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PubMed2000

Effects of gamma-aminobutyric acid(A) receptor manipulation on migrating gonadotropin-releasing hormone neurons through the entire migratory route in vivo and in vitro.

GnRH neurons originate in the nasal compartment and migrate along vomeronasal fibers over the cribiform plate to the forebrain. Previously, we found gamma-aminobutyric acid (GABA) present in GnRH neurons during development. To clarify the influence of GABA across the entire GnRH migration route, we examined the effects of muscimol and bicuculline (GABA(A) agonist and antagonist) in vivo and in vitro, maintaining the integrity of the nasal-forebrain connection. For in vivo experiments, mice were administered muscimol, bicuculline, or vehicle on days 10-15 of pregnancy and were killed on embryonic day 15 (E15). For in vitro experiments, 250-microm parasagittal slices of whole heads of E13 mice were incubated with muscimol, bicuculline, or vehicle for 2 days. Muscimol inhibited GnRH cell migration and decreased extension of GnRH fibers. Bicuculline treatment led to a disorganized distribution of GnRH cells in the forebrain and a concomitant dissociation of GnRH cells from fibers of guidance. These results suggest that GABA's influence on GnRH development changes as the cells move out of the nasal compartment and extend processes toward the median eminence.

Animals↗
PubMed1995

GABAergic stimulation switches from enhancing to repressing BDNF expression in rat hippocampal neurons during maturation in vitro.

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the adult mammalian central nervous system. However, GABA depolarizes immature rat hippocampal neurons and increases intracellular Ca2+ ([Ca2+]i). Here we show, that GABA and the GABAA receptor agonist muscimol induce c-Fos immunoreactivity and increase BDNF mRNA expression in embryonic hippocampal neurons cultured for 5 days. In contrast, after 3 weeks in culture, GABA and muscimol failed to induce c-fos and BDNF expression. Fura-2 fluorescence microscopy revealed that muscimol produces a dihydropyridine-sensitive transient increase in [Ca2+]i, comparable to the effect of the non-NMDA receptor agonist kainic acid in neurons cultured for 5 days, but not in 3-week-old cultures. The increase in c-Fos immunoreactivity and BDNF mRNA levels by GABA were dependent upon the activation of voltage-gated Ca2+ channels, as shown using the L-type specific Ca2+ channel blocker nifedipine. The differential regulation of c-fos and BDNF expression by GABA and muscimol in developing and mature hippocampal neurons is due to a switch in the ability of GABAA receptors to activate voltage-gated Ca2+ channels. These observations support the hypothesis that GABA might have neurotrophic effects on embryonic or perinatal hippocampal neurons, which are mediated by BDNF.

Animals↗
PubMed1998

Inhibition by gamma-aminobutyric acid system activation of epileptic seizures in spontaneously epileptic rats.

The effects of muscimol, a gamma-aminobutyric acid (GABA)A-receptor agonist, and aminooxy-acetic acid (AOAA), an inhibitor of GABA-converting enzyme, on tonic and absence-like seizures in spontaneously epileptic rats (SER: zi/zi, tm/tm) were investigated to elucidate whether GABAergic function operates normally in these animals. Muscimol at doses of 1 and 3 mg/kg (i.p.) induced high-voltage slow waves in the cortical and hippocampal EEG of SER, although the behavioral observation suggested inhibition of absence-like seizures. Similar high-voltage slow waves were also observed in the cortical and hippocampal EEG of normal rats with muscimol (1 and 3 mg/kg). Tonic convulsions in SER were dose-dependently inhibited by muscimol. AOAA (3 and 10 mg/kg, i.v.) inhibited both tonic and absence-like seizures in SER, although there were no obvious changes in EEG pattern. The inhibitory effects of AOAA on tonic convulsions appeared more slowly and lasted longer than those on absence-like seizures. Cerebral, hippocampal and cerebellar GABA levels were significantly higher in SER than the normal Kyo:Wistar and zitter rat (zi/zi), which were both the parent strains. These findings suggest that GABA receptors and GABAergic neurons are functional in SER and that the GABA system is involved in the inhibition of both seizures.

4-Aminobutyrate Transaminase↗
PubMed2002

Positive and negative motivation in nucleus accumbens shell: bivalent rostrocaudal gradients for GABA-elicited eating, taste "liking"/"disliking" reactions, place preference/avoidance, and fear.

Microinjection of the GABA(A) agonist muscimol in the rostral medial accumbens shell in rats elicits appetitive eating behavior, but in the caudal shell instead elicits fearful defensive treading behavior. To further test the hypothesis that rostral shell muscimol microinjections produce positive motivational states, whereas caudal shell muscimol produces negative states, we measured behavioral place preference/avoidance conditioning and affective hedonic and aversive orofacial expressions of taste-elicited "liking" and "disliking" (gapes, etc.) in addition to fear and feeding behaviors. Farthest rostral muscimol microinjections (75 ng) caused increased eating behavior and also caused positive conditioned place preferences and increased positive hedonic reactions to the taste of sucrose. By contrast, caudal shell microinjections elicited negative defensive treading and caused robust negative conditioned place avoidance and negative aversive reactions to sucrose or quinine tastes. Intermediate rostral microinjections elicited effects of mixed positive/negative valence (positive appetitive eating behavior but negative place avoidance and negative taste reactions at mid-rostral sites, and sometimes positive eating simultaneously with fearful defensive treading more caudally). These results indicate that GABAergic neurotransmission in local microcircuits in nucleus accumbens mediates motivated/affective behavior that is bivalently organized along rostrocaudal gradients.

Animals↗
PubMed1999

GABAA receptor agonists modulate K+ currents in adult hippocampal glial cells in situ.

Glial cells are known for their role in development and expression of GABA receptors. However, there seems to be a lack of in situ studies characterizing GABA receptor expression and function in glial cells from early development to adulthood. Consequently, we examined GABA receptor expression on rat hippocampal glial cells in both neonatal and adult slices using the whole-cell patch-clamp technique. Glial cells in adult and neonatal slices exhibit responses to muscimol (1 mM; GABAA), but not baclofen (1 mM; GABAB), demonstrating that receptor electrophysiology remains qualitatively similar in glial cells throughout development. Adult muscimol current densities however, do show a decrease in size to approximately 36% of the neonatal response. Muscimol responses were found to be sensitive to bicuculline, suggesting that they are mediated by GABAA receptors. In addition to receptor currents, muscimol causes a concomitant long-term blockade of outward K+ currents in glial cells of both neonatal and adult slices. Comparisons of percentage peak blockade in adult and neonatal glial cells show no significant difference. However, when comparing average absolute conductance blockade, we see that adult glial cells display a significantly smaller response than neonatal and cultured astrocytes. Therefore, although the percentage blockade of outward currents remains consistent throughout development, neonatal glial cells display a larger physiological effect. Thus, it can be concluded that, although the complex GABA response in glial cells is affected by development, the receptor current and secondary blockade are a basic mechanism for neuronal-glial interaction throughout life.

Aging↗
PubMed2000

Effects of superior colliculus inhibition on visual motion processing in the lateral suprasylvian visual area of the cat.

PURPOSE: To clarify whether visual inputs of the tectothalamocortical pathway influence motion processing within the lateral suprasylvian (LS) area of the cat. METHODS: This study was conducted in five cats. Tungsten microelectrodes were used for recording visual evoked potentials. The electrodes were introduced into the LS area. An array of 120 randomly located dots was projected onto the stimulus field (40 degrees x 40 degrees) in front of the animal by a slide projector. The dots were moved rightward and leftward alternatively with interstimulus intervals by a mirror attached to a galvanometer, the movements of which were controlled by a microcomputer. Each motion sequence consisted of an abrupt onset of motion that continued for 100 msec followed by an abrupt offset and a stationary phase of 900 msec; the total duration of each sequence was thus 1000 msec. The velocity of the motion was varied in 12 steps. The onset of motion was used as the trigger for recording evoked potentials. Single or multiple injections (two to three) of muscimol were made, mainly into the rostral superior colliculus (SC). The amplitudes of evoked potentials before and after the muscimol injection were compared. RESULTS: A large negative wave (N1) with the peak latency of 89.80+/-16.39 msec (mean +/- SD, n = 191) was recorded consistently. The amplitude of N1 was not altered by the muscimol injection into the SC when the velocity of motion was 50 deg/sec or less. When the velocity of motion was 75 deg/sec or more, however, the amplitude of N1 was reduced to 62% to 72% of that noted before the muscimol injection. CONCLUSIONS: These findings suggest that the LS area processes the visual motion inputs reaching through the two parallel pathways, the geniculostriate pathway and the tectothalamocortical pathway, when the velocity of visual motion is 75 deg/sec or more.

Animals↗
PubMed2001

Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction.

Recent studies implicate the hippocampus in contextual memory retrieval. The present experiments explore this possibility by examining the impact of reversible inactivation of the dorsal hippocampus (DH) on the context-specific expression of extinction. In experiment 1, rats were conditioned to fear a tone conditional stimulus (CS) and subsequently extinguished either in the same context as conditioning or in a novel context. A third group of rats underwent fear conditioning but did not receive extinction. After extinction, conditional fear to the tone CS was assessed in the conditioning context by measuring freezing. Rats extinguished in the conditioning context exhibited low levels of freezing, whereas those extinguished in a different context and those that received no extinction showed high levels of freezing. This indicates that the expression of extinction is context-specific. In experiment 2, the context-specific expression of extinction was disrupted by infusion of muscimol, a GABA(A) receptor agonist, into the DH. Rats that received muscimol infusions into the DH showed little freezing to the tone CS, regardless of whether the CS had been extinguished in the testing context or another context. In experiment 3, intrahippocampal muscimol infusions did not disrupt the expression of conditional freezing to the tone CS in rats that did not receive extinction. Thus, muscimol infusion into the DH produced a selective impairment in the context-specific expression of extinction. These results extend findings from other behavioral paradigms and provide additional support for a role for the hippocampus in contextual memory retrieval.

Acoustic Stimulation↗
PubMed1991

cAMP analogs inhibit gamma-aminobutyric acid-gated chloride flux and activate protein kinase A in brain synaptoneurosomes.

The effects of permeant cAMP analogs were studied on the function of the gamma-aminobutyric acidA (GABAA) receptor and on the activation of protein kinase A in brain synaptoneurosomes. Incubation of cerebral cortical synaptoneurosomes with permeant cAMP analogs decreased muscimol-induced 36Cl- uptake in a concentration-dependent manner. The order of potency was chlorophenylthio-cAMP (CPT-cAMP) greater than dibutyryl-cAMP greater than 8-bromo-cAMP. This order of potency was reflected by the ability of the analogs to gain access to the intravesicular compartment. cAMP, which failed to penetrate the membrane, had no effect. The half-maximal and maximal effects of the cAMP analogs were similar in the cerebral cortex, hippocampus, striatum, and cerebellum. To determine whether the cAMP analogs were acting through the activation of protein kinase A, protein kinase A activity was measured in lysed synaptoneurosomes, using kemptide as the substrate. In the lysed preparation, where the cAMP analogs have direct access to intracellular enzymes, the order of potencies of the cAMP analogs to activate protein kinase A (8-bromo-cAMP greater than CPT-cAMP greater than dibutyryl-cAMP) differed from the order of potencies to inhibit muscimol-induced 36Cl- uptake. In regional studies, the greatest effect of CPT-cAMP was observed in the cortex, whereas the smallest effect was observed in the hippocampus and cerebellum. To determine whether cAMP inhibition of GABA-gated ion flux was due to activation of protein kinase A, the time course for each response was measured. Inhibition of muscimol-induced 36Cl- uptake by cAMP analogs was nearly complete by 5 sec. Significant activation of protein kinase A by CPT-cAMP was also observed as early as 5 sec, but protein kinase A activation continued up to 10 min. The protein kinase inhibitor peptide inhibited protein kinase A activity in lysed synaptoneurosomes but had no effect on ion flux in intact synaptoneurosomes, as expected. However, a permeant kinase inhibitor, H-8, also failed to inhibit the effect of cAMP analogs on the muscimol response, yet it inhibited protein kinase A activity. The failure of H-8 to inhibit cAMP analog effects on GABAA receptor function was most likely due to the presence of ATP inside the synaptoneurosomes, because H-8 inhibition of protein kinase A was reduced in the presence of ATP. These results indicate that cAMP and cAMP analogs must penetrate the intravesicular compartment to inhibit GABAA receptor function. Although cAMP analogs decrease GABA-gated ion flux under conditions in which they activate protein kinase A, a causal relationship remains to be established.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1990

Comparison of contractile responses of the guinea pig ileum longitudinal muscle to ethanol and GABAA agonists.

The guinea pig ileum myenteric plexus contains GABAA receptors linked to chloride ion channels which are pharmacologically similar to those in the central nervous system. The present study examined the reported ability of acute ethanol treatment to directly activate GABAA receptors or to increase GABAA agonist-mediated activation of the GABAA receptor in the myenteric plexus. Direct addition of ethanol to preparations of the guinea pig ileum longitudinal muscle had two effects. Immediately after ethanol (10-300 mM) was added to the tissue bath a concentration-related contractile response was observed which became maximal within 10 sec and then decayed over the next 60 sec. Contractile responses to higher concentrations of ethanol (greater than 100 mM) also were followed by a sustained reduction of longitudinal muscle tone. Contractions evoked by gamma-aminobutyric acid (GABA) and GABAA agonists, 3-aminopropane sulfonic acid (APSA) (3-100 microM) or muscimol (0.3-30 microM) developed maximally and decayed within 20 sec. Acetylcholine (0.01-10 microM) induced contractions were sustained over several minutes. Preincubation of tissue strips in ethanol (30 mM) for 1 min did not alter concentration relationships for GABA, muscimol or APSA contractile responses. Furthermore, addition of ethanol (10-100 mM) simultaneously with APSA, or 0.5, 2 or 5 min before the addition of APSA, also failed to consistently enhance contractile responses. Ethanol (30 mM) also did not alter desensitization-induced reductions in contractile responses to muscimol (3 microM) caused by preincubation of tissues with muscimol (1 microM). Finally, contractile responses to ethanol and APSA were completely blocked by atropine (0.1 microM) and tetrodotoxin (0.1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Binding interactions of convulsant and anticonvulsant gamma-butyrolactones and gamma-thiobutyrolactones with the picrotoxin receptor.

Alkyl-substituted gamma-butyrolactones (GBLs) and gamma-thiobutyrolactones (TBLs) are neuroactive chemicals. beta-Substituted compounds are convulsant, whereas alpha-alkyl substituted GBLs and TBLs are anticonvulsant. The structural similarities between beta-alkyl GBLs and the convulsant picrotoxinin suggested that alkyl substituted GBLs and TBLs act at the picrotoxin receptor. To test this hypothesis we examined the interactions of convulsant and anticonvulsant GBLs and TBLs with the picrotoxin, benzodiazepine and gamma-aminobutyric acid (GABA) binding sites of the GABA receptor complex. All of these convulsants and anticonvulsants studied competitively displaced 35S-t-butylbicyclophosphorothionate (35S-TBPS), a ligand that binds to the picrotoxin receptor. This inhibition of 35S-TBPS binding was not blocked by the GABA antagonist bicuculline methobromide. The convulsant GBLs and TBLs also partially inhibited [3H]muscimol binding to the GABA site and [3H]flunitrazepam binding to the benzodiazepine site, but they did so at concentrations substantially greater than those that inhibited 35S-TBPS binding. The anticonvulsant GBLs and TBLs had no effect on either [3H]muscimol or [3H]flunitrazepam binding. In contrast to the GBLs and TBLs, pentobarbital inhibited TBPS binding in a manner that was blocked by bicuculline methobromide, and it enhanced both [3H]flunitrazepam and [3H]muscimol binding. Both ethosuximide and tetramethylsuccinimide, neuroactive compounds structurally similar to GBLs, competitively displaced 35S-TBPS from the picrotoxin receptor and both compounds were weak inhibitors of [3H] muscimol binding. In addition, ethosuximide also partially diminished [3H]flunitrazepam binding. These data demonstrate that the site of action of alkyl-substituted GBLs and TBLs is different from that of GABA, barbiturates and benzodiazepines. We suggest that the GBLs and TBLs act at the picrotoxin receptor.

4-Butyrolactone↗
PubMed1988

Chronic ethanol administration alters gamma-aminobutyric acid, pentobarbital and ethanol-mediated 36Cl- uptake in cerebral cortical synaptoneurosomes.

The effect of chronic ethanol exposure on the function of the gamma-aminobutyric acid (GABA) receptor-coupled chloride ion channel was studied in synaptoneurosomes from rat cerebral cortex. Ethanol was administered to rats by inhalation resulting in high blood ethanol levels which have previously been shown to produce tolerance and dependence. After 14 days of ethanol exposure, the stimulation (apparent Vmax) of 36Cl- uptake by the GABA agonist muscimol was decreased by approximately 26%. Similarly, stimulation of 36Cl- uptake by the barbiturate pentobarbital was also reduced to the same extent and there was an increase in the apparent EC50 concentration. Direct stimulation of 36Cl- uptake by ethanol was unchanged after chronic ethanol exposure when measured in the same membrane preparations in which a decrease in muscimol and pentobarbital-stimulated 36Cl- uptake were observed. However, ethanol's ability to potentiate muscimol-stimulated 36Cl- uptake was abolished completely in synaptoneurosomes from ethanol-treated rats. The decrease in GABA receptor-coupled chloride ion channel function observed after chronic ethanol administration was observed only in animals where the mean blood ethanol concentration was greater than or equal to 150 mg%. These blood levels have previously been shown to be associated with ethanol withdrawal after ethanol discontinuation in this rat strain. Four days after ethanol administration, after all signs of ethanol withdrawal had subsided, the decrease in muscimol and pentobarbital-stimulated 36Cl- uptake was reversed. These data suggest that subsensitivity of the GABA receptor-coupled chloride ion channel after chronic ethanol administration may contribute to ethanol tolerance and the ethanol withdrawal syndrome.

Administration, Inhalation↗
PubMed1988

Dopaminergic and indoleamine-accumulating amacrine cells express GABA-like immunoreactivity in the cat retina.

Colocalization of indoleamine uptake and GABA-like immunoreactivity was studied in the cat retina. Consecutive, semithin sections were incubated in antisera to either 5-HT (5-hydroxytryptamine) or GABA. More than 90% of all 5-HT-accumulating amacrine cells expressed GABA-like antigens. With the same approach, the colocalization of 5-HT uptake and GABA-like immunoreactivity was studied in rabbit and 75-80% of the 5-HT-accumulating amacrine cells expressed GABA-like immunoreactivity, thus confirming a previous study (Osborne and Beaton, 1986). Since, in both cat and rabbit, endogenous 5-HT could not be found by immunocytochemistry, one must consider the possibility that some GABAergic amacrine cells take up indoleamines. In the cat retina, antibodies against tyrosine hydroxylase (TH) label dopaminergic amacrine cells (Oyster et al., 1985). By incubating consecutive, semithin sections in antisera to either TH or GABA, it was found that 84% of the dopaminergic amacrine cells also expressed GABA-like immunoreactivity. GABA-like immunoreactivity and 3H-muscimol uptake were found to be colocalized in more than 90% of the amacrine cells labeled. However, dopaminergic amacrine cells did not accumulate 3H-muscimol. Evidence is presented from colocalization studies for 2 types of interplexiform cell in the cat retina. One is stained by GABA-like immunocytochemistry and by 3H-muscimol uptake. The other is the dopaminergic amacrine cell, which also expresses GABA-like immunoreactivity, but does not accumulate 3H-muscimol.

Animals↗
PubMed1986

[2 types of GABA receptors in the intact olfactory bulb and primordial hippocampus of the frog: the pharmacological data].

The in vivo effects of (+/-) baclofen (10(-6)-10(-4) M), muscimol (10(-5)-10(-4) M), and (+) bicuculline (10(-4)-10(-3) M) applications on evoked potentials in the olfactory bulb (OB) and primordial hippoccamp (PH) were studied in frogs. Baclofen was found to decrease drastically postsynaptic components of OB orthodromic potential and to slightly increase OB antidromic potential. Muscimol decreased only the second component of OB orthodromic potential and OB antidromic potential. Baclofen and muscimol decreased all the components of PH orthodromic potential, but for the first positive one. All the effects were reversible and dose-dependent. Bicuculline antagonized muscimol effects, without affecting baclofen effects in both structures under study. The results suggest the presence of two types of GABA-receptors in OB and PH of frogs. GAGAB-receptors are shown to be located on the primary olfactory afferents and to be responsible for presynaptic inhibition in OB.

Animals↗
PubMedDate not supplied

Diazepam enhances fentanyl and diminishes meperidine antinociception.

A rabbit tooth pulp antinociceptive model was used to investigate the effect of prior administration of diazepam or muscimol on the potency and duration of fentanyl and meperidine Potency experiments compared ED(50) values in all-or-none dose-response assays between both muscimol (0.25 mg/kg) and saline, and diazepam (1.5 mg/kg) and propylene glycol vehicle. An all-or-none effect was defined as doubling of voltage threshold to elicit a lick/chew evoked response. Duration experiments compared time (minutes) to 50% maximum possible effect (MPE) of an ED(90) dose of fentanyl (0.04 mg/kg) and to 50% and 20% MPE of an ED(98) dose of meperidine (17 mg/kg) 10 minutes after pretreatment with diazepam (1.5 mg/kg). Prior (10 minutes) injection of diazepam (1.5 mg/kg) increased the ED(50) value for meperidine (3.06 mg/kg) compared with its control (1.48 mg/kg), indicating a decrease in antinociceptive potency. The same dose of diazepam decreased the ED(50) value for fentanyl (1.1 μg/kg) compared with its control (13.1 μg/kg), indicating an increase in antinociceptive potency. Muscimol also had a similar effect on fentanyl (ED(50), 1.8 μg/kg) compared with saline control (ED(50), 13.8 μg/kg). Diazepam, vehicle, and muscimol by themselves had no effect on voltage thresholds to elicit a lick/chew response. Time to 50% MPE for diazepam-fentanyl was 38 minutes vs. 25 minutes for vehicle-fetanyl; time to 20% MPE for diazepam-meperidine was 38 minutes vs. 54 minutes for vehicle-meperidine (maximum percentage of MPE produced by diazepam-meperidine was 40% compared with 100% MPE for vehicle-meperidine). Percentages of MPE for diazepam-meperidine were significantly lower than those for vehicle-meperidine at all time intervals, whereas percentages of MPE for diazepam-fentanyl were significantly greater than those for vehicle-fentanyl over time.

Animals↗
PubMed1985

gamma-Aminobutyric acid- and benzodiazepine-induced modulation of [35S]-t-butylbicyclophosphorothionate binding to cerebellar granule cells.

t-Butylbicyclophosphorothionate (TBPS) is a bicyclophosphate derivative with potent picrotoxin-like convulsant activity that binds with high affinity and specificity to a Cl- channel-modulatory site of the gamma-aminobutyric acid (GABA)/benzodiazepine receptor complex. Using intact cerebellar granule cells maintained in primary culture, we have studied the modifications induced by GABA and diazepam on the ion channel-modulatory binding site labeled by [35S]TBPS. At 25 degrees C, and in a modified Locke solution, the [35S]TBPS specific binding, determined by displacing the radioligand with an excess (10(-4) M) of picrotoxin, was approximately 70% of the total radioactivity bound to the cells. [35S]TBPS specific binding was saturable with a Kd of approximately 100 nM, a Bmax of approximately 440 fmol/mg of protein, and a Hill coefficient of 1.18. Neither cerebellar astrocytes maintained in culture for 2 weeks nor a neuroblastoma cell line (NB-2A) exhibited any specific [35S]TBPS binding. Muscimol (0.3 to 5 microM) enhanced and bicuculline (0.1 to 5 microM) inhibited [35S]TBPS specific binding to intact cerebellar granule cells. The effect of muscimol and bicuculline on [35S]TBPS binding was noncompetitive. Muscimol (0.1 to 5 microM) reversed bicuculline inhibition in a dose-dependent fashion but failed to reverse picrotoxin-induced inhibition. [35S]TBPS binding was also modulated by benzodiazepine receptor ligands. The binding was increased by diazepam and decreased by 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid methylester. Muscimol (0.05 microM) failed to reverse bicuculline inhibition in the absence of diazepam, but it became effective in the presence of 0.1 to 1 microM diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Characterization of susceptibility to audiogenic seizures in ethanol-dependent rats after microinjection of gamma-aminobutyric acid (GABA) agonists into the inferior colliculus, substantia nigra or medial septum.

The relative anticonvulsant potential of the gamma-aminobutyric acid (GABA) agonist, muscimol, was compared after microinjection into either the inferior colliculus, substantia nigra or medial septum of ethanol-dependent rats. Bilateral microinjection of muscimol (10-30 ng) into the inferior colliculus 15 to 60 min before testing suppressed all sound-induced seizure components (wild running, clonus and tonus) in rats withdrawn from ethanol for 6.5 to 8.5 hr. However, forelimb tremors were not altered. Audiogenic seizures were suppressed for at least 3 hr after muscimol (30 ng). In the medial septum and substantia nigra, microinjection of muscimol (30-100 ng) only partially reduced the tonic component of audiogenic seizures and exerted no effect on the frequency of wild running or clonus. GABA (10 micrograms) and two other GABA agonists [4,5,6,7-tetrahydroisoxazolo[5, 40c]pyridin-3-ol (THIP), 300 ng and chlordiazepoxide, 10-30 micrograms], microinjected into the inferior colliculus, also reduced audiogenic seizure susceptibility. However, 1, 3-butanediol, which suppresses ethanol withdrawal seizures after peripheral administration in rats, was inactive. The relative proconvulsant potential of the GABA antagonist, bicuculline methiodide, also was compared after microinjection into either the inferior colliculus, substantia nigra or medial septum of ethanol naive rats. In each animal, audiogenic seizure-like wild running, clonus and tonus were evoked by microinjecting bicuculline methiodide into the inferior colliculus at the rate of 6.0 ng/6 min. However, these reactions did not occur when bicuculline methiodide was applied at a slower rate (1.8 ng/6 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗
PubMed1984

Evidence implicating substantia nigra in regulation of kindled seizure threshold.

We studied the effects of microinjected drugs and brainstem lesions on motor and limbic seizures in the kindling model of epilepsy. The duration of motor seizures was determined by timing the colonic and tonic movements of the extremities. The duration of limbic seizures was determined by measuring afterdischarge recorded on the electroencephalogram. Bilateral microinjection of a gamma-aminobutyric acid (GABA) agonist, muscimol, into the area of the substantia nigra (SN) markedly suppressed both motor and limbic seizures induced by stimulation of amygdala, olfactory structures, or lateral entorhinal cortex. Microinjection of saline did not suppress seizures. The suppressive effect of muscimol: (i) dissipated after several hours and was dependent on dose; (ii) was due to an elevation of the seizure threshold, since typical seizures could be elicited with electrical current far exceeding the threshold; and (iii) exhibited spatial specificity since muscimol injections 1 to 2 mm dorsal to the SN or into neocortex did not suppress the seizures. The actions of muscimol were probably mediated by its GABA agonist properties, since microinjection of an irreversible inhibitor of GABA transaminase (gamma-vinyl GABA) into the area of the SN also suppressed kindled seizures. Destruction of brainstem structures was produced by microinjection of the neurotoxin, N-methyl-D,L-aspartate. Seizures were markedly suppressed in animals with bilateral destruction of the SN but not in animals in which the SN was spared bilaterally. We interpret the data to indicate that the SN is the site at which the GABA agonists and lesions act to raise the threshold for kindled seizures. The suppression of limbic seizures indicates that this brainstem nucleus can regulate the intrinsic neuronal excitability of hemispheric sites.

Aminocaproates↗
PubMed1995

Regulation of allosteric coupling and function of stably expressed gamma-aminobutyric acid (GABA)A receptors by chronic treatment with GABAA and benzodiazepine agonists.

Chronic treatments with drugs that stimulate or potentiate gamma-aminobutyric acid (GABA)A receptor function cause uncoupling of allosteric sites and downregulation of the GABAA receptors expressed in neurons. To study these effects on receptors having a defined subunit composition, we treated stably transfected mouse Ltk- cells (PA3 cells) with drugs known to uncouple GABAA receptors. Because dexamethasone controls the expression of bovine alpha-1, beta-1 and gamma 2L GABAA receptor subunit genes in PA3 cells, this expression system provides a way to study receptors in the absence of neuronal subunit gene promoters. We assayed binding of [3H]flunitrazepam to measure allosteric coupling and uptake of 36Cl- to measure GABAA receptor function. Chronic (4 day) treatment of PA3 cells with muscimol, GABA or flunitrazepam reduced the GABA enhancement of binding of [3H]flunitrazepam to PA3 cells. Chronic flurazepam or muscimol treatments also caused downregulation of benzodiazepine potentiation of muscimol-stimulated 36Cl- uptake. Chronic treatment with muscimol did not affect levels of subunit mRNAS and alpha 1- or beta 1-subunit protein of GABAA receptors and chronic flunitrazepam did not affect subunit mRNAs or alpha 1 protein. We conclude that chronic drug treatments regulate allosteric coupling and function of GABAA receptors in stably transfected cells and this regulation cannot be attributed to decreases in the expression of receptor subunits or to expression of subunits other than alpha 1 beta 1 or gamma 2L.

Allosteric Regulation↗