The globus pallidus occupies a critical position in the 'indirect' pathway of the basal ganglia and, as such, plays an important role in the modulation of movement. In recent years, the importance of the globus pallidus in the normal and malfunctioned basal ganglia is emerging. However, the function and operation of various transmitter systems in this nucleus are largely unknown. GABA is the major neurotransmitter involved in the globus pallidus. By means of electrophysiological recording, immunohistochemistry and behavioral studies, new information on the distribution and functions of the GABAergic neurotransmission in the rat globus pallidus has been generated. Morphological studies revealed the existence of GABA(A) receptor, including its benzodiazepine binding site, and GABA(B) receptor in globus pallidus. At subcellular level, GABA(A) receptors are located at the postsynaptic sites of symmetric synapses (putative GABAergic synapses). However, GABA(B) receptors are located at both pre- and postsynaptic sites of symmetric, as well as asymmetric synapses (putative excitatory synapses). Consistent with the morphological results, functional studies showed that activation of GABA(B) receptors in globus pallidus reduces the release of GABA and glutamate by activating presynaptic auto- and heteroreceptors, and hyperpolarizes pallidal neurons by activating postsynaptic receptors. In addition to GABA(B) receptor, activation of GABA(A) receptor benzodiazepine binding site and blockade of GABA uptake change the activity of globus pallidus by prolonging the duration of GABA current. In agreement with the in vitro effect, activation of GABA(B) receptor, GABA(A) receptor benzodiazepine binding site and blockade of GABA uptake cause rotation in behaving animal. Furthermore, the GABA system in the globus pallidus is involved in the etiology of Parkinson's disease and regulation of seizures threshold. It has been demonstrated that the abnormal hypoactivity and synchronized rhythmic discharge of globus pallidus neurons associate with akinesia and resting tremor in parkinsonism. Recent electrophysiological and behavioral studies indicated that the new anti-epileptic drug, tiagabine, is functional in globus pallidus, which may present more information to understand the involvement of globus pallidus in epilepsy.
Animals ; Basal Ganglia ; metabolism ; physiology ; Epilepsy ; metabolism ; Globus Pallidus ; metabolism ; physiology ; Humans ; Parkinson Disease ; metabolism ; Presynaptic Terminals ; metabolism ; physiology ; Receptors, GABA ; physiology ; Receptors, GABA-A ; metabolism ; physiology ; Receptors, GABA-B ; metabolism ; physiology ; Synapses ; metabolism ; physiology ; gamma-Aminobutyric Acid ; metabolism

OBJECTIVE: To observe the expression of GABA(A) receptor alpha1 (GABA(A)alpha1) and GABA(B) receptor 1 (GABA(B)1) in human medulla oblongata solitary nucleus and ambiguous nucleus due to tramadol-induced death. METHODS: GABA(A)alpha1 and GABA(B)1 were detected by immunohistochemical SP method in tramadol-induced death group and control group. All results were evaluated by images analysis system. RESULTS: Low expression of GABA(A)alpha1 and GABA(B)1 were detected in solitary nucleus and ambiguous nucleus in the control brain tissue. In cases of tramadol-induced death, the expression of GABA(A)alpha1 and GABA(B)1 significantly increased. CONCLUSION The mechanism of tramadol intoxication death could be caused by respiratory depression induced by over-expression of GABA(A)alpha1 and GABA(B)1 in medulla oblongata solitary nucleus and ambiguous nucleus.
Adult ; Analgesics, Opioid/poisoning* ; Autopsy ; Case-Control Studies ; Cause of Death ; Female ; Forensic Toxicology ; Humans ; Immunohistochemistry ; Male ; Medulla Oblongata/metabolism* ; Receptors, GABA-A/metabolism* ; Receptors, GABA-B/metabolism* ; Respiration Disorders/etiology* ; Solitary Nucleus/metabolism* ; Staining and Labeling ; Tramadol/poisoning*

The mechanisms of general anesthesia, which was introduced about 170 years ago, remain poorly under- stood. Even less well understood are the effects of general anesthesia on the human body. Recently we identified 18 G-protein coupled receptor (GPCR) genes of Daphnia pulex, an invertebrate model organism. Phylogenetic analysis identified these genes to be the homologs of the human γ-aminobutyric acid, type B (GABAB) receptor, metabotropic glutamate receptors (mGluR), adrenergic receptor, serotonin (5-HT) receptor, dopamine receptor and muscarinic acetylcholine receptor (mAChR). Using reverse transcription and quantitative PCR techniques, we systematically measured the effects of propofol, etomidate and ethanol on these 18 GPCR mRNA expressions in Daphnia pulex.
Animals ; Daphnia ; drug effects ; metabolism ; Ethanol ; pharmacology ; Etomidate ; pharmacology ; Phylogeny ; Propofol ; pharmacology ; RNA, Messenger ; genetics ; metabolism ; Receptors, GABA-B ; genetics ; metabolism

<b>OBJECTIVEb>Febrile seizure (FS) is one of the most common seizure types in children. Our previous studies have demonstrated that both gamma-aminobutyric acid B receptor (GABABR) and hydrogen sulfide (H2S) are involved in the pathogenesis of FS. This study was designed to explore the effect of GABABR on H2S/cystathionine-beta-synthase (CBS) system in recurrent FS.

<b>METHODSb>Sixty-four Sprague-Dawley rats aged 21 days were randomly assigned into four groups: Control (37 degrees C water bath exposure), FS, FS+baclofen (GABABR excitomotor), and FS+phaclofen (GABABR inhibitor) groups (n=16 each). FS was induced by warm water bath exposure (45.2 degrees C, once every 2 days, 10 times in total. The plasma level of H2S was detected by the spectrophotometer. The expression of CBS mRNA was examined by in situ hybridization. The expressions of CBS protein was observed by immunohistochemistry.

<b>RESULTSb>The plasma level of H2S increased in the FS+baclofen group (427.45 +/- 15.91 micromol/L) but decreased in the FS+phaclofen group (189.72 +/- 21.53 micromol/L) compared with that in the FS group (362.14 +/- 19.71 micromol/L). The expressions of CBS mRNA and protein were up-regulated in the FS+baclofen group but were down-regulated in the FS+phaclofen group compared with those in the FS group.

<b>CONCLUSIONSb>GABABR modulated the expression of H2S/CBS system in recurrent FS.

Animals ; Baclofen ; pharmacology ; Cystathionine beta-Synthase ; genetics ; physiology ; Hydrogen Sulfide ; blood ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-B ; physiology ; Recurrence ; Seizures, Febrile ; metabolism

<b>OBJECTIVEb>This study investigated the effects of flurothyl-induced neonatal recurrent seizures on gamma-aminobutyric acid B1 receptor (GABAB1R) expression in neonatal and adult rat brain, and explored the possible relationship between the alterations of GABAB1R in mature brain and the changes of spatial memory and seizure susceptibility in adult rats.

<b>METHODSb>Forty-eight postnatal day (P) 7 Sprague-Dawley rats were randomly assigned into two groups: Control and Seizure group (n=24 each). Seizures were induced by inhalant flurothyl daily for six consecutive days in rat pups from the Seizure group. Twelve rats selected randomly in each group were sacrificed on the 7th day after the last seizure for detecting the expressions of GABAB1R mRNA and protein in cerebral cortex and hippocampus by reverse transcription-polymerase chain reaction (RT-PCR) and immuno-histochemistry method. The spatial memory was tested by using the Morris water maze task during P61 to P64 and the seizure threshold was measured at P75 following intraperitoneal injection of pentylenetetrazol ( PTZ ) in the remaining rats. The rats were then sacrificed for detecting the expressions of GABAB1R mRNA and protein in cerebral cortex and hippocampus.

<b>RESULTSb>The expressions of GABAB1R mRNA and protein in the cerebral cortex on the 7th day after the last seizure and at P75 decreased significantly in the Seizure group when compared with the Control group (P < 0.05). The GABAB1R protein expression in the dentate gyrus on the 7th day after the last seizure in the Seizure group was significantly lower than that in the Control group (P < 0.05), but the GABAB1R mRNA expression in the hippocampus was not different from that in the Control group. There were no significant differences in the expressions of GABAB1R mRNA and protein in the hippocampus between the two groups at P75. The escape latencies in water maze of the rats in the Seizure group at P64 were significantly longer than those in the Control group (98,533.8 +/- 27,205.4 ms vs 46,723.3 +/- 40,666.5 ms; P <0.05). There were no differences in the seizure threshold between the two groups.

<b>CONCLUSIONSb>The expressions of GABAB1R mRNA and protein in the cerebral cortex and hippocampus of neonatal rats with recurrent seizures decreased significantly, suggesting the changes of GABAB1R may be related to acute brain injury following neonatal recurrent seizures and the memory deficit in adult rats caused by neonatal recurrent seizures.

Animals ; Animals, Newborn ; Brain ; metabolism ; Cerebral Cortex ; metabolism ; Female ; Hippocampus ; metabolism ; Male ; Maze Learning ; RNA, Messenger ; analysis ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-B ; analysis ; genetics ; Recurrence ; Seizures ; metabolism

<b>OBJECTIVEb>Febrile seizure (FS) is closely related to an altered transmission of gamma-aminobutyric acid (GABA). GABA exerts its effects through ionotropic receptors (GABA(AR) and GABA(CR)) and metabotropic receptors (GABA(BR)). GABA(BRs) are located at pre- and postsynaptic sites. Stimulation of postsynaptic receptors generates long-lasting inhibitory postsynaptic potentials (IPSPs) that are important for the fine-tuning of inhibitory neurotransmission and caused by an increase in K(+) conductance. At presynaptic sites, GABA(BRs) mediate a suppression on the release of neurotransmitters such as of GABA or glutamate by inhibiting voltage-sensitive Ca(2+) channels. The present study aimed to explore the long-term changes of GABA(B) receptor subunits in immature rats after recurrent febrile seizures.

<b>METHODSb>Rats were randomly divided into control group and hyperthermia treatment group. The control rats (n = 64) were put into 37 degrees C water for 5 minutes. Rats with hyperthermia treatment were put into 44.8 degrees C water for 5 minutes. If a rat in hyperthermia treatment group showed seizure within 5 min, the rat was taken out of the water as soon as the seizure occurred. Water-immersion was carried out 10 times, once every 2 days. Rats showing 10 seizures (FS(10), n = 64) were studied. Rats exposed to hyperthermia for 10 times without seizure were also studied as hyperthermia-only (H, n = 64) group. Rats showing one seizure at the last time of 10 times of hyperthermia treatment were studied as one-seizure group (FS(1), n = 64). The other rats were studied for other research. The changes of GABA(B)R(1) and GABA(B)R(2) co-localization were detected by double fluorescence;the quantitative alteration of GABA(B)R(1) and GABA(B)R(2) were detected by quantitative RT-PCR; the binding of GABA(B)R(2) to GABA(B)R(1) was detected by immunoprecipitation/Western blot.

<b>RESULTSb>GABA(B)R(1), GABA(B)R(2), and the binding of GABA(B)R(2) to GABA(B)R(1) decreased after the last febrile seizure in FS(10) group, the expression of GABA(B)R(1) returned to normal in later phase while GABA(B)R(2) and the binding of them did not.

<b>CONCLUSIONb>Recurrent FS down-regulated the expression of GABA(B)R subunits in a long term.

Age Factors ; Animals ; Blotting, Western ; Disease Models, Animal ; Down-Regulation ; Fluorescent Antibody Technique ; Hippocampus ; metabolism ; Immunoprecipitation ; RNA, Messenger ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-B ; classification ; genetics ; metabolism ; Recurrence ; Reverse Transcriptase Polymerase Chain Reaction ; Seizures, Febrile ; genetics ; metabolism ; Time Factors

<b>OBJECTIVEb>To investigate the protective mechanism of neuroactive steroid allopregnanolone on N-methyl-D-aspartate (NMDA) induced toxicity in primary mouse cortical neurons.

<b>METHODSb>Primary cultured mouse cortical neurons were subjected to allopregnanolone, the expression of beta-aminobutyric acid receptor beta2 subunit (beta2-GABA-R) mRNAs was detected by RT-PCR and Akt phosphorylation was assayed by Western blot using Akt-phosphoserine 473-specific antibody. After the cultured mouse cortical neurons were pretreated with or without allopregnanolone prior to treatment with NMDA , DNA isolated was analyzed by agarose gel electrophoresis and proteins collected were analyzed by Western blot with anti-cleaved-PARP, anti-cleaved caspase-3, and anti-cleaved caspase-9 antibodies.

<b>RESULTSb>When cultured mouse cortical neurons were exposed to allopregnanolone both the expression of beta2-GABA-R mRNAs and Akt phosphorylation increased. Allopregnanolone inhibited the NMDA-induced apoptosis and decreased the level of active-PARP, active-caspase-3 and active-caspase-9 notably at a final concentration of 5 x 10(6) mol/L.

<b>CONCLUSIONb>Pretreatment with allopregnanolone may be neuroprotective on NMDA-induced neuronal cells apoptosis by increasing beta2-GABA-R expression and Akt phosphorylation.

Animals ; Animals, Newborn ; Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Caspase 9 ; metabolism ; Cerebral Cortex ; cytology ; Mice ; N-Methylaspartate ; antagonists & inhibitors ; toxicity ; Neurons ; cytology ; Neuroprotective Agents ; pharmacology ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; metabolism ; Pregnanolone ; pharmacology ; Primary Cell Culture ; RNA, Messenger ; genetics ; metabolism ; Receptors, GABA-B ; genetics ; metabolism

Kainic acid (KA) is well-known as an excitatory, neurotoxic substance. In mice, KA administered intracerebroventricularly (i.c.v.) lead to morphological damage of hippocampus expecially concentrated on the CA3 pyramidal neurons. In the present study, the possible role of gamma-aminobutyric acid B (GABA B) receptors in hippocampal cell death induced by KA (0.1 microgram) administered i.c.v. was examined. 5-Aminovaleric acid (5-AV; GABA B receptors antagonist, 20 microgram) reduced KA-induced CA3 pyramidal cell death. KA increased the phosphorylated extracellular signal-regulated kinase (p-ERK) and Ca2+ /calmodulin-dependent protein kinase II (p-CaMK II) immunoreactivities (IRs) 30 min after KA treatment, and c-Fos, c-Jun IR 2 h, and glial fibrillary acidic protein (GFAP), complement receptor type 3 (OX-42) IR 1 day in hippocampal area in KA-injected mice. 5-AV attenuated KA-induced p-CaMK II, GFAP and OX-42 IR in the hippocampal CA3 region. These results suggest that p-CaMK II may play as an important regulator on hippocampal cell death induced by KA administered i.c.v. in mice. Activated astrocytes, which was presented by GFAP IR, and activated microglia, which was presented by the OX-42 IR, may be a good indicator for measuring the cell death in hippocampal regions by KA excitotoxicity. Furthermore, it showed that GABA B receptors appear to be involved in hippocampal CA3 pyramidal cell death induced by KA administered i.c.v. in mice.
Amino Acids, Neutral/pharmacology ; Animals ; Ca(2+)-Calmodulin Dependent Protein Kinase/metabolism ; Cell Death/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Glial Fibrillary Acidic Protein/metabolism ; Hippocampus/anatomy & histology/*cytology/*drug effects ; Kainic Acid/*toxicity ; Mice ; Mice, Inbred ICR ; Mossy Fibers, Hippocampal/drug effects/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-fos/metabolism ; Proto-Oncogene Proteins c-jun/metabolism ; Receptors, GABA-B/*metabolism ; Research Support, Non-U.S. Gov't