+, had no effect on GABA responses. 4. Iontophoretic application of the GABAA-receptor agonist muscimol caused a rapid decrease of 80-100% in the amplitude of IPSCs evoked at depolarized membrane potentials (Vm). Recovery was 80% complete in 30 s. The second of two paired applications of muscimol, delivered at the same iontophoretic intensity, was reduced in amplitude 35%. This was shown to result from a decrease in driving force rather than from desensitization. We conclude that muscimol decreases IPSCs by causing an increase in the intracellular Cl- concentration. 5. Iontophoretic application of the GABAB-receptor agonist (+/-)-baclofen caused a decrease of only 30% in the amplitude of IPSCs evoked at depolarized Vms. This effect outlasted the post-synaptic effects of baclofen; recovery was 80% complete between 60 and 90 s. 6. Bath application of (-)-baclofen was found to decrease gIPSC without affecting the IPSC reversal potential. This effect was rapid in onset, could be observed at concentrations as low as 1 X 10(-7) M, and recovered quickly. The EC50 was roughly 5 X 10(-7) M and appeared similar to that for the baclofen-activated increase in postsynaptic conductance. No effect on responses to iontophoretically applied GABA was observed, demonstrating that baclofen decreases gIPSC by reducing presynaptic release via GABAB receptors. 7. Iontophoretic application of GABA reduced IPSCs in a dose-dependent manner. At low iontophoretic intensities, IPSCs were reduced only 30% and recovered slowly, as with baclofen iontophoresis. At higher iontophoretic intensities, IPSCs were more completely blocked. Recovery was initially fast, but took 60-90 s to be complete.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Proconvulsant Action of Two GABAB Receptor Antagonists Is Age-Dependent

2013 ◽  
pp. S109-S114 ◽  
Author(s):  
P. MAREŠ
Keyword(s):  
Gabab Receptor ◽  
Water Soluble ◽  
Gabab Receptors ◽  
Implanted Electrodes ◽  
Rat Pups ◽  
Age Dependent ◽  
Old Rats ◽  
Gabab Receptor Antagonists ◽  
Epileptic Afterdischarges

Antagonists of GABAB receptors are expected to have proconvulsant action also in developing brain. Two antagonists (CGP55845 and CGP46381) were tested in a model of cortical epileptic afterdischarges (ADs) in 12-, 18- and 25-day-old rat pups with implanted electrodes. CGP55845 was dissolved in dimethylsulfoxide and the results demonstrated marked proconvulsant action of this solvent which masked possible action of the antagonist. Water soluble antagonist CGP46381 led to marked potentiation of ADs in 12-day-old animals, its action decreased with age, it was negligible in 25-day-old rats. Our results demonstrated important inhibitory role of GABAB receptors at very early stages of maturation.

Properties of the GABAA receptor of rat posterior pituitary nerve terminals

1995 ◽  
Vol 73 (3) ◽  
pp. 1135-1144 ◽  
Author(s):  
S. J. Zhang ◽  
M. B. Jackson
Keyword(s):  
Gabaa Receptor ◽  
Nerve Terminal ◽  
Gabaa Receptors ◽  
Gabab Receptor ◽  
Gabab Receptors ◽  
Receptor Protein ◽  
Nerve Terminals ◽  
Posterior Pituitary ◽  
Pipette Solution ◽  
Long Duration

1. We investigated gamma-aminobutyric acid (GABA) receptors using thin slice patch-clamp techniques in the swellings along axons of posterior pituitary nerve terminals. 2. Activation of the nerve terminal GABAA receptor induced a mean conductance change of 1.5 nS. Normalizing to area gave a mean conductance density of 0.38 mS/cm2. 3. Whereas GABAA receptor-mediated responses could be seen in 91% of the nerve terminals tested, GABAB receptor-mediated responses could not be detected. The GABAB receptor agonist baclofen had no effect on holding current or on voltage-activated K+ and Ca2+ channels. It is unlikely that nerve terminals of the posterior pituitary contain GABAB receptors. 4. The channel gated by the nerve terminal GABAA receptor exhibited only a single open conductance level. Only fully open and fully closed states were observed. Subconductance states typical of other GABAA receptor channels were not seen in the GABA-gated channels of posterior pituitary nerve terminals. 5. Both open time and closed time distributions were biexponential, indicating at least two open and two closed conformations of the channel. At a higher GABA concentration, long-duration openings predominated, suggesting that long-duration openings were distinguished from short-duration openings by the occupation of a greater number of agonist binding sites. 6. Sustained application of GABA desensitized the receptor with simple exponential kinetics. The time constant for desensitization was approximately 9 s for both GABA and muscimol. 7. Zinc ions at concentrations of 100 microM reduced GABA responses by only 22%. This weak sensitivity to zinc, together with a previous observation of benzodiazepine sensitivity, suggested that the nerve terminal GABAA receptor possesses a gamma-subunit. 8. Responses mediated by the GABAA receptor persist in whole terminal recordings without Mg-ATP in the pipette solution. Thus, in contrast to many other GABAA receptors, this receptor showed no rundown in the absence of ATP. 9. The GABAA receptor channel of posterior pituitary nerve terminals has many properties in common with GABAA receptors of other preparations. A number of subtle differences between the nerve terminal receptor described here and cell body receptors described elsewhere may reflect the presence of receptor protein subunits unique to nerve terminals.

Sign in / Sign up

Export Citation Format

Share Document