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PubMed1999

Effects of GABAergic system on naloxone-induced jumping in morphine-dependent mice.

The effect of GABA (gamma-aminobutyric acid system) receptor agonists and antagonists on naloxone-induced jumping in morphine-dependent mice was examined. Intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) injection of different doses of the GABA(B) receptor agonist, baclofen (2.5, 5 and 10 mg/kg), reduced naloxone-induced jumping in morphine-dependent mice. The i.p. administration of the GABA(B) receptor antagonist, CGP35348 (P-[3-aminopropyl]-p-diethoxymethyl-phosphinic acid), but not the i.c.v. injection of the drug, increased naloxone-induced jumping. The antagonist also decreased the baclofen response. Administration of the GABA(A) receptor agonist, muscimol, but not the GABA(A) receptor antagonists bicuculline and picrotoxin, decreased the naloxone response in morphine-dependent animals. It is concluded that both GABA(A) and GABA(B) receptor subtypes may have an inhibitory influence on naloxone-induced withdrawal jumping in mice.

Animals↗
PubMed2004

Overwhelmingly asynchronous firing of rat subthalamic nucleus neurones in brain slices provides little evidence for intrinsic interconnectivity.

In Parkinson's disease the neurones of the subthalamic nucleus show increased synchrony and oscillatory burst discharge, thought to reflect a breakdown of parallel processing in basal ganglia circuitry. To understand better the mechanisms underlying this transition, we sought to mimic this change in firing pattern within sagittal slices of rat midbrain. The firing patterns of up to four simultaneously extracellularly recorded subthalamic nucleus (STN) neurones were analysed using burst and oscillation detection programs, and correlated activity between pairs of neurones assessed. In control conditions all but 11 of 488 (2%) neurones fired in a predominantly tonic pattern (with mean oscillation frequency >3 Hz), with no significantly cross-correlated activity in any of 393 pairs of neurones. The glutamate antagonists DL-2-amino-phosphonopentanoic acid (APV), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-methyl-2-(phenylethynyl)pyridine (MPEP) did not change the firing rate or pattern of these cells, providing no evidence for a role of glutamatergic collaterals within the STN under these conditions. The GABA(A) receptor antagonist bicuculline and GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl]phenylmethyl phosphinic acid (CGP 55845) were also without effect on firing rate or pattern in these cells, suggesting that there was no active input from other GABAergic basal ganglia nuclei in this slice. The dopamine receptor antagonist haloperidol caused no significant change to firing rate or pattern of firing in these cells, suggesting that there was no active dopaminergic input in this slice. Excitations of STN neurones by muscarine, (+)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD), N-methyl-D-aspartic acid (NMDA) or dopamine were all unaccompanied by a change in firing pattern or any significant correlated activity between STN neurone pairs. Burst firing could be induced in STN neurones with either the potassium channel blocker tetraethylammonium (TEA; 10 mM; in 100/138 [72%] of cells) or with a combination of NMDA and the calcium-activated potassium channel blocker apamin (in 101/216 [47%] of cells). Burst firing in TEA was unchanged by CNOX and APV, MPEP, CGP55845, haloperidol, dopamine, and ACPD, although muscarine produced a significant increase in oscillation frequency. Burst firing in NMDA and apamin was unchanged by CNQX and APV, dopamine, muscarine and ACPD, although bicuculline caused a significant increase in oscillation frequency. Such burst firing was not accompanied by synchrony in any condition, either alone, or during application of excitatory agents or glutamate or GABA antagonists. As the bursting seen here was unaccompanied by the synchronous activity that has often been observed (pathologically) in vivo, it probably reflects solely intrinsic STN neuronal properties, rather than network activity. No functional role was found for glutamatergic collaterals within the STN, either when cells are firing tonically or burst firing. The circuitry needed to produce synchrony in the STN is most likely not intrinsic to the STN itself, but requires connections with other basal ganglia nuclei, and/or the cortex, which are not present in this preparation.

Action Potentials↗
PubMed1993

gamma-Aminobutyric acid (GABA) autoreceptors in rat cerebral cortex and spinal cord represent pharmacologically distinct subtypes of the GABAB receptor.

gamma-Aminobutyric acid (GABA) autoreceptors regulating release of [3H]GABA have been characterized pharmacologically by using rat cerebral cortex and spinal cord synaptosomes exposed in superfusion to mild depolarization (9 mM KCl). In both regions GABA inhibited the K(+)-evoked overflow of [3H]GABA. The EC50 values amounted to 1.23 microM (cortex) and to 1.01 microM (spinal cord). Also the GABAB receptor agonist 3-aminopropylphosphonous acid (3-APPA) decreased the [3H]GABA overflow: EC50 values = 0.095 microM (cortex) and 0.078 microM (spinal cord). The classical GABAB receptor agonist (-)-baclofen was equipotent to GABA at the cortical autoreceptor (EC50 = 1.37 microM), whereas it was almost ineffective in the spinal cord (EC50 = 425 microM). (+)-Baclofen was extremely weak in both brain areas. Two GABAB receptor antagonists, phaclofen and (CGP 35348) [3-aminopropyl(diethoxymethyl)phosphinic acid] provided opposite results at the two autoreceptors examined. The IC50 values for phaclofen amounted to 47.9 microM (cortex) and to > 1000 microM (spinal cord), respectively. In contrast, CGP 35348 was almost ineffective at the cortex autoreceptors (IC50 > 300 microM), but was rather potent in the spinal cord (IC50 = 1.07 microM). To conclude, GABA autoreceptors in the cerebral cortex are classically sensitive to (-)-baclofen and to 3-APPA; they are also sensitive to phaclofen, but resistant to CGP 35348. Surprisingly, GABA autoreceptors in the spinal cord are poorly sensitive to (-)-baclofen, although they are as sensitive as the cortical autoreceptors to 3-APPA; moreover they are resistant to phaclofen, but highly sensitive to CGP 35348. The data show that pharmacologically distinct release-regulating GABAB autoreceptors exist in the central nervous system of a same animal species.

Animals↗
PubMed2003

Phosphinic, phosphonic and seleninic acid bioisosteres of isonipecotic acid as novel and selective GABA(C) receptor antagonists.

A number of amino acids bioisosterically derived from the specific GABA(A) agonist, isonipecotic acid, were electrophysiologically characterized as antagonists at GABA(C) rho(1) receptors expressed in Xenopus oocytes. The phosphinic acid analogue of isonipecotic acid, piperidin-4-ylphosphinic acid (2), was comparable with the standard GABA(C) antagonist, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), in terms of potency and GABA(C) versus GABA(A) receptor selectivity. Whereas the phosphonic acid analogue, piperidin-4-ylphosphonic acid (4), was at least an order of magnitude weaker than piperidin-4-ylphosphinic acid as a GABA(C) antagonist, the seleninic acid analogue, piperidin-4-ylseleninic acid (SEPI, 6), was the most potent and selective GABA(C) antagonist within the group of isonipecotic acid derived amino acids studied.

Animals↗
PubMed1999

Functional pharmacology of cloned heterodimeric GABAB receptors expressed in mammalian cells.

1. In this study we report a new assay of heterodimeric gamma-amino-butanoic acid subtype B (GABAB) receptors where either GABABR1a or GABABR1b are co-expressed with GABABR2 and the chimeric G-protein Galphaq-z5 in tsA cells. In this manner we obtained a robust response to GABAB agonists measured as increase in phosphoinositide hydrolysis. 2. We used this assay to characterize a number of commonly used GABAB receptor ligands. Both splice variants displayed the same rank order of agonist potency; 3-aminopropyl(methyl)phosphinic acid (SKF-97541)>GABA>(R)-4-amino-3-(4-chlorophenyl)butanoic acid ((R)-baclofen)>(RS)-4-amino-3-(5-chloro-2-thienyl)butanoic acid (BCTG)>3-aminopropylphosphonic acid (3-APPA) and furthermore, the absolute agonist potency values were very close to each other. 3. 3-APPA was a partial agonist displaying maximal responses of 41 and 61% compared to GABA at GABABR1a and GABABR1b, respectively. The antagonist (RS)-3-amino-2-(4-chlorophenyl)-2-hydroxypropylsulphonic acid (2-OH-saclofen) displayed KB values of 15 and 7.8 microM at GABABR1a and GABABR1b, respectively. 4. The rank order of agonist potency as well as the absolute ligand potencies correspond very well with those previously reported in different tissues, and this study thus provides a functional assay of cloned GABAB receptors which should be a valuable tool for further characterization of GABAB ligands. Finally, we can conclude that the functional pharmacological profiles of the two GABABR1 splice variants are very similar.

Alternative Splicing↗
PubMed1995

Role of GABAergic systems in the development of morphine tolerance in formalin-treated mice.

Since the development of tolerance to morphine antinociception in formalin-treated mice was delayed and diazepam normalized the delay, the involvement of GABAergic systems in the process was investigated. Gamma amino-n-butyric acid (GABA) at 10 mg/kg and the GABAA-receptor agonist muscimol at 0.05 mg/kg, i.p., 30 min before daily morphine injection at 10 mg/kg, s.c. completely reversed the delay in the development of morphine tolerance in the formalin-treated mice. The GABAA antagonist bicuculline at 1 mg/kg and the Cl(-)-channel blocker picrotoxin at 1 mg/kg extinguished the reverse effect of muscimol and GABA, respectively. In contrast, the GABAB antagonist CGP 35348 (3-aminopropane-diethoxymethyl-phosphinic acid) up to 100 mg/kg, i.p. failed to abolish the GABA effect; and baclofen, a GABAB-receptor agonist, at 0.5 and 2 mg/kg, i.p., 30 min before morphine was without effect on the delay. On the other hand, bicuculline was incapable of abolishing the reverse effects of diazepam on the delay of tolerance development; and likewise, the reverse effect of muscimol was not affected by flumazenil. No appreciable influence of these GABA-related compounds was seen on morphine antinociception itself nor the development of tolerance in normal mice. These results suggest that the benzodiazepine-GABAA-Cl- channel complex is involved in the mechanism underlying the delay of the development of morphine tolerance in formalin-treated mice; however, it is deduced that benzodiazepine-receptor and GABAergic systems are not always functionally coupled to each other in the mechanisms.

Analgesics, Opioid↗
PubMed1984

Phosphorus analogues of gamma-aminobutyric acid, a new class of anticonvulsants.

A series of phosphorus compounds, designed as analogues of gamma-aminobutyric acid (GABA) in that they possess a P = O moiety separated by three atoms from an amino or acetamido group, was synthesized and tested by using in vitro GABAA and GABAB receptor binding, GABA uptake assays, and was examined for anticonvulsant activity. Weak GABAB receptor affinity was noted for one agent, whereas six compounds displayed moderate to high potencies as inhibitors of electroshock- and pentylenetetrazol-induced seizures. The best anticonvulsant effect was found with the (m-aminophenyl) phosphinic acid compounds, with members of this class selected for further study.

Animals↗
PubMed2002

Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (gamma-hydroxybutyric aciduria).

Therapeutic intervention for human succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria) has been limited to vigabatrin (VGB). Pharmacologically, VGB should be highly effective due to 4-aminobutyrate-transaminase (GABA-transaminase) inhibition, lowering succinic semialdehyde and, thereby, gamma-hydroxybutyric acid (GHB) levels. Unfortunately, clinical efficacy has been limited. Because GHB possesses a number of potential receptor interactions, we addressed the hypothesis that antagonism of these interactions in mice with SSADH deficiency could lead to the development of novel treatment strategies for human patients. SSADH-deficient mice have significantly elevated tissue GHB levels, are neurologically impaired, and die within 4 weeks postnatally. In the current report, we compared oral versus intraperitoneal administration of VGB, CGP 35348 [3-aminopropyl(diethoxymethyl)phosphinic acid, a GABA(B) receptor antagonist], and the nonprotein amino acid taurine in rescue of SSADH-deficient mice from early death. In addition, we assessed the efficacy of the specific GHB receptor antagonist NCS-382 (6,7,8,9-tetrahydro-5-[H]benzocycloheptene-5-ol-6-ylideneacetic acid) using i.p. administration. All interventions led to significant lifespan extension (22-61%), with NCS-382 being most effective (50-61% survival). To explore the limited human clinical efficacy of VGB, we measured brain GHB and gamma-aminobutyric acid (GABA) levels in SSADH-deficient mice receiving VGB. Whereas high-dose VGB led to the expected elevation of brain GABA, we found no parallel decrease in GHB levels. Our data indicate that, at a minimum, GHB and GABA(B) receptors are involved in the pathophysiology of SSADH deficiency. We conclude that taurine and NCS-382 may have therapeutic relevance in human SSADH deficiency and that the poor clinical efficacy of VGB in this disease may relate to an inability to decrease brain GHB concentrations.

Aldehyde Oxidoreductases↗
PubMed2006

(-)-Epigallocatechin gallate attenuates acute stress responses through GABAergic system in the brain.

(-)-Epigallocatechin gallate (EGCG), a flavonoid, is the principal catechin found in green tea and is distributed in the brain after tea consumption. The aim of the present study was to investigate the effects of EGCG in the chick brain under an acute stressful condition and to clarify the mechanism by which EGCG attenuates stress behavior with special reference to gamma-aminobutyric acid (GABA). Intracerebroventricular (i.c.v.) injection of EGCG (50, 100 and 200 microg) suppressed the vocalization which normally occurs during social separation stress. EGCG decreased the time spent in active wakefulness and induced sleep-like behavior in a dose-dependent manner. Additionally, i.c.v. injection of EGCG attenuated plasma corticosterone release under social separation stress. These effects of EGCG on distress-induced vocalization were significantly attenuated by the GABAA receptor antagonist picrotoxin but not by the GABAB receptor antagonist CGP 54626 (3-N-(1-(3,4-dichlorophenyl)ethylamino)-2-hydroxypropyl cyclohexylmethyl phosphinic acid hydrochloride). These results indicate that EGCG has sedative and hypnotic effects in the brain, partially through GABAA receptors, and consequently moderates an acute stress response.

Animals↗
PubMed1993

Release of endogenous glutamic and aspartic acids from cerebrocortex synaptosomes and its modulation through activation of a gamma-aminobutyric acidB (GABAB) receptor subtype.

The depolarization-evoked release of endogenous glutamate (GLU) and -aspartate (ASP) and its modulation mediated by gamma-aminobutyric acid (GABA) heteroreceptors was investigated in superfused rat cerebrocortical synaptosomes. Exposure to 12 mM K+ enhanced the release of GLU and ASP. The K(+)-evoked overflow of both amino acids was largely Ca(2+)-dependent. Exogenous GABA inhibited the K(+)-evoked overflow of GLU (EC50 2.8 microM) and ASP (EC50 2.7 microM). The effect of GABA was mimicked by the GABAB receptor agonist (-)-baclofen (EC50 2.0 microM for GLU and 1.3 microM for ASP release) but not by the GABAA receptor agonist muscimol, up to 100 microM. Accordingly, the GABA-induced inhibition of GLU and ASP release was not affected by the GABAA receptor antagonists, bicuculline or picrotoxin, but was antagonized by the GABAB receptor antagonist, 3-amino-propyl(diethoxymethyl)phosphinic acid (CGP 35348). The GABA effect was, however, insensitive to another GABAB receptor antagonist, phaclofen, up to 1,000 microM. It can be concluded that GABA heteroreceptors of the GABAB type regulating the depolarization-evoked release of GLU and ASP are present on cortical GLU/ASP-releasing nerve terminals. These receptors may be classified as a phaclofen-insensitive GABAB receptor subtype.

Animals↗
PubMed2003

Specific gamma-hydroxybutyrate-binding sites but loss of pharmacological effects of gamma-hydroxybutyrate in GABA(B)(1)-deficient mice.

gamma-Hydroxybutyrate (GHB), a metabolite of gamma-aminobutyric acid (GABA), is proposed to function as a neurotransmitter or neuromodulator. gamma-Hydroxybutyrate and its prodrug, gamma-butyrolactone (GBL), recently received increased public attention as they emerged as popular drugs of abuse. The actions of GHB/GBL are believed to be mediated by GABAB and/or specific GHB receptors, the latter corresponding to high-affinity [3H]GHB-binding sites coupled to G-proteins. To investigate the contribution of GABAB receptors to GHB actions we studied the effects of GHB in GABAB(1)-/- mice, which lack functional GABAB receptors. Autoradiography reveals a similar spatial distribution of [3H]GHB-binding sites in brains of GABAB(1)-/- and wild-type mice. The maximal number of binding sites and the KD values for the putative GHB antagonist [3H]6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene acetic acid (NCS-382) appear unchanged in GABAB(1)-/- compared with wild-type mice, demonstrating that GHB- are distinct from GABAB-binding sites. In the presence of the GABAB receptor positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol GHB induced functional GTPgamma[35S] responses in brain membrane preparations from wild-type but not GABAB(1)-/- mice. The GTPgamma[35S] responses in wild-type mice were blocked by the GABAB antagonist [3-[[1-(S)-(3,4dichlorophenyl)ethyl]amino]-2-(S)-hydroxy-propyl]-cyclohexylmethyl phosphinic acid hydrochloride (CGP54626) but not by NCS-382. Altogether, these findings suggest that the GHB-induced GTPgamma[35S] responses are mediated by GABAB receptors. Following GHB or GBL application, GABAB(1)-/- mice showed neither the hypolocomotion, hypothermia, increase in striatal dopamine synthesis nor electroencephalogram delta-wave induction seen in wild-type mice. It, therefore, appears that all studied GHB effects are GABAB receptor dependent. The molecular nature and the signalling properties of the specific [3H]GHB-binding sites remain elusive.

4-Butyrolactone↗
PubMed1991

gamma-Aminobutyric acidB receptors mediate inhibition of somatostatin release from cerebrocortex nerve terminals.

The effects of gamma-aminobutyric acid (GABA) and of various GABA receptor agonists and antagonists on the calcium-dependent depolarization-evoked release of somatostatin (SRIF) from rat cerebrocortex synaptosomes have been studied by a superfusion technique. GABA (0.3-30 microM) decreased the K+ (15 mM)-evoked overflow of SRIF-like immunoreactivity (SRIF-LI) in a concentration-dependent manner (EC50 = 1.3 microM; maximal inhibition, 45% reached at 10 microM GABA). The effect of the amino acid was insensitive to the GABAA receptor antagonist bicuculline. Accordingly, the K(+)-evoked SRIF-LI release was not affected by muscimol, a GABAA receptor agonist, up to 100 microM. The effect of GABA was mimicked by the GABAB receptor agonist (-)-baclofen (EC50 = 1.2 microM; maximal effect, about 45% reached at 10 microM). The effect of baclofen was stereoselective, the (+)-enantiomer being inactive up to 100 microM. The inhibition of SRIF-LI release brought about by GABA was sensitive to the GABAB receptor antagonists 2-hydroxy-saclofen and CGP 35348 [3-aminopropyl(diethoxymethyl)phosphinic acid]. Also, the effect of (-)-baclofen was antagonized by CGP 35348 (IC50 = 4.8 microM). It is concluded that GABA can inhibit the depolarization-evoked release of SRIF by activating receptors which are located on SRIF-releasing nerve terminals and belong to the GABAB type.

Animals↗
PubMed2002

Effect of intracerebroventricular injection of GABA receptor agents on morphine-induced antinociception in the formalin test.

In the present study, the effects of gamma-aminobutyric acid (GABA) receptor agonists and antagonists on antinociception induced by morphine in the formalin test were investigated in rats. Intraperitoneal (i.p.) injection of different doses of morphine (1, 3, 6 and 9 mg/kg) and intracerebroventricular (i.c.v.) injection of different doses of muscimol (0.5, 1 and 2 microg per rat) or baclofen (0.25, 0.5 and 1 microg per rat) induced a dose-related antinociception in the both first and second phases of the formalin test. The responses induced by muscimol or baclofen in both phases were reduced by bicuculline or CGP35348 [p-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid], respectively. Bicuculline alone has produced antinociception in the second phase and CGP35348 alone has had antinociception in both phases of the formalin test. Morphine in combination with different doses of muscimol or baclofen did not elicit potentiation. The opioid receptor antagonist naloxone reduced the response induced by muscimol in the second phase and baclofen in both phases of the formalin test. It may be concluded that central GABA(A) and GABA(B) receptor stimulation induces antinociception in the formalin test. However, the antinociception induced by GABA receptor agonists may be mediated partly through supraspinal opioid receptor mechanisms and, for the GABA(B) receptor agonist, through spinal and supraspinal opioid receptor mechanisms.

Analgesics, Opioid↗
PubMed1999

Tiagabine antinociception in rodents depends on GABA(B) receptor activation: parallel antinociception testing and medial thalamus GABA microdialysis.

The effects of a new antiepileptic drug, tiagabine, (R)-N-[4,4-di-(3-methylthien-2-yl)but-3-enyl] nipecotic acid hydrochloride, were studied in mice and rats in antinociceptive tests, using three kinds of noxious stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate). In vivo microdialysis was performed in parallel in awake, freely moving rats in order to evaluate possible alterations in extracellular gamma-aminobutyric acid (GABA) levels in a pain-modulating region, the medial thalamus. Systemic administration of tiagabine, 30 mg kg(-1) i.p., increased nearly twofold the extracellular GABA levels in rats and increased significantly the rat paw pressure nociceptive threshold in a time-correlated manner. Dose-related significant tiagabine-induced antinociception was also observed at the doses of 1 and 3 mg kg(-1) i.p. in the mouse hot plate and abdominal constriction tests. The tiagabine antinociception was completely antagonised by pretreatment with the selective GABA(B) receptor antagonist, CGP 35348, (3-aminopropyl-diethoxy-methyl-phosphinic acid) (2.5 microg/mouse or 25 microg/rat i.c.v.), but not by naloxone (1 mg kg(-1) s.c.), both administered 15 min before tiagabine. Thus, it is suggested that tiagabine causes antinociception due to raised endogenous GABA levels which in turn activate GABA(B) receptors.

Abdomen↗
PubMed2004

Analysis of gamma-aminobutyric acid-mediated responses in the pulmonary vascular bed of the cat.

In this investigation, we sought to identify the role of gamma-aminobutyric acid (GABA)(A) and GABA(B) receptors in the feline pulmonary vascular bed. Using adult mongrel cats and in separate experiments, we investigated the effects of l-N(5)-(1-iminoethyl) ornithine hydrochloride (l-NIO) (a nitric oxide synthase inhibitor), glibenclamide (an adenosine triphosphate (ATP)-sensitive K(+) channel blocker), meclofenamate (a nonselective cyclooxygenase inhibitor), bicuculline (a GABA(A) receptor antagonist), and saclofen (a GABA(B) receptor antagonist) on pulmonary arterial responses to pinacidil (an ATP-sensitive K(+) channel activator), bradykinin (a nitric oxide synthase inducer), muscimol (a GABA(A) receptor agonist), and 3-aminopropyl(methyl)phosphinic acid, hydrochloride (SKF-97541; a GABA(B) receptor agonist). Under increased tone conditions in the isolated left lower lobe vascular bed of the cat, muscimol induced a dose-dependent vasodepressor response that was not significantly altered after the administration of l-NIO, glibenclamide, meclofenamate, and saclofen. SKF-97541-induced vasodepression was not significantly attenuated after the administration of l-NIO, meclofenamate, and bicuculline. Responses to SKF-97541 were significantly attenuated after the administration of glibenclamide and saclofen. Responses to muscimol were significantly reduced after the administration of bicuculline. The results suggest that muscimol and SKF-97541 have potent vasodepressor activity in the feline pulmonary vascular bed and that these responses are modulated by, respectively, GABA(A) and GABA(B) receptor-sensitive pathways. Further, SKF-97541-induced vasodepression is mediated or modulated by an ATP-sensitive K(+) channel.

Animals↗
PubMed1995

Intrathecal baclofen and muscimol, but not midazolam, are antinociceptive using the rat-formalin model.

Both gamma-aminobutyric acid (GABA)A and GABAB receptor subtypes have been implicated in spinally mediated antinociception in acute pain models. In the current study, the formalin test was used as a model of protracted nociception to examine the effect of intrathecally (i.t.) administered baclofen (GABAB agonist), muscimol (GABAA agonist) or midazolam (a benzodiazepine) on antinociception. At doses that did not affect motor function, baclofen (0.3 and 1.0 micrograms, i.t.) decreased the flinch response in a dose-dependent manner during Phase 1 and Phase 2. This effect was reversible by the GABAB-specific antagonist, CGP35348 ([P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid]). Muscimol (0.3 and 1.0 microgram i.t.) evoked a dose-dependent, bicuculline-reversible decrease in flinching during Phase 1 and Phase 2, but midazolam had no effect on either phase. No attenuation of the quiescent period between Phase 1 and Phase 2 was seen upon administration of baclofen, muscimol or midazolam. Additionally, no increase in nocifensive behavior was observed upon administration of either GABAA or GABAB antagonists alone. Therefore, our conclusions are that both GABAA and GABAB agonists are antinociceptive at the spinal cord level and that endogenous spinal GABA levels are insufficient for a GABA potentiator to act alone in an antinociceptive manner.

Animals↗
PubMed1994

gamma-Aminobutyric acid receptor-mediated regulation of periventricular-hypophysial dopaminergic neurons: possible role in mediating stress- and 5-hydroxytryptamine-induced decreases in neuronal activity.

The present study examined the effects of gamma-aminobutyric acid (GABA) agonists and antagonists on basal periventricular-hypophysial dopaminergic (PHDA) neuronal activity with a focus on the role of endogenous GABA in mediating 5-hydroxytryptamine- and stress-induced decreases in PHDA neuronal activity. PHDA neuronal activity was estimated by measuring concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in terminals of these neurons in the intermediate lobe of the pituitary. Plasma concentrations of alpha-melanocyte-stimulating hormone (alpha MSH) also were determined to provide a further index of PHDA neuronal activity. Administration of the GABAB agonist baclofen, but not the GABAA agonist isoguvacine, produced dose- and time-related decreases in intermediate lobe DOPAC concentrations and corresponding increases in plasma alpha MSH concentrations. Administration of either the GABAA antagonist SR-95,531 [2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)-pyridazinium bromide] or GABAB antagonists 2-hydroxysaclofen and CGP-35,348 [P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid; SR-95-531 did not alter basal intermediate lobe DOPAC concentrations or plasma alpha MSH concentrations per se, indicating that endogenous GABA does not tonically inhibit PHDA neuronal activity or alpha MSH secretion. 2-Hydroxysaclofen and CGP-35,348 did, however, reverse the baclofen-induced decrease in intermediate lobe DOPAC concentrations and increase in plasma alpha MSH concentrations. In a similar fashion, 2-hydroxysaclofen blocked the inhibitory effects of stress and the 5-hydroxytryptamine2/1c receptor agonist DOI [1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane] on PHDA neuronal activity. These results indicate that GABAB and not GABAA receptor activation inhibits basal PHDA neuronal activity, and that GABAB receptor activation mediates the inhibitory effects of 5-hydroxytryptamine and stress on PHDA neurons.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Activation of picrotoxin-resistant GABA receptors by GABA and related compounds induces modulation of cockroach dorsal paired median (DPM) neuron firing.

Activation of gamma-aminobutyric acid (GABA) receptors in insect dorsal paired median (DPM) neurons induced two types of response which appeared to be mediated by two different GABA receptor subtypes. When activated by bath application of GABA, one receptor subtype, insensitive to picrotoxin (PTX), mediated a drastic reduction in the firing frequency, leading to a blockade of the spontaneous electrical activity. These effects were accompanied by decreases in the amplitude and duration of the plateau action potential (AP) and the spike after-hyperpolarization (AHP). In most cases, a slight depolarization of the resting membrane potential occurred. Bath application of the vertebrate GABA(B) receptor agonists 3-aminopropyl(methyl)phosphinic acid (SKF 97541) and 3-aminopropylphosphinic acid (CGA 147823/CGP 27492) induced similar responses. Another GABA receptor subtype, less sensitive to GABA, mediated a chloride dependent hyperpolarization that was suppressed by bath application of PTX. The approximate locations of these two GABA receptor subtypes were determined by local pressure microapplications of GABA and vertebrate GABAergic agonists. The PTX-sensitive receptors were located predominantly on the surface of the ganglion where the apical pole of the soma is situated, while the PTX-resistant receptors appeared to be located deeper within the ganglion.These results reveal the existence of two GABA receptor subtypes on the DPM neurons and provide evidence for a functional role for PTX-resistant GABA receptors in the regulation of spontaneous firing.

Journal Article↗