Autoreceptors modify the evoked release of [3H]GABA from cerebellar neurons in dissociated cell culture

We investigated the effect of GABA, muscimol and THIP on the K+ -stimulated and spontaneous release of [3H]GABA from neuron-enriched cell cultures of the rat cerebellum. Each agonist produced significant reductions in evoked [3H]GABA without causing marked changes in spontaneous release. The agonist-induced inhibition of K+ -stimulated [3H]GABA release was reversed by the GABA antagonists bicuculline and picrotoxin. It is suggested that GABAergic neurons in cerebellar cell cultures possess GABA receptors which are involved in the regulation of evoked transmitter release.     

Pharmacological characteristics of two different types of inhibitory GABA receptors on Achatina fulica neurones

GABA (gamma-aminobutyric acid) receptors of Achatina fulica neurones have been classified into two types associated with neuronal inhibition and one type with excitation. The pharmacological features of muscimol I and baclofen types associated with inhibition were investigated in this study. Activation of muscimol I type receptors on TAN (tonically autoactive neurone) by GABA, muscimol and trans-4-aminocrotonic acid (TACA) produced a transient outward current (Iout) with an increase in membrane conductance (g). Their relative potencies at GABA ED50 (approximately 10(-4) M) were: GABA: muscimol: TACA = 1:0.6:0.3. The relation between Iout and g increase (delta g) induced by various concentrations of these compounds was linear. The Hill coefficients for GABA were close to 1.0. The GABA effects were potentiated by pentobarbitone, antagonized competitively by pitrazepin and non-competitively by picrotoxin and diazepam, and unaffected by bicuculline. The reversal potentials of the effects of GABA, muscimol and TACA on TAN changed under various [Cl-]0 according to the Nernst equation for Ec1, but not under various [K+]0 and [Na+]0. Activation of baclofen type GABA receptors on RPeNLN (right pedal nerve large neurone) by GABA and (+/-)-baclofen produced a slow Iout with an increase in g. The two compounds were almost equipotent (ED50: approximately 3 x 10(-4) M). The relation between Iout and delta g produced by various concentrations was linear. The Hill coefficients for GABA were also close to 1.0. The reversal potentials of GABA and (+/-)-baclofen on RPeNLN changed under various [K+]0 according to the Nernst equation for EK, but not under various [Cl-]0 and [Na+]0. The two compounds hardly affected the voltage-gated and slowly inactivating calcium current. The Iout produced by GABA and (+/-)-baclofen was reduced by tetraethylammonium chloride, but was unaffected by 4-aminopyridine, bicuculline, pitrazepin and picrotoxin. In conclusion, the pharmacological features of muscimol I type GABA receptors are partly comparable to those of mammalian GABAA receptors, except for the influences of bicuculline and diazepam: the features of the baclofen type GABA receptor, which did not occur with muscimol I type receptors in the same neurone, were similar to those of GABAB.     

Studies on [3H]GABA and endogenous GABA release in rat cerebral cortex suggest the presence of autoreceptors of the GABAB type

The presence of autoreceptors for gamma-aminobutyric acid (GABA) in the CNS was reinvestigated using rat cortex synaptosomes prelabeled with [3H]GABA and exposed to GABA by superfusion in the presence of a new GABA uptake inhibitor, N-(4,4-diphenyl-3-butenyl)-nipecotic acid (SK&F 89976A). This compound itself did not increase the basal or the depolarization-evoked release of [3H]GABA. GABA reduced in a concentration-dependent way the release of [3H]GABA evoked by 15 mM K+. The effect was not antagonized by bicuculline, picrotoxin or by the new GABAA antagonist SR 95531. The GABAA agonist muscimol did not affect [3H]GABA release. This was reduced by (-)baclofen (but not by the (+) isomer) and the concentration-inhibition curve of (-)baclofen was superimposable on to that of GABA. Also the K+-evoked release of endogenous GABA was stereoselectively and concentration dependently inhibited by the (-) enantiomer of baclofen. It is concluded that the release of GABA from rat cortical nerve endings may be inhibited through the activation of autoreceptors which appear to belong to the GABAB type.     

Presynaptic GABAB receptors and the regulation of [3H]noradrenaline release from rat anococcygeus muscle

The release of preaccumulated [3H]noradrenaline from the isolated rat anococcygeus muscle, a tissue endowed with a rich noradrenergic innervation, was investigated. Field stimulation produced a marked, calcium-dependent enhancement in release, which could be substantially inhibited by the inclusion of low concentrations of GABA or (-)-baclofen (but not the (+)-isomer) in the bathing medium. Classical GABAA site agonists such as muscimol or 3-aminopropanesulphonic acid were inactive, or only weakly so. Picrotoxin and bicuculline were unable to antagonise the effects of GABA or baclofen on [3H]noradrenaline release, although 5-aminovalerate was effective. These data provide further evidence for the existence of GABAB receptors associated with presynaptic noradrenergic terminals in the rat anococcygeus muscle.     

Modulation of calcium uptake and D-aspartate release by GABAB receptors in cultured cerebellar granule cells

(-)Baclofen, a GABAB receptor agonist, and GABA attenuated by 60% the high K+-evoked 45Ca2+ uptake into cultured cerebellar granule cells with an EC50 of 110 +/- 18 nM and 2.4 +/- 0.2 microM, respectively. The attenuation by baclofen of 45Ca2+ uptake was stereospecific and the effect of GABA was unaffected by bicuculline. Moreover, muscimol, a GABAA receptor agonist did not affect the K+-evoked 45Ca2+ uptake. (-)Baclofen and GABA also decreased the K+-evoked and calcium-dependent release of preloaded [3H]D-aspartate from granule cells; however, their potency and efficacy appeared to be less than those for inhibiting the 45Ca2+ uptake. (+)Baclofen and muscimol failed to change this K+-evoked release. The release of [3H]D-aspartate induced by the calcium ionophore A23187 was unaffected by (-)-baclofen. The K+-evoked release of [3H]D-aspartate was effectively inhibited by nimodipine, a voltage sensitive calcium channel blocker. The results suggest that GABAB receptor in cultured cerebellar granule cells plays a crucial role in modulating the uptake of calcium and release of the excitatory transmitter. Moreover, these two effects mediated by GABAB receptor activation may be casually related.     

GABAB autoreceptors in rat cortex synaptosomes: response under different depolarizing and ionic conditions

Rat cerebral cortex synaptosomes prelabeled with [3H]gamma-aminobutyric acid [( 3H]GABA) were exposed in superfusion to various concentrations of KCl (9-50 mM). The evoked release of [3H]GABA reached a plateau at about 35 mM KCl. The K+-induced release was Ca2+-dependent, particularly at the lowest K+ concentrations. The GABAB agonist (-)-baclofen concentration dependently inhibited the release of [3H]GABA evoked by K+; this effect decreased with increasing K+ concentration and disappeared at 35 mM KCl. The GABAA agonist muscimol (1-100 microM) was totally ineffective to inhibit the release of [3H]GABA. Veratrine (1-30 microM) induced the release of [3H]GABA and the effect was tetrodotoxin-sensitive. (-)-Baclofen, but not muscimol, decreased the veratrine-induced [3H]GABA release; the GABAB agonist was particularly effective in presence of low concentrations of veratrine (1-3 microM) but the effect disappeared when 30 microM of the alkaloid was used. The inhibitory effect of (-)-baclofen on the release of [3H]GABA evoked by 15 mM KCl was dependent on the concentration of Ca2+: the effect increased as the concentration of Ca2+ was raised, reaching a plateau at 0.6 mM Ca2+. Exogenous GABA, in presence of the GABA uptake blocker SK & F 89976A, inhibited the release of [3H]GABA evoked by K+; this effect was antagonized by phaclofen. The data support the idea that terminal GABA autoreceptors in the rat cerebral cortex are of the GABAB type.     

Baclofen (beta-p-chlorophenyl-gamma-aminobutyric acid) enhances [3H]gamma-aminobutyric acid (3H-GABA) release from rat globus pallidus in vitro.

The rat globus pallidus has been investigated as a possible model in which to study pre-synaptic GABA mechanisms in vitro. (+/-)-Baclofen (300 micrometer-1 mM) significantly enhanced the release of radioactivity from superfused slices of rat globus pallidus prelabelled with 3H-GABA in vitro. This releasing action was specific to the (+)-isomer of baclofen: neither the (-)-isomer nor another neuronal depressant dl-alpha-epsilon-diaminopimelic acid had any significant effect. The releasing effect of baclofen appeared unrelated to the phenethylamine moiety of its structure as neither beta-phenethylamine nor dopamine evoked release of 3H-GABA from pallidal slices. Baclofen increased the efflux of radioactivity from pallidal slices prelabelled with either [3H]-beta-alanine or [3H]diaminobutyric acid in vitro. The use of specific glial and neuronal GABA uptake blocking compounds (beta-alanine and (+/-)-cis-1,3-amino-cyclohexanecarboxylic acid) did not permit resolution of the elements from which baclofen was evoking [3H]GABA release. Baclofen also inhibited uptake of [3H]GABA into pallidal slices with an IC50 value of 6 x 10(-4) m. The GABA-like properties of baclofen may be related to the (+)-isomer while non-specific neuronal depressant actions are an effect of the (-)-isomer. The potential of the (+)-isomer as an antipsychotic agent while (-)-baclofen remains the effective antispastic drug free from unwanted side-effects, is discussed.     

Coexistence of carriers for dopamine and GABA uptake on a same nerve terminal in the rat brain.

The ability of gamma-aminobutyric acid (GABA) to affect the release of [3H]-dopamine in rat brain synaptosomes prepared from corpus striatum, frontal cortex and hypothalamus and prelabelled with the radioactive catecholamine in the presence of desipramine was examined. GABA (10-300 microM) increased in a concentration-dependent way the basal release of [3H]-dopamine from striatum and cortical synaptosomes; however, its effect was much less pronounced in hypothalamic nerve terminals. 2,4-Diaminobutyric acid (DABA) mimicked GABA although less potently. Neutral amino acids such as leucine, valine or alpha-aminoisobutyric acid (100-300 microM) did not affect or increased minimally the release of [3H]-dopamine. The GABA-induced [3H]-dopamine release was not prevented by the GABAA-receptor antagonists, bicuculline or picrotoxin. The GABAA-receptor agonist, muscimol (10-300 microM), displayed only a very weak, not significant, enhancing effect on [3H]-dopamine release. The GABAB-receptor agonist (-)-baclofen (100 or 300 microM) had no effect. Three novel and selective inhibitors of GABA uptake, N-(4,4-diphenyl-3-butenyl)-nipecotic acid (SK&F 89976A), N-(4,4-diphenyl-3-butenyl)-guvacine (SK&F 100330A) and N-(4,4-diphenyl-3-butenyl)-homo-beta-proline (SK&F 100561) potently counteracted the enhancing effect of GABA on [3H]-dopamine release. Nipecotic acid also reduced the effect of GABA. It is concluded that carriers for the uptake of dopamine and GABA may coexist on the same nerve terminal in the rat brain.     

GABA terminal autoreceptors in the pars compacta and in the pars reticulata of the rat substantia nigra are GABAB

The depolarization-evoked release of gamma-aminobutyric acid (GABA) and its modulation mediated by autoreceptors were studied in superfused synaptosomes prepared from the pars compacta and from the pars reticulata of the rat substantia nigra. The release of [3H]GABA evoked by 9 mM KCl was almost totally calcium-dependent in both nigral subregions. In the presence of SK&F 89976A (N-(4,4-diphenyl-3-butenyl)nipecotic acid), a GABA uptake inhibitor added to minimize carrier-mediated homoexchange, GABA (0.3-10 microM) inhibited, in a concentration-dependent way, the K(+)-evoked overflow of [3H]GABA from both pars compacta and pars reticulata synaptosomes. Similarly to GABA, (-)-baclofen (0.3-10 microM) reduced the [3H]GABA overflow, being roughly equipotent to GABA in both nigral subregions. The (+) enantiomer of baclofen was ineffective. The overflow of [3H]GABA was not consistently affected by muscimol in either the pars compacta or the pars reticulata. The effects of GABA were bicuculline- and picrotoxin-insensitive. However, the inhibition by GABA of the [3H]GABA overflow was antagonized by phaclofen. It is concluded that (a) GABA autoreceptors are sited on GABAergic nerve endings in both the pars compacta and pars reticulata of the rat substantia nigra; (b) these autoreceptors belong to the GABAB type.     

On the involvement of GABA in the analgesia produced by baclofen,muscimol and morphine

In the mouse hot-plate test (50°C), muscimol produced analgesia which was blocked by bicuculline but not by picrotoxin. Analgesia produced by baclofen was dose-dependent and stereoselective, but was not blocked by bicuculline, picrotoxin or naloxone. Morphine-induced analgesia was not altered by bicuculline. The inhibitors of GABA-transaminase, amino-oxyacetic acid, γ-acetylenic GABA and γ-vinyl GABA, produced analgesia which was much more prolonged than that observed with muscimol, baclofen or morphine. The analgesic action of these agents was not significantly altered by bicuculline. At a higher plate temperature (55°C), GABA-transaminase inhibitors produced minimal analgesia but significantly enhanced the analgesic action of baclofen. γ- Vinyl GABA markedly increased both the peak effect and the duration of analgesia but γ-acetylenic GABA and amino-oxyacetic acid caused smaller increases. In the mouse hot-plate test, bicuculline-sensitive GABA receptors appear to mediate the analgesic action of muscimol. Analgesia produced by baclofen, morphine and inhibitors of GABA-transaminase may involve another class of GABA receptors which are insensitive to bicuculline.     

Reversal of GABA-mediated inhibition of the electrically and potassium chloride evoked [3H]-GABA release from rat substantia nigra slices by DL-3-hydroxy-3-phenyl pentanamide

The phenyl alcohol amides, DL-2-hydroxy-2-phenyl butyramide (CAS 52839-87-9), DL-3-hydroxy-3-phenyl pentanamide (CAS 131802-69-2, DL-HEPP) and DL-4-hydroxy-4-phenyl hexanamide (CAS 67880-30-2) and their fluorine and chlorine analogs, at a concentration of 100 micromol/L, did not displace [3H]-gamma-aminobutyric acid ([3H]-GABA, CAS 108158-36-7) from GABAA receptors and only weakly displaced [3H]-GABA and [3H]-CGP62349 (CAS 186986-97-0), a GABAB receptor antagonist, from GABAB receptors in rat brain crude synaptic membranes. The electrically and potassium chloride (15 mmol/L) evoked [3H]-GABA release in the presence of DL-HEPP, GABA and GABAB receptor ligands from rat brain substantia nigra (SN) slices was studied. R-Baclofen (CAS 69308-37-8) (10 micromol/L), a GABAB receptor agonist, produced an inhibition of the electrically evoked [3H]-GABA release and this inhibition was blocked by CGP 55845A (CAS 149184-22-5) (10 micromol/L), a GABAB receptor antagonist, but was not affected by DL-HEPP (100 micromol/L). CGP 55845A (10 micromol/L) did not alter the electrically evoked [3H]-GABA release in the absence of baclofen. The addition of DL-HEPP (100 micromol/L) alone did not affect the electrically-evoked release of [3H]-GABA release control, but it was able to significantly reduce the inhibitory effect of GABA (CAS 56-12-2) (10 micromol/L) on [3H]-GABA release evoked both by electrical and potassium chloride stimulation, in the presence of tiagabine (CAS 115103-54-3) (10 micromol/L), a GABA uptake blocker. In three preliminary experiments, bicuculline (CAS 485-49-4) (10 micromol/L) and picrotoxinin (CAS 17617-45-7) (10 micromol/L), two GABAA antagonists, inhibited the electrically evoked release of [3H]-GABA from rat SN slices, and DL-HEPP (100 micromol/L) reversed this inhibition. The mechanism of action of DL-HEPP is not known but, it might act as a negative GABA modulator in rat brain slices.     

Effect of GABA Analogues on Blood Pressure and Central GABA Metabolism in the Rat

Abstract: Gamma aminobutyric acid (GABA) and different GABA analogues were examined for their cardiovascular actions and their influence on striatal dopamine (DA) levels and GABA accumulation after aminooxyacetic acid (AOAA). Gamma hydroxybutyric acid (GHBA) and baclofen caused hypertension and tachycardia after systemic as well as intracerebroventricular administration, while the opposite was true for GABA and muscimol. The hypertension after GHBA and baclofen was not reduced by picrotoxin or bicuculline and was not influenced by varying GABA levels by 3-mercaptopropionic acid (3-MPA)or AOAA. GHBA and muscimol but not baclofen reduced GABA accumulation induced by AOAA. Picrotoxin in a subconvulsive dose increased GABA accumulation and antagonized the inhibition after GHBA or muscimol. Bicuculline and a moderate dose of picrotoxin tended to decrease GABA accumulation by themselves and if anything augmented the effects of GHBA and muscimol. GHBA and baclofen but not muscimol in combination with AOAA increased DA levels, which was not prevented by picrotoxin or bicuculline. We conclude that the cardiovascular actions of GHBA and baclofen are probably not mediated by mechanisms identical to those of muscimol or exogenous GABA. In view of the biochemical results their actions would however be compatible with a concept of different GABA receptors.     

Baclofen and phaclofen modulate GABA release from slices of rat cerebral cortex and spinal cord but not from retina.

1. The effects of (-)-baclofen, muscimol and phaclofen on endogenous gamma-aminobutyric acid (GABA) release from rat cortical slices, spinal cord slices and entire retinas were studied. 2. The spontaneous resting release of GABA from the three tissues was 3 to 6 pmol mg-1 wet wt 10 min-1. Depolarization of cortical slices with KCl (50 mM) (high-K) produced an 8 fold increase in GABA release but high-K did not evoke an increased release of GABA from spinal slices or retinas. 3. When rats were injected with gamma-vinyl-GABA (250 mg kg-1 i.p.) (GVG) 18 h before death, the tissue GABA stores were increased 3 to 6 fold and high-K then evoked striking Ca-dependent releases of GABA from all three tissues. Thus, in subsequent experiments, unless otherwise stated, the nervous tissues were taken from GVG-treated rats. 4. (-)-Baclofen (10 microM) significantly reduced the K-evoked release of GABA from cortical and spinal slices but retinal release was not affected, even at a concentration of (+/-)-baclofen of 1 mM. For cortical slices, the IC50 for baclofen was approximately 5.2 microM. The inhibitory effect of baclofen on GABA release from cortical slices also occurred in slices prepared from saline-injected rats, indicating that GVG treatment did not qualitatively affect the results. 5. The inhibitory effect of (-)-baclofen on the K-evoked release of GABA from cortical and spinal slices was antagonised by phaclofen (500 microM), confirming that baclofen was producing its effects by acting at the GABAB-receptor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carriers for GABA and noradrenaline uptake coexist on the same nerve terminal in rat hippocampus

gamma-Aminobutyric acid (GABA; 1-300 microM) increased the basal release of [3H]noradrenaline ([3H]NA) from rat hippocampal synaptosomes. The effect of GABA at low concentrations (below 10 microM) was largely bicuculline-sensitive while the sensitivity to bicuculline decreased at higher concentrations. Muscimol mimicked GABA but only below 10 microM; bicuculline antagonized the effect of muscimol. Up to 300 microM (-)baclofen did not modify [3H]NA release. The effect of GABA was potently counteracted by SK & F 89976A, SK & F 100330A and SK & F 100561, three novel inhibitors of neuronal GABA uptake. These compounds could not entirely prevent the effect of GABA, being least effective at the lowest GABA concentrations (below 10 microM) and becoming progressively more effective when the concentrations of GABA were increased. The effect of muscimol was insensitive to SK & F 89976A. The effect of 100 microM GABA was totally prevented when bicuculline and uptake inhibitor were added together to the superfusion medium. The results suggest that the basal release of [3H]NA can be enhanced by GABA through two mechanisms: GABAA receptor activation and penetration into NA terminals by a GABA uptake process. Thus a carrier for the uptake of NA and a carrier for the uptake of GABA appear to coexist on the same nerve terminal in rat hippocampus.     

GABA(B)-related activity involved in synaptic processing of somatosensory information in S1 cortex of the anaesthetized cat.

1. The possible role of GABA(B) receptor mechanisms in information processing in primary somatosensory (S1) cortex was assessed by use of extracellular recording combined with microiontophoretic methods from 161 neurones in anaesthetized, paralysed cats. 2. Baclofen-induced suppressions of cell responses were reversible and stereoselective, the (+)-isomer being inactive and the (-)-isomer having two to three times the apparent potency of gamma-aminobutyric acid (GABA). The responses measured were threshold to natural stimulation of receptive fields (RFs), responsiveness to thalamic electrical stimulation, change in RF size and magnitude of firing elicited by iontophoretic glutamate. 3. The action of GABA always was mimicked by muscimol or 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) but not always by (-)-baclofen; in certain cases (-)-baclofen enhanced neuronal responses while the opposite occurred with GABA or with the other GABA(A) agonists. The elevation of response thresholds by (-)-baclofen was relatively stronger in peripheral than in central subregions of cutaneous RFs, by contrast with the action of muscimol which was relatively non-selective as to the area in which it was effective. 4. Glutamate-induced and thalamically-evoked cortical responses as well as spontaneous activity were differentially sensitive to the suppressant effects of muscimol and (-)-baclofen. 5. Bicuculline methiodide reversibly blocked THIP- and muscimol-induced suppressions of tactile- (air puffer)-induced S1 responses but spared those produced by (-)-baclofen. Phaclofen and delta-amino-n-valeric acid were essentially inactive as blockers of (-)-baclofen-induced effects and in fact often acted as (-)-baclofen-like agonists, phaclofen being considerably weaker than delta-amino-n-valeric acid in this respect. 6. The range of suppressant effects produced by GABA as well as by muscimol and THIP, considered in conjunction with the actions of bicuculline methiodide, suggest that the effects observed by ejected GABA are likely to be due principally to GABA(A) processes, those mediated by GABA(B) receptors largely being masked. However, GABA(B) mechanisms are extant and do appear to be active, probably presynaptically and probably at sites distal to the soma.     

GABAB-receptor mediated inhibition of potassium-evoked release of endogenous 5-hydroxytryptamine from mouse frontal cortex.

The effect of baclofen, the GABAB-agent, on the potassium-evoked release of endogenous 5-hydroxytryptamine (5-HT) from slices of mouse frontal cortex has been investigated. The release of endogenous 5-HT evoked by addition of K+ (35 mM) was inhibited by (+/-)-baclofen in a dose-dependent manner with an IC50 of 0.1 microM. Inhibition of K+-evoked release of 5-HT was produced by (+/-)- and (-)-baclofen but not (+)-baclofen. This action of the (-)-enantiomer was not altered by the presence of the (+)-enantiomer. Addition of GABA (0.1-10 microM) also induced a dose-dependent inhibition of 5-HT release. This effect was neither enhanced by flurazepam (1 microM) nor antagonized by bicuculline (10 microM). The progabide metabolite, 4-[( (4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methylene]amino)butyric acid (SL75.102) (1 microM) inhibited the K+-evoked release of 5-HT by 61%. These data suggest that baclofen is a potent inhibitor of the K+-evoked release of endogenous 5-HT from the cortex and further indicate that the release of 5-HT may be controlled by a GABAB-receptor located presynaptically.     

Opioid and prostaglandin mechanisms involved in the effects of GABAergic drugs on body temperature.

1. Intraperitoneal (i.p.) injection to restrained rats of GABA (250-1000 mg/kg) or the GABAA-receptor agonist muscimol (0.05-1 mg/kg) induced a dose-dependent decrease in body temperature (BT). 2. Intraperitoneal injection of low doses of the GABAB-receptor agonist (+/-)-baclofen (1-10 mg/kg) did not significantly affect BT. However, baclofen, at high doses (30 mg/kg), produced an increase in BT. 3. Pretreatment with either bicuculline (3 mg/kg) or naloxone (1 mg/kg) did not significantly modify the hypothermic response observed with GABA or muscimol, except for the high dose of GABA (1000 mg/kg) which was potentiated by bicuculline pretreatment. 4. Indomethacin pretreatment (5 mg/kg) significantly antagonized the hypothermia induced by GABA and muscimol. 5. Injection of baclofen alone (1 mg/kg) did not significantly affect BT, but in presence of the GABAA antagonist bicuculline, baclofen significantly decreased BT. 6. Baclofen-induced hyperthermia appear to be via prostaglandin and opioid mechanisms since both indomethacin and naloxone abolish this effect. 7. The hypothermia induced by GABA-agonists appears to be due to simultaneous activation of GABAA and GABAB receptors, while the hyperthermic effect of baclofen appears to be due to stimulation of GABAB receptors. 8. The present results suggest that involvement of prostaglandins in the effects of GABA, muscimol and baclofen, while endogenous opiates seem to be implicated only in baclofen induced hyperthermia. 9. It can be concluded that GABA may be involved in the control of BT through GABAA and GABAB receptors.     

Gamma-aminobutyric acid enhancement of potassium-stimulated release of [3H]norepinephrine by multiple mechanisms in rat cortical slices

Gamma-Aminobutyric acid (GABA) and GABAA agonists enhance stimulated release of [3H]norepinephrine [( 3H]NA) in several regions of the rat brain. In this study, the mechanisms by which GABA and GABAergic agonists augment potassium-stimulated release of [3H]NA from rat frontal cortical slices were examined. GABA enhanced potassium-stimulated [3H]NA release, but did not alter release of [3H]NA evoked by the calcium ionophore A23187, 10(-5) M, either in the presence or the absence of extracellular calcium. The effect of GABA on potassium-stimulated [3H]NA release was apparently reduced by the GABAA antagonist bicuculline methiodide, 10(-4) M, and by the selective inhibitor of GABA uptake SKF 89976A, 10(-5) M, but was abolished only when bicuculline methiodide and SKF 89976A were present in combination. The GABAA agonist muscimol enhanced potassium-stimulated release of [3H]NA in a manner similar to GABA. In addition, nipecotic acid, a substrate for GABA uptake, enhanced potassium-stimulated [3H]NA release. Thus, GABA appears to enhance potassium-stimulated [3H]NA release by acting upon both GABA uptake and GABAA receptors. The GABAA receptors involved in this effect may be a subtype of GABAA receptors since they are not modulated by benzodiazepines. These results support the involvement of the GABA uptake carrier and the GABAA receptor in mediating the enhancement by GABA of potassium-stimulated [3H]NA release in the cortex of the rat.     

GABAA and GABAB receptor-mediated effects on the spontaneous activity of the longitudinal layer in cat terminal ileum.

1. GABA and GABAergic agonists-muscimol and (+/-)baclofen changed the spontaneous mechanical activity in isolated cat terminal ileum. 2. GABA at doses ranging from 5 microM to 2 mM produced concentration-dependent biphasic responses consisting of a transient relaxation followed by contractions with a tonic and a phasic components. 3. The GABA-induced relaxation was sensitive to bicuculline and picrotoxinin and was mimicked by muscimol, while the GABA-induced contractions were insensitive to bicuculline and picrotoxinin and were mimicked by (+/-)baclofen. Specific cross desensitization occurred between GABA and muscimol or GABA and (+/-)baclofen. 4. The bicuculline-sensitive relaxation induced by GABA and muscimol was abolished by atropine or tetrodotoxin (TTX), while the bicuculline-insensitive contractions induced by GABA and (+/-)baclofen were not antagonized by atropine or TTX, though they were slightly suppressed. 5. The GABA effects in the longitudinal layer of cat terminal ileum were mediated by the following receptors: -GABAA prejunctional receptors whose activation causes relaxation, probably through an inhibitory action on cholinergic neurons; -GABAB prejunctional receptors whose activation cause contractions; -GABAB postjunctional receptors located on the smooth muscle membrane whose activation induces tonic and phasic contractions.     

GABA enhancement of [3H]dopamine release from slices of rat striatum: Dependence of slice size

The effect of GABA on potassium-evoked tritium release from two sizes of ribbon of rat striatum previously loaded with [³H]dopamine was studied. GABA had no effect on the release of tritium from 100 × 100 μm ribbons but produced a dose-related enhancement of potassium-evoked tritium release from 250 × 250 μm ribbons. The enhancement was unaffected by the presence of bicuculline or picrotoxin but was antagonised by tetrodotoxin. The effect of GABA was not mimicked by the GABA agonists muscimol or baclofen. The possible involvement of an interneurone is discussed. From antagonist studies the neurotransmitter released by the postulated interneurone did not appear to be acetylcholine, 5-hydroxytryptamine, glycine, glutamate of enkephalin.