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Experiments were performed to examine neurochemically the functional diversity of GABAA receptors as measured by muscimol-, 5 alpha-pregnane-3 alpha,21-diol-20-one (THDOC)-, and pentobarbital-stimulated 36Cl- uptake, and region-specific changes in muscimol-, THDOC- and THDOC-induced potentiation of muscimol-stimulated 36Cl- uptake in rats treated acutely or subacutely with a subconvulsive dose of bicuculline. The data for stimulation of 36Cl- uptake by muscimol showed a single binding site interaction in the cerebral cortex, hippocampus and cerebellum. The concentration-response curves for muscimol in the cerebral cortex and hippocampus were steep and indicated an increase of approximately 130% at the maximum concentration. In contrast, the curve for the cerebellum was shallow and exhibited a smaller maximal response (approximately 60%). Apparent affinity for muscimol also differed among these brain regions. The regional differences in 36Cl- uptake induced by THDOC and pentobarbital were not as apparent as those induced by muscimol; however, the maximal modulatory effect of pentobarbital in the hippocampus was significantly higher than that in the cerebellum. In rats treated subacutely with a subconvulsive dose of bicuculline, a significant increase in muscimol-stimulated 36Cl- uptake was observed in the cerebellum but not in the frontal cortex or hippocampus. Analysis of the concentration-response curves for muscimol-stimulated 36Cl- uptake in the cerebellum revealed that the Vmax for muscimol in the subacutely treated group was significantly higher than those for muscimol in the control and acutely treated groups without any differences in the KD value.(ABSTRACT TRUNCATED AT 250 WORDS)
The present study aimed to elucidate the pharmacological features of GABA receptors on identifiable neurones of Achatina fulica Férussac by testing the effects of GABA analogues, muscimol, (+/-)-baclofen, (-)-beta-hydroxy GABA and those conformationally fixed in either the extended or folded form of carbon chain, such as trans- and cis-isomers of (+/-)-2-(aminomethyl)cyclopropane-1-carboxylic acid [+/-)-cyclo-GABA-extended and (+/-)-cyclo-GABA-folded) and trans-4-amino-crotonic acid (GABA-extended). The giant neurones used were TAN, d-LPeLN, v-VNAN, v-LCDN and RPeNLN. The minimum effective concentrations (MEC) of these compounds to produce hyper- or depolarization of the membrane potentials of the neurones were determined, and the effective potency quotient (EPQ) of each compound vis-à-vis that of GABA was calculated for each neurone. The GABA receptors in these neurones were classified into the muscimol I, muscimol II and baclofen types. The muscimol I (TAN and d-LPeLN) and muscimol II (v-VNAN and v-LCDN) receptors were respectively hyperpolarized and depolarized by GABA and muscimol but were insensitive to (+/-)-baclofen. These muscimol receptors are inferred to accept GABA in an extended form of its carbon chain, since muscimol, conformationally fixed in this form from C-1 to C-4, was quite effective. Muscimol was more potent on the muscimol II receptors (MEC: 3 X 10(-7)-3 X 10(-6) M; EPQ: 30-10) than on the muscimol I type (MEC: 3 X 10(-5)-10(-4) M; EPQ: 1-0.3).(ABSTRACT TRUNCATED AT 250 WORDS)
UNLABELLED: Previous reports indicate that there may be an interaction between gamma-aminobutyric acid receptors and opioid receptors systems within the spinal cord, the antinociceptive effects of which have not been elucidated. We examined the effects of intrathecally coadministered morphine and muscimol or baclofen on somatic and visceral antinociception in rats. The tail flick (TF) test and colorectal distension (CD) test were used to assess somatic and visceral antinociceptive effects, respectively. Motor function was also assessed. The measurements were performed for 180 min after the intrathecal administration of morphine (0.1-10 micrograms), muscimol (0.2-10 micrograms), baclofen (0.03-1 microgram), combination of morphine and muscimol or baclofen, or saline. Morphine, muscimol, or baclofen increased both TF latency and CD threshold in a dose-dependent fashion. Although morphine 0.1 microgram, muscimol 0.2 microgram, or baclofen 0.03 microgram alone did not significantly increase TF latency and CD threshold, the combination of morphine 0.1 microgram and muscimol 0.2 microgram or baclofen 0.03 microgram significantly increased both TF latency and CD threshold. The coadministration of muscimol or baclofen increased the antinociceptive effects of morphine in intensity and duration. None of the rats showed motor dysfunction after the coadministration of morphine and muscimol 0.2 microgram, although muscimol produced motor paralysis of the lower limbs in a dose-dependent fashion. Those results suggest a clinical relevance of the coadministration of mu-opioids and GABA receptor agonists for pain control. IMPLICATIONS: We examined the antinociceptive interaction between morphine and muscimol or baclofen at the spinal level in rats. Intrathecal muscimol or baclofen potentiated both somatic and visceral antinociceptive effects of morphine.
The effects of arachidonic acid and its metabolites on gamma-aminobutyric acid (GABAA) receptor function were determined in rat cerebral cortical synaptoneurosomes. Incubation of synaptoneurosomes with phospholipase A2 decreased muscimol-induced 36Cl- uptake. Arachidonic acid, the major unsaturated fatty acid released by phospholipase A2, also inhibited muscimol-induced 36Cl uptake. Similar inhibition was obtained with other unsaturated fatty acids (docosahexaenoic, oleic) but not with saturated fatty acids (stearic, palmitic). The effect of arachidonic acid on muscimol responses was inhibited by bovine serum albumin (BSA), and BSA enhanced muscimol responses directly, indicating the generation of endogenous arachidonic acid in the synaptoneurosome preparation. The generation of endogenous arachidonic acid was also indicated by the ability of 2 inhibitors of arachidonic acid metabolism, indomethacin and nordihydroguaiaretic acid (NDGA), to inhibit muscimol-induced 36Cl uptake. We conclude that arachidonic acid probably has both direct and indirect actions on muscimol responses since both enzyme inhibitors inhibited muscimol responses but did not prevent the effect of exogenously added arachidonic acid. In additional experiments, arachidonic acid metabolites generated by cyclooxygenase, prostaglandins D2, E2 and F2 alpha, each decreased muscimol responses; prostaglandins F2 alpha was the most potent inhibitor. Since the unsaturated fatty acids and their metabolites are most susceptible to peroxidation, a generating system of superoxide radicals was tested on muscimol responses. A combination of xanthine and xanthine oxidase inhibited muscimol-induced 36Cl uptake in a concentration-dependent manner. We propose that the inhibition of GABAA neurotransmission by arachidonic acid and its metabolites can lead to increased neuronal excitability. This mechanism may play an important role in the development of neuronal damage following seizures or cerebral ischemia.
The gamma-aminobutyric acid agonist muscimol and the gamma-aminobutyric acid antagonist bicuculline were studied to determine their effects on basal net water and electrolyte transport in the rat ileum. Whereas the intraperitoneal injection of muscimol caused a reversible, dose-dependent decrease in net water absorption, bicuculline produced a reversible, dose-dependent increase in net water and ion absorption. The threshold doses of muscimol and bicuculline were greater than 2.1 and 2.2 micrograms/kg, respectively. Lower doses of muscimol (0.1 microgram) or bicuculline (0.3 microgram) administered into the cerebrospinal fluid had the same effect as higher doses given systemically. Vagotomy prevented the effect of intracerebroventricular muscimol. Atropine (6 micrograms intracerebroventricularly) alone did not alter basal water absorption but abolished the muscimol effect, suggesting that muscimol promoted the release of acetylcholine from central cholinergic neurons. Atropine did not prevent the bicuculline effect. We conclude that (a) muscimol decreases ileal water absorption and bicuculline enhances ileal water absorption by an action at a gamma-aminobutyric acid receptor in the central nervous system, (b) the muscimol effect is due to an alteration in parasympathetic vagal outflow to the intestine, (c) the muscimol effect is mediated by a central cholinergic interneuron, and (d) the bicuculline effect is not mediated by the release of acetylcholine from central cholinergic neurons.
1. GABA receptors in Achatina identifiable giant neurones were classified into the muscimol I, muscimol II and baclofen types. Muscimol I and II type GABA receptors were sensitive to GABA and muscimol but insensitive to baclofen, whereas baclofen type receptors were sensitive to GABA and baclofen but insensitive to muscimol. Muscimol I and baclofen types were associated with the inhibition caused by GABA, while muscimol II type with the GABA excitation. 2. GABA, muscimol and TACA produced a transient outward current (Iout) with an increase in membrane conductance (g) of an Achatina neurone, TAN, having the muscimol I type GABA receptors. Their relative potency values (RPV) at GABA ED50 (approximately 10(-4) M) were: GABA:muscimol:TACA = 1:0.6:0.3. The GABA effects were potentiated by pentobarbitone, antagonized competitively by pitrazepin and non-competitively by picrotoxin and diazepam, and unaffected by bicuculline. The ionic mechanism of effects of GABA and its two analogues was the increase in membrane Cl- conductance (gCl). 3. GABA and (+/-)-baclofen produced a slow Iout with a g increase of another Achatina neurone, RPeNLN, having the baclofen type GABA receptors. The two compounds were almost equipotent (ED50: approximately 3 x 10(-4) M). The ionic mechanism of their effects was the increase in gk. The two compounds hardly affected the voltage-gated and slowly inactivating calcium current. Iout produced by GABA and (+/-)-baclofen were reduced by TEA, but unaffected by 4-AP, bicuculline, pitrazepin and picrotoxin. 4. Beta-hydroxy-L-glutamic acid (L-BHGA) showed the marked effects on the Achatina giant neurones; the two neurones were excited by the compound, whereas the three inhibited. D-BHGA, L-Glu, D-Glu and NMDA were less effective than L-BHGA or almost ineffective. Erythro-L-BHGA was more or less effective than threo-L-BHGA according to the neurones tested. 5. alpha-Kainic acid and domoic acid excited the two neurones, which were excited by L-BHGA. L-Quisqualic acid showed the similar effects to L-BHGA, which were mostly much stronger than L-BHGA. Erythro-L-tricholomic acid and DL-ibotenic acid showed the effects similar to L-BHGA selectively on some neurones. 6. It was pointed out that the pharmacological features of GABA on the Achatina neurones are simpler than those of L-BHGA, due to the simpler structure of the former compound having less binding sites than the latter.
The effects of GABAA (muscimol) and GABAB (baclofen) receptor agonists on spontaneous motor activity and food consumption of rats were compared to those produced by taurine and related compounds (3-aminopropanesulphonic acid, 5-aminovaleric acid, and guanidinoethanesulphonic acid). Local application of muscimol into the nucleus raphe dorsalis caused a dose-dependent increase in spontaneous motor activity. Muscimol-stimulated motor activity was blocked by picrotoxin. High doses relative to muscimol of 3-aminopropanesulphonic acid, guanidinoethanesulphonic acid, and 5-aminovaleric acid also attenuated the action of muscimol. Taurine by itself was ineffective on locomotion but enhanced the effect of a small dose of muscimol. Baclofen also stimulated activity but to a lesser extent than muscimol. Baclofen's stimulatory action on motor activity was partially blocked by 5-aminovaleric acid, whereas 3-aminopropanesulphonic acid was without effect. Muscimol and baclofen both increased food consumption of rats. Picrotoxin blocked this effect of muscimol, whereas the action of baclofen was blocked by 5-aminovaleric acid. Muscimol, taurine, and guanidinoethanesulphonic acid all reduced 5-hydroxytryptamine (5-HT) concentration in the hypothalamus. In radioligand binding studies, guanidinoethanesulphonic acid at micromolar concentrations displaced [3H]GABA from GABAA receptors. It is concluded that taurine may have a slight direct effect on GABA receptors but is more likely to act as an indirect neuromodulator of GABAergic neurotransmission in the brain.
Pharmacologic experiments were carried out to test the degree of interdependence of rostral vasopressor and caudal vasodepressor neuron pools in the ventrolateral medulla (VLPA and VLDA, respectively). In two groups of urethane-anesthetized rats, the gamma-aminobutyric acid (GABA) agonist muscimol (10 ng/site) was bilaterally microinjected into both the VLPA and VLDA to inhibit neuronal activity at these sites. In one group of experiments, muscimol was microinjected first into the VLPA and then into the VLDA. Following muscimol microinjection in the VLPA the mean arterial pressure (MAP) and heart rate (HR) decreased to 40 +/- 6 mm Hg and 310 +/- 21 beats/min (bpm) from a control level of 90 +/- 3 mm Hg and 403 +/- 23 bpm. Subsequent microinjection of muscimol in the VLDA had no significant effect on BP or HR. This lack of response was not due to severe fall in BP caused by microinjection of muscimol into the VLPA. In the second group of experiments muscimol was first injected into the VLDA followed by muscimol microinjection into the VLPA. In the VLDA muscimol significantly increased MAP and HR to 139 +/- 4 mm Hg and 427 +/- 4 bpm from a control level of 87 +/- 2 mm Hg and 356 +/- 23 bmp. The aortic depressor nerve response (-37 +/- 1 mm Hg and -47 +/- 4 bpm) was converted to an aortic 'pressor' response (+20 +/- 1 mm Hg and -13 +/- 6 bpm). Subsequent microinjection of muscimol into the VLPA caused MAP and HR to fall to 43 +/- 5 mm Hg and 338 +/- 17 bpm. The aortic 'pressor' response was also abolished (2 +/- 2 mm Hg). These results indicate that neuronal activity in the rostral VLPA is an important determinant for changes in BP and its reflex regulation mediated by the VLDA. However, BP changes mediated by the rostral VLPA are independent of the level of neuronal activity in the VLDA. Sites of VLPA and VLDA interaction are discussed.
Effects of ethanol and pentobarbital on the GABA receptorchloride channel complex were evaluated in mice selected for differential sensitivity to the hypnotic effects of ethanol (long sleep and short sleep lines). 36Cl- influx, [35S]tbutylbicyclophosphorothionate (TBPS) and [3H]muscimol binding were measured in a membrane vesicle suspension (microsacs) from cerebellum or forebrain. Muscimol was found to be a more potent stimulator of 36Cl- flux in the LS cerebellum, as compared to the SS cerebellum, but a similar maximal level of uptake was achieved in the two lines. Muscimol displaced [35S]TBPS (a ligand for the convulsant site) from cerebellar microsacs, and LS mice were also more sensitive than SS mice to this action of muscimol. However, the number or affinity of high affinity [3H]muscimol binding sites did not differ between the lines. Physiologically relevant concentrations of ethanol (15-50 mM) potentiated muscimol stimulation of 36Cl- uptake in LS cerebellum but had no effect in SS cerebellum. Ethanol failed to alter stimulated chloride flux hippocampal microsacs from either line. Both the LS and SS lines responded similarly to pentobarbital potentiation of muscimol stimulated chloride uptake regardless of brain region. The demonstrated difference between the LS and SS mice in muscimol stimulated chloride uptake as well as in muscimol displacement of [35S]TBPS binding offers a biochemical explanation for the line differences in behavioral responses to GABAergic agents. Moreover, the findings suggest that genetic differences in ethanol hypnosis are related to differences in the sensitivity of GABA-operated chloride channels to ethanol.
This study addressed the amygdala's role in avoidance conditioning in rabbits (Oryctolagus cuniculus). Intra-amygdalar muscimol infusion before 60 or 120 conditioning trials blocked training-induced neuronal activity (TIA) in the medial geniculate (MG) nucleus. One hundred twenty trials with muscimol blocked TIA permanently, during conditioning with muscimol and then later without muscimol; 60 trials with muscimol blocked TIA only when muscimol was present. Cingulate cortical TIA was blocked only when muscimol was present. Behavioral learning did not occur with muscimol, but later learning was facilitated (i.e., savings occurred) in rabbits initially given muscimol plus training. These results define the time period wherein amygdalar processes initiate TIA in the MG nucleus and suggest that distinct forms of amygdalar processes induce TIA in the MG nucleus and cingulate cortex.
UNLABELLED: To examine whether the gamma-aminobutyric acid (GABA) receptor agonists and L-type voltage-dependent calcium channel blockers potentiate each other on the visceral antinociceptive effects at the spinal cord, we assessed visceral nociception with colorectal distension (CD) test in rats with an intrathecal catheter. The measurements were performed after intrathecal administration of a GABA agonist (muscimol or baclofen), a calcium channel blocker (diltiazem), or the combination of the two. CD threshold did not change after muscimol 0.1 microg, baclofen 0.01 microg, or diltiazem 100 microg, but increased slightly after muscimol 1 microg and baclofen 0.1 microg. When muscimol 0.1 microg or 1 microg was administered with diltiazem, the increase in CD threshold was significantly larger than muscimol alone (at 5 min, 26.2% versus 0.6% MPE (maximum possible effect) or 84.5% versus 19.5%MPE, respectively; P < 0.01). The CD threshold after the combination of baclofen 0.1 microg and diltiazem also showed a significantly larger increase than that seen after baclofen alone (at 5 min, 48.0% versus 14.3% MPE; P < 0.01). Motor paralysis observed with muscimol 1 microg did not increase when muscimol was coadministered with diltiazem. In conclusion, intrathecal diltiazem in combination with a GABA agonist, muscimol or baclofen, potentiated the GABA agonists-induced visceral antinociception without increasing motor paralysis. IMPLICATIONS: Intrathecal administration of diltiazem in combination with a gamma-aminobutyric acid (GABA) agonist, muscimol or baclofen, potentiated the GABA agonists-induced visceral antinociception but did not affect motor paralysis. The present results indicate that the coadministration of the two types of drugs may be clinically useful.