OBJECTIVE: The genes encoding for gamma-aminobutyric acid (GABA) A and B receptors may be considered as candidates for alcoholism; genetic alterations at this level may produce structural and functional diversity and thus play a role in the response to alcohol addiction treatment. To investigate these aspects further, we conducted a preliminary genetic association study on a population of Italian male alcohol addicts, focusing on GABA A and B receptors. METHODS: A total of 186 alcohol-dependent subjects (in the first phase 139, then 47 more samples) and 182 controls were genotyped for 25 single nucleotide polymorphisms (SNPs) of genes encoding the alpha-1 subunit of GABA A receptor (GABRA1) and subunits 1 and 2 of GABA B receptor (GABBR1 and GABBR2). The chi-squared test for allele and genotype distributions and Hardy-Weinberg equilibrium analysis of both subjects and controls were performed. Bonferroni's correction for multiple comparisons was applied. RESULTS: Preliminary results comparing 139 alcohol-dependent subjects and 182 controls showed differences in genotype distribution in the former for SNP rs29253, located in the intron region of the GABBR1 gene. In order to clarify the meaning of this association, 47 more samples from alcohol-dependent subjects were tested for this SNP only: the previously found association was not confirmed. CONCLUSION: The lack of significant differences between the two groups does not provide evidence that GABRA 1 and GABBR1 and 2 genes are candidates for alcoholism in this population. Further studies with larger samples are needed, together with investigation of other components of the GABA pathway.
Alcoholism* ; Alleles ; gamma-Aminobutyric Acid ; Genetic Association Studies ; Genotype ; Humans ; Introns ; Male ; Polymorphism, Single Nucleotide ; Receptors, GABA* ; Receptors, GABA-A ; Receptors, GABA-B

This study was designed to investigate the effect of diazepam on the spontaneous contraction and oxytocin induced contraction of the isolated rat uterus. Female rat (Sprague-Dawley) pretreated with oophorectomy and 4 days administration of estrogen. Weighing about 200 g, was sacrificed by cervical dislocation, and the uteruses were isolated. A longitudinal muscle strip was placed in temperature controlled (37℃) muscle chamber containing Locke's solution and myographied isometrically. Diazepam inhibited the spontaneous contraction and oxytocin induced contraction of the isolated rat uterus in a concentration-dependent manner. GABA, muscimol, a GABA A receptor agonist, bicuculline, a competitive GABA A receptor antagonist, picrotoxin, a non competitive GABA A receptor antagonist, baclofen, a GABA B receptor agonist, and delta-aminovaleric acid, a GABA B receptor antagonist, did not affect on the spontaneous and oxytocin induced contraction of the isolated rat uterus. The inhibitory actions of diazepam on the spontaneous and oxytocin induced contraction were not affected by all the GABA receptor agonists and antagonists, but exceptionally potentiated by bicuculline. This potentiation-effect by bicuculline was not antagonized by muscumol. In normal calcium PSS, addition of calcium restored the spontaneous contraction preinhibited by diazepam and recovered the contractile of oxtrocin preinhibited by diazepam. A23187, a calcium inophore, enhanced the restoration of both the spontaneous and oxytocin induced contraction by addition of calcium. In calcium-free PSS, diazepam suppressed the restoration of spontaneous motility by addition of calcium but allowed the recovery of spontaneous motility to a considerable extent. Diazepam could not inhibit some development of contractility by oxytocin in calcium-free PSS, but inhibited the increase in contractility by subsequent addition of calcium. These results suggest that the inhibitory action of diazepam on the rat uterine motility does not depend on or related to GABA receptors and that diazepam inhibits the extracellular calcium influx to suppress the spontaneous and oxytocin induced contractilities.
Animals ; Baclofen ; Bicuculline ; Calcimycin ; Calcium ; Diazepam* ; Dislocations ; Estrogens ; Female ; GABA Agonists ; GABA-A Receptor Agonists ; GABA-A Receptor Antagonists ; GABA-B Receptor Agonists ; GABA-B Receptor Antagonists ; gamma-Aminobutyric Acid ; Humans ; Muscimol ; Ovariectomy ; Oxytocin* ; Picrotoxin ; Rats* ; Receptors, GABA ; Uterus*

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

BACKGROUND: This study was conducted to investigate the roles of the spinal and peripheral gamma-aminobutyric acid (GABA)-ergic systems for the mechanical hypersensitivity produced by chronic compression of the dorsal root ganglion (CCD). METHODS: CCD was performed at the left 5th lumbar dorsal root ganglion. The paw withdrawal threshold (PWT) to von Frey stimuli was measured. The mechanical responsiveness of the lumbar dorsal horn neurons was examined. GABAergic drugs were delivered with intrathecal (i.t.) or intraplantar (i.pl.) injection or by topical application onto the spinal cord. RESULTS: CCD produced mechanical hypersensitivity, which was evidenced by the decrease of the PWT, and it lasting for 10 weeks. For the rats showing mechanical hypersensitivity, the mechanical responsiveness of the lumbar dorsal horn neurons was enhanced. A similar increase was observed with the normal lumbar dorsal horn neurons when the GABA-A receptor antagonist bicuculline was topically applied. An i.t. injection of GABA-A or GABA-B receptor agonist, muscimol or baclofen, alleviated the CCD-induced hypersensitivity. Topical application of same drugs attenuated the CCD-induced enhanced mechanical responsiveness of the lumbar dorsal horn neurons. CCD-induced hypersensitivity was also improved by low-dose muscimol applied (i.pl.) into the affected hind paw, whereas no effects could be observed with high-dose muscimol or baclofen. CONCLUSIONS: The results suggest that the neuropathic pain associated with compression of the dorsal root ganglion is caused by hyperexcitability of the dorsal horn neurons due to a loss of spinal GABAergic inhibition. Peripheral application of low-dose GABA-A receptor agonist can be useful to treat this pain.
Animals ; Back Pain ; Baclofen ; Bicuculline ; GABA-A Receptor Agonists ; GABA-A Receptor Antagonists ; GABA-B Receptor Agonists ; gamma-Aminobutyric Acid ; Ganglia, Spinal ; Hyperalgesia ; Hypersensitivity* ; Muscimol ; Neuralgia ; Posterior Horn Cells ; Rats* ; Receptors, GABA ; Spinal Cord

<b>OBJECTIVEb>To investigate whether or not the gamma-aminobutyric acid (GABA) receptor subtype A genes GABRA5 and GABRB3 are associated with childhood absence epilepsy (CAE).

<b>METHODSb>Two microsatellite DNA, GABRA5 and GABRB3, adjoining to chromosome 15q11.2-q12 were used as genetic markers. Both case-control study and transmission/disequilibrium test (TDT) as well as fluorescence-based semi-automated genotyping technique were used in 90 trios with CAE and 100 controls to conduct association analysis.

<b>RESULTSb>The allele frequencies of the 2 microsatellite DNA in Chinese normal population are in good agreement with Hardy-Weinberg equilibrium. The polymorphism information content of microsatellite DNA GABRA5 and GABRB3, are 0.80 and 0.66 respectively. The allele 2 frequency of microsatellite DNA GABRA5 and the allele 5 frequency of microsatellite DNA GABRB3 are significantly higher in CAE patients than those in normal controls(P<0.001).

<b>CONCLUSIONb>Both microsatellite DNA GABRA5 and GABRB3 are good genetic markers. The gamma-aminobutyric acid receptor subtype A genes GABRA5 and GABRB3 may be directly involved either in the etiology of CAE or in linkage disequilibrium with disease-predisposing sites.

Adolescent ; Alleles ; Case-Control Studies ; Child ; DNA ; genetics ; Epilepsy, Absence ; genetics ; Female ; Gene Frequency ; Humans ; Linkage Disequilibrium ; Male ; Microsatellite Repeats ; Receptors, GABA-A ; genetics ; Receptors, GABA-B ; genetics

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*

No abstract available.
gamma-Aminobutyric Acid* ; Nervous System* ; Receptors, GABA*

No abstract available.
Benzodiazepines* ; gamma-Aminobutyric Acid* ; Receptors, GABA-A*

This study aimed to investigate the existence of GABA receptor and the mechanisms of action of GABA and diazepam of the trachealis muscle isolated from dog. Horizontal muscle strips of 2mm×15mm were prepared from canine trachea, and isometric myography in isolated muscle chamber bubbled with 95/5%-O₂/CO₂ at 36℃, at the pH of 7.4 was performed. Muscle strips contracted responding to the electrical field stimulation (ESP) by 2~20 Hz, 20 msec, monophasic square wave of 60 VDC. GABA and diazepam suppressed the EFS-induced contractions to the similar extent, significantly. (p<0.05). Bicuculline, a GABA(A) receptor antagonist blocked both GABA- and diazepam-inhibitions; but DAVA, a GABA(B) receptor antagoinst did not affect either of them. These results suggest than in the canine trachealis muscle, there may be only GABA(A) receptor, and GABA and diazepam inhibit the contractility via GABA(A) receptor.
Animals ; Bicuculline ; Diazepam ; Dogs ; gamma-Aminobutyric Acid* ; Hydrogen-Ion Concentration ; Myography ; Receptors, GABA ; Receptors, GABA-A ; Trachea

Induced activation of the gamma-aminobutyric acidA (GABA(A)) receptor in the retina of goldfish caused the fish to rotate in the opposite direction to that of the spinning pattern during an optomotor response (OMR) measurement. Muscimol, a GABA(A) receptor agonist, modified OMR in a concentration-dependent manner. The GABA(B) receptor agonist baclofen and GABA(C) receptor agonist CACA did not affect OMR. The observed modifications in OMR included decreased anterograde rotation (0.01~0.03 micrometer), coexistence of retrograde rotation and decreased anterograde rotation (0.1~30 micrometer) and only retrograde rotation (100 micrometer~1 mM). In contrast, the GABA(A) receptor antagonist bicuculline blocked muscimolinduced retrograde rotation. Based on these results, we inferred that the coding inducing retrograde movement of the goldfish retina is essentially associated with the GABA(A) receptor-related visual pathway. Furthermore, from our novel approach using observations of goldfish behavior the induced discrete snapshot duration was approximately 573 ms when the fish were under the influence of muscimol.
Baclofen ; Bicuculline ; Clinical Coding ; Cytarabine ; Goldfish ; Injections, Intraocular ; Muscimol ; Receptors, GABA ; Receptors, GABA-A ; Retina ; Visual Pathways