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PubMed1985

Differential modulation of gamma-aminobutyric acid receptors by caprolactam derivatives with central nervous system depressant or convulsant activity.

The effects of a series of caprolactam derivatives with central depressant, convulsant or muscle relaxant activity were investigated upon gamma-aminobutyric acid (GABA) receptor-ionophore binding to rat brain membranes using [3H]GABA, [3H]GABA, [3H]muscimol and [35S]-tert.-butylbicyclophophorothionate ([35S]TBPS) as ligands, and GABA responses in mouse spinal cord neurones in dissociated cell culture. Some caprolactams produced a picrotoxin-like chloride-dependent partial inhibition of muscimol binding and were potent inhibitors of TBPS binding. One compound that was further investigated (4,4,6,6-tetramethylhexahydro-2H-azepin-2-one), inhibited GABA responses and increased the frequency of paroxysmal depolarizations in cultured neurones. Other caprolactams enhanced muscimol binding and were relatively weak inhibitors of TBPS binding, and one (3,3-diallyl-6,6-dimethylhexahydro-2H-azepin-2,4-dione) was shown to enhance GABA responses and produced quiescence of activity in cultured neurones. There was a direct correlation between caprolactam effects on muscimol binding in the presence of chloride ions and their effects on TBPS binding suggesting a similar site of action for the caprolactams influencing the binding of these two ligands. For the two classes of caprolactams, with respect to inhibition or enhancement of muscimol binding, there appeared to be a relationship between in vitro effects and their convulsant or depressant activity in mice. Caprolactams may be useful low molecular weight probes for the study of GABA receptor-ionophore complexes.

Animals↗
PubMed1986

Differential effects of striatal injections of dopaminergic, cholinergic and GABAergic drugs upon swimming behavior of rats.

The present study provides a detailed report about similarities and dissimilarities between the effects of neostriatally applied dopaminergic (apomorphine, 250-300 ng; haloperidol, 250-500 ng), cholinergic (carbachol, 50-100 ng; scopolamine, 200-500 ng), and GABAergic (muscimol, 1-2 ng; bicuculline, 5-35 ng) drugs upon swimming of rats. The used swimming test consisted of 4 parts: (a) open-field test for analyzing drug-induced changes in normal behavior; (b) 'swimming without escape' test for analyzing drug-induced changes in the ability to switch from one type of behavior to another; (c) 'swimming with escape' test for analyzing drug-induced changes in the ability to switch from ongoing swimming behavior to climbing behavior by allowing the rats to escape via a rope; and (d) 'rope' test for analyzing drug-induced changes in the kind of contact behaviors needed to switch to the latter climbing behavior. In the open-field test the drugs produced neither abnormal behavior nor motor disturbances, which prevented the display of normal behavior in the remaining tests. Both apomorphine and carbachol produced identical effects in all tests. Muscimol produced overall effects which were not only opposite to those of apomorphine and carbachol, but also comparable to those of scopolamine. All effects elicited by apomorphine, carbachol and muscimol were antagonized by their corresponding antagonists: haloperidol, scopolamine and bicuculline respectively, whereas the effects of the latter were suppressed by their corresponding agonists. These data globally show that dopamine and acetylcholine act in the same direction but opposite to that of GABA as far as it concerns the regions investigated. The finding that haloperidol injected into the GABA target area produced effects which were not only similar to those of haloperidol injected into the dopamine target area, but also dissimilar to those of muscimol and bicuculline injected into the GABA target area, shows that the effects were drug-specific rather than region-specific. Though 3 distinct cholinergic regions were investigated, cholinergic-specific effects could only be elicited from one region, suggesting that the neostriatum is heterogeneous in this respect. Finally, well-delineated dissimilarities between haloperidol-, scopolamine-, and muscimol-treated rats were found in the rope test. These data show that behavior-relevant information transmitted by GABAergic drugs surmounted that transmitted by cholinergic drugs which, in turn, surmounted behavior-relevant information transmitted by dopaminergic drugs.

Acetylcholine↗
PubMed1992

Inhibition of baroreflex bradycardia by ethanol involves both GABAA and GABAB receptors in the brainstem of the rat.

The effects of ethanol on baroreceptor reflex bradycardia and its interactions with cardiovascular effects mediated by GABA receptors in the dorsal vagal complex were studied in urethane-anaesthetised rats. Ethanol, 1 g kg-1 administered i.v. or 25-200 nmol microinjected bilaterally into the dorsal vagal complex, inhibited the reflex bradycardic response to bolus i.v. doses of phenylephrine both in spontaneously breathing and in paralysed, artificially ventilated animals, and this effect could be prevented by pretreatment with the GABA-depleting agent, 3-mercaptopropionate in both groups of rats. Ethanol, 1 g kg-1 i.v., did not influence the bradycardic response to electrical stimulation of the cervical vagus. Microinjection of muscimol into the dorsal vagal complex caused a dose-dependent pressor response and inhibited baroreflex bradycardia. The pressor response was potentiated and a tachycardic response to muscimol emerged following microinjection of ethanol into the dorsal vagal complex. Similar administration of baclofen caused dose-dependent increases in blood pressure and heart rate and inhibited baroreflex bradycardia. Injection of ethanol into the dorsal vagal complex potentiated the pressor response to a low dose of baclofen but did not affect the tachycardic response. Bicuculline, 10 pmol/side into the dorsal vagal complex, blocked the effects of muscimol but not those of baclofen and reduced the baroreflex inhibitory action of ethanol. 2-Hydroxysaclofen, microinjected at 400 pmol to 1 nmol/side, blocked the effects of baclofen but not those of muscimol. 2-Hydroxysaclofen or phaclofen, 2 mg kg-1 s.c., prevented the baroreflex inhibitory action of ethanol and also prevented ethanol potentiation of the pressor and, less effectively, the tachycardic effects of muscimol. It is concluded that ethanol inhibits baroreflex bradycardia through potentiation of the actions of endogenous GABA in the dorsal vagal complex. Both GABAA and GABAB receptors appear to be involved in this action of ethanol.

3-Mercaptopropionic Acid↗
PubMed1987

Characterization of GABAA receptor-mediated 36chloride uptake in rat brain synaptoneurosomes.

gamma-Aminobutyric acid (GABA) receptor-mediated 36chloride (36Cl-) uptake was measured in synaptoneurosomes from rat brain. GABA and GABA agonists stimulated 36Cl- uptake in a concentration-dependent manner with the following order of potency: Muscimol greater than GABA greater than piperidine-4-sulfonic acid (P4S)greater than 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP) = 3-aminopropanesulfonic acid (3APS) much greater than taurine. Both P4S and 3APS behaved as partial agonists, while the GABAB agonist, baclofen, was ineffective. The response to muscimol was inhibited by bicuculline and picrotoxin in a mixed competitive/non-competitive manner. Other inhibitors of GABA receptor-opened channels or non-neuronal anion channels such as penicillin, picrate, furosemide and disulfonic acid stilbenes also inhibited the response to muscimol. A regional variation in muscimol-stimulated 36Cl- uptake was observed; the largest responses were observed in the cerebral cortex, cerebellum and hippocampus, moderate responses were obtained in the striatum and hypothalamus and the smallest response was observed in the pons-medulla. GABA receptor-mediated 36Cl- uptake was also dependent on the anion present in the media. The muscimol response varied in media containing the following anions: Br- greater than Cl- greater than or equal to NO3- greater than I- greater than or equal to SCN- much greater than C3H5OO- greater than or equal to ClO4- greater than F-, consistent with the relative anion permeability through GABA receptor-gated anion channels and the enhancement of convulsant binding to the GABA receptor-gated Cl- channel.

Animals↗
PubMed2006

Progestins' effects on sexual behaviour of female rats and hamsters involving D1 and GABA(A) receptors in the ventral tegmental area may be G-protein-dependent.

In the ventral tegmental area (VTA), progestins have actions involving dopamine type 1-like receptors (D(1)) and gamma-aminobutyric acid (GABA)(A)/benzodiazepine receptor complexes (GBRs) for lordosis. Evidence suggests that D(1) and GBRs can have G-protein-mediated effects. We investigated if, in the VTA, inhibiting G-proteins prevents D(1)- and/or GBR-mediated increases in progestin-facilitated lordosis. Hamsters, with bilateral guide cannulae to the VTA, received systemic E(2) (10 microg) at hour 0 and progesterone (P, 250 microg) at hour 45. At hour 48, hamsters were pre-tested for lordosis and infused with the G-protein inhibitor, guanosine 5'-O-(2-thiodiphosphate) (GDP-beta-S, 50 microM/side), or 10% DMSO saline vehicle. Thirty minutes after initial infusions, hamsters were re-tested and then immediately infused with the D(1) agonist, SKF38393 (100 ng/side), the GBR agonist, muscimol (100 ng/side), or saline vehicle. Hamsters were post-tested for lordosis 30 min later. For rats, E(2) (10 microg) priming at hour 0 was followed by lordosis pre-testing at hour 44. After pre-testing, rats received infusions of GDP-beta-S or vehicle, followed by infusions of SKF38393, muscimol, or vehicle and then infusions of the neurosteroid, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP, 100 or 200 ng/side), or beta-cyclodextrin vehicle. Rats were tested immediately after each infusion of SKF38393, muscimol or vehicle, as well as 10 and 60 min after 3alpha,5alpha-THP or vehicle infusions. Inhibiting G-proteins, in the VTA, reduced the ability of systemic P or intra-VTA SKF38393 or muscimol to facilitate lordosis of E(2)-primed hamsters. Blocking G-proteins, in the VTA, prevented SKF38393-, muscimol- and/or 3alpha,5alpha-THP-mediated increases in lordosis of E(2)-primed rats. Thus, progestins' actions in the VTA for lordosis that involve D(1) and/or GBRs may also include recruitment of G-proteins.

Analysis of Variance↗
PubMed2006

Co-modulation of acute ethanol-induced motor impairment by mouse cerebellar adenosinergic A1 and GABA(A) receptor systems.

We have previously demonstrated that cerebellar adenosine modulates ethanol ataxia. Using Rotorod method, we investigated the role of cerebellar GABA(A) receptors in the adenosinergic modulation of ethanol ataxia in mice. Direct cerebellar microinfusion of GABA(A) agonist, muscimol (2.5, 5 and 10 ng) and antagonist, bicuculline (50, 100 and 200 ng), via permanently implanted guide cannulas, produced a marked and dose-dependent accentuation and attenuation, respectively, of ethanol (2g/kg; IP) ataxia. The accentuation of ethanol ataxia by intracerebellar muscimol was through GABA(A) receptor because intracerebellar pretreatment with bicuculline virtually abolished muscimol effect. Intracerebellar microinfusion of adenosine A(1) agonist, N(6)-cyclohexyladenosine (CHA: 4 ng), and antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX: 100 ng) markedly accentuated and attenuated, respectively, ethanol ataxia consistent with our previously published data. Intracerebellar microinfusion of CHA (4 ng) or DPCPX (100 ng) markedly enhanced and reduced, respectively, muscimol (10 ng)-induced accentuation of ethanol ataxia suggesting co-modulation of ethanol ataxia by cerebellar adenosinergic A(1) and GABA(A) receptors. Similarly, intracerebellar bicuculline (200 ng) pretreatment not only prevented CHA-induced accentuation of ethanol ataxia, but caused further decrease in ethanol ataxia. No change in the normal coordination was observed when microinfusion of the highest dose of muscimol, bicuculline, DPCPX or CHA alone or in combination was followed by saline injection instead of ethanol. The results of the present study suggest a functional similarity between GABA(A) and adenosine A(1) receptors even though both receptor types are known to couple to different signaling system and their location is on the opposite ends of the cerebellar granule cells, axons and axonal terminals (i.e., GABA(A) at the granule cells and adenosine A(1) on axons and axonal terminals of the granule cells) and act as co-modulators of ethanol ataxia.

Acute Disease↗
PubMed2003

Excitatory actions of GABA in developing brain are mediated by l-type Ca2+ channels and dependent on age, sex, and brain region.

Although GABA is the major inhibitory neurotransmitter in adult brain, it exerts depolarizing actions in developing neurons that include activation of voltage-gated calcium channels. The depolarizing actions of GABA serve an obvious trophic function, but the specific physiological significance of excitatory versus inhibitory GABA action has been largely ignored. We previously demonstrated that estradiol enhances the magnitude and duration of calcium influx through L-type voltage-gated calcium channels following GABA(A) receptor activation in neonatal hypothalamic neurons. This has led us to propose that GABA action represents a major divergence point in steroid-mediated sexual differentiation of rat brain. Presently, we examined sex differences in phosphorylation of the calcium-regulated transcription factor, cyclic AMP response element binding protein, following activation of the GABA(A) receptor with muscimol, in vivo. Muscimol given 30 min before killing significantly increased the number of neurons exhibiting phosphorylated cyclic AMP response element binding protein in newborn male hypothalamus and CA1 hippocampus but decreased phosphorylated cyclic AMP response element binding protein in most brain regions in females. Muscimol-induced increases in phosphorylated cyclic AMP response element binding protein in hypothalamus and hippocampus of newborn males were attenuated by pretreatment with the L-type voltage-gated calcium channel blocker, nimodipine, suggesting that calcium influx is involved in phosphorylation of cyclic AMP response element binding protein in neonate brain. Muscimol treatment had no effect on hypothalamic or hippocampal phosphorylated cyclic AMP response element binding protein levels in juvenile males and females. These results are consistent with a divergence in male and female rat brain in the calcium-mediated cellular response to muscimol that is restricted to the early neonatal period, a time critical for estradiol-mediated sexual differentiation.

Age Factors↗
PubMedDate not supplied

Distribution of GABA(C)-like responses among acutely dissociated rat retinal neurons.

GABAergic responses of acutely dissociated rat retinal neurons, including both bipolar cells (BCs) and other, morphologically round cells (RCs), were assayed with the fluorescent (FL), voltage-sensitive probe oxonol DiBaC4(5). Using intensified video microscopy and simultaneous recording, GABA responses were identified in one-third of cells in a typical microscope field; of these 85% hyperpolarized (0.05-0.3 log unit FL decreases) while the remainder depolarized (0.05-0.2 log unit FL increases). GABA-sensitive cells were also TACA-sensitive (trans-4-Aminocrotonic acid), and these ligands appeared interchangeable in ability to evoke responses. In RCs, an asymmetric co-responsive pattern was observed between GABA- and muscimol-evoked events. Muscimol-sensitive RCs responded well to GABA, but not all GABA-sensitive RCs responded to muscimol. In GABA-sensitive BCs, muscimol responses were typically weak or absent. Few BCs or RCs responded to CACA (cis-4-Aminocrotonic acid). Bicuculline-resistant GABA responses occurred in approximately 80% of GABA-responsive RCs and BCs. Both bicuculline-sensitive (GABA(A)-like) and bicuculline-insensitive (GABAc-like) responses were resistant to picrotoxin. Although a small minority of GABA-sensitive cells hyperpolarized in response to R(+)baclofen, bicuculline-insensitive responses were not antagonized by 2-hydroxysaclofen, and were abolished in low [Cl-]o. Results suggested (1) that bicuculline-insensitive, Cl(-)-dependent, GABAc-like responses were broadly distributed and predominant among dissociated rat retinal neurons; (2) that muscimol was a particularly weak agonist for rat retinal BCs; and (3) that oxonol was a sensitive probe for retinal GABA responses.

Animals↗
PubMed1998

Differential involvement of cortical receptor mechanisms in working, short-term and long-term memory.

Rats received, through bilaterally implanted indwelling cannulae, 0.5 microliter infusions of 6-cyano-7-nitroquinoxaline2,3-dione (CNQX) (0.5 microgram), D-2-amino-5-phophono pentanoic acid (AP5) (5.0 micrograms), muscimol (0.5 microgram), scopolamine (2.0 micrograms), SCH23390 (2.5 micrograms), saline or a vehicle into the CA1 region of the hippocampus, or into the antero-lateral prefrontal (PRE), posterior parietal (PP) and entorhinal cortex (EC). The infusions were given 6 min prior to one-trial step-down inhibitory avoidance training in order to measure their effect on working memory (WM), or immediately post-training in order to measure their effect on short-term (STM) and long-term memory (LTM), 1.5 and 24 h later, respectively. WM was inhibited by CNQX or muscimol given into any of the cortical areas, by SCH23390 given into CA1, PRE or PP, and by scopolamine given into PRE or EC. STM was unaffected by any of the treatments given into PRE, and was inhibited by CNQX or muscimol given into CA1, PP and EC and by scopolamine given into PP, and enhanced by SCH given into CA1. LTM was inhibited by CNQX, muscimol, scopolamine or SCH23390 given into PRE, by scopolamine given into PP, by SCH23390 given into the entorhinal cortex, and by AP5, CNQX, muscimol or scopolamine given into CA1. The results indicate a differential involvement of the various neurotransmitter systems in the three types of memory in the various brain areas, and a separation of the mechanisms and of the regions involved in each. In addition, some of the findings suggested links between WM and LTM processing in PRE, between WM and STM processing in EC and PP, and between all three types of memory in CA1.

Animals↗
PubMed2004

Prenatal nicotine exposure increases the strength of GABA(A) receptor-mediated inhibition of respiratory rhythm in neonatal rats.

Infants born to mothers that smoke while pregnant have a relatively high incidence of central respiratory control abnormalities. Recent studies have shown that prenatal nicotine exposure increases GABA release and the frequency of GABAergic currents, leading to an up-regulation of GABA(A) receptors in central neurones. Activation of GABA(A) receptors inhibits ventilatory activity, with intense activation causing apnoea. These observations lead us to hypothesize that prenatal nicotine exposure alters GABAergic control of respiratory motor pattern in the early neonatal period. Osmotic minipumps were implanted in pregnant Sprague-Dawley rats on the fifth day of gestation, and filled with nicotine (6 mg kg(-1) day(-1), 2.5 microl h(-1)) or physiological saline (2.5 microl h(-1)). Brainstem-spinal cord preparations from 1- to 3-day-old neonates were studied under in vitro conditions. Electrical activity was recorded from the fourth cervical ventral root (C4 VR), which contains the axons of phrenic motoneurones. Bath application of GABA(A) receptor agonists muscimol (250 microM) or pentobarbital sodium (60 microM) to the brainstem led to consistent, reversible and significant reductions in C4 VR burst frequency. In saline-exposed animals, frequency (bursts min(-1)) fell from 6.8 +/- 0.4 to a nadir of 2.8 +/- 0.5 with muscimol, and from 6.5 +/- 0.3 to a nadir of 2.9 +/- 0.3 for pentobarbital; in nicotine-exposed animals, frequency fell from 6.3 +/- 0.4 to 1.0 +/- 0.4 with muscimol and from 6.4 +/- 0.2 to 1.7 +/- 0.4 with pentobarbital (P < 0.05 in all cases). The decrease in C4 VR frequency was significantly greater in nicotine-exposed compared to saline-exposed preparations with both muscimol and pentobarbital (P < 0.001 for both). There were no changes in the amplitude of C4 VR bursts under any condition. The GABA(A) receptor antagonist bicuculline methiodide (8 microM) did not change C4 VR frequency or amplitude in either group, although it was effective in reversing the effects of muscimol. These experiments demonstrate that prenatal nicotine exposure alters the GABAergic regulation of respiratory rhythm in a reduced preparation. The results may lead to a better understanding of the perturbed breathing pattern observed in neonates that are exposed to nicotine in utero.

Animals↗
PubMed2003

Saccade dysmetria during functional perturbation of the caudal fastigial nucleus in the monkey.

The caudal fastigial nucleus (cFN) is the output nucleus by which the medioposterior cerebellum influences the brainstem saccade generator. In the monkey, inactivation of one cFN by local injection of muscimol impairs all saccades: ipsiversive saccades become hypermetric, contraversive saccades become hypometric, and saccades aimed at a target located in the upper or lower visual fields are biased horizontally toward the injected side. The pharmacological action of muscimol does not allow deficits that are presaccadic to be distinguished from those occurring during saccade execution. To determine the interval during which altered cFN activity affects saccade accuracy, we applied low-frequency electrical microstimulation (100 Hz for 100-300 ms) to the cFN of three monkeys while they were making saccades toward a flashed target. Similar to the effect of muscimol injection in cFN, low-frequency microstimulation biased all saccades toward the ipsilateral side. When the microstimulation was applied after target flash and before saccade onset, the ipsilateral bias was absent. However, when the stimulation was applied during the ongoing movement, the saccade trajectory was biased toward the stimulated side. The muscimol-like effect of the microstimulation suggests that the stimulation inhibits cFN activity, possibly by recruiting the inhibitory afferents from the cerebellar vermis (axons of Purkinje cells). Low-frequency microstimulation had to be applied during the saccade to bias its trajectory. These data suggest that the ipsilateral horizontal bias observed during muscimol inactivation results from an imbalance in the intrasaccadic activity between the two caudal fastigial nuclei.

Animals↗
PubMed1996

Evidence that GABA(A) but not GABA(B) receptor activation in the dorsal raphe nucleus modulates ethanol intake in Wistar rats.

Injection of the GABA(A) agonist muscimol into the dorsal raphe nucleus produces a marked and selective increase in voluntary ethanol intake. The purpose of the present study was threefold: first, to demonstrate that the effect of muscimol on ethanol consumption is mediated by GABA(A) receptors; secondly, to test the generalizability of this effect by examining the effects of another GABA(A) agonist, THIP, on ethanol drinking; and finally, to examine whether GABA(B) receptors within the dorsal raphe also play a role in modifying voluntary ethanol consumption under the same experimental conditions. Rats were trained to drink a 12% ethanol solution in a limited access paradigm with water concurrently available. Muscimol (50ng) injected into the dorsal raphe enhanced intake by at least 100%. Peripheral administration of the GABA(A) antagonist bicuculline (4mg/kg), but not the 5-HT(1A) antagonist (+)- WAY100135 (1 and 3mg/kg), antagonized the stimulatory effect of muscimol at a dose which, when administered alone, did not alter ethanol intake. This supports the suggestion that the effect of muscimol is mediated via GABA(A) receptors. This conclusion was further supported by the finding that another GABA(A) agonist, THIP (500ng), also selectively increased ethanol intake in this paradigm. Injection of bicuculline (60ng) into the dorsal raphe reduced ethanol intake, but also appeared to reduce water intake. Finally, intra-dorsal raphe injection of the GABA(B) agonist baclofen (62.5 and 125ng) did not produce any change in ethanol or water consumption. Together, these findings suggest that enhancement of GABAergic activity in the dorsal raphe increased voluntary ethanol intake via activation of GABA(A) but not GABA(B) receptors.

Journal Article↗
PubMed1990

Characterization of steroid interactions with gamma-aminobutyric acid receptor-gated chloride ion channels: evidence for multiple steroid recognition sites.

The potentiation of gamma-aminobutyric acid (GABA) receptor-mediated 36Cl- uptake by various steroids has been characterized in rat cerebral cortical synaptoneurosomes. Several of these steroids, including 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-OH-DHP) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (THDOC), increase the potency of muscimol to stimulate 36Cl- uptake in a concentration-dependent and stereospecific manner. Concentration-response curves for 3 alpha-OH-DHP, THDOC, 3 alpha-hydroxy-pregn-4-en-20-one, and pentobarbital enhancement of muscimol-stimulated 36Cl- uptake are biphasic, with Hill coefficients significantly less than 1.0. Computer-modeling (ALLFIT analysis) of these curves suggests that these steroids and pentobarbital interact with multiple binding sites on GABAA receptor(s). In contrast, the concentration-response curve for THDOC 21-mesylate is monophasic, with a smaller maximal response, and yields a Hill coefficients of 1.0. In addition to modulating GABA receptor-mediated 36Cl- uptake, THDOC enhanced the ability of the benzodiazepine clonazepam to potentiate muscimol-stimulated 36Cl- uptake. The central benzodiazepine antagonist Ro15-1788 failed to inhibit THDOC-induced potentiation of muscimol-stimulated 36Cl- uptake, although it has been previously reported to inhibit some of the behavioral actions of THDOC. In contrast to the A ring-reduced metabolites and analogues of progesterone and deoxycorticosterone, glucocorticoids had no effect on muscimol-stimulated 36Cl- uptake in cerebral cortical synaptoneurosomes at concentrations between 20 nM and 5 microM.

20-alpha-Dihydroprogesterone↗
PubMed1990

Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. I. Acute effects of ethanol.

Acute exposure to ethanol was found to enhance the ability of a benzodiazepine (BZ) inverse agonist, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), to reduce muscimol-activated 36Cl- uptake by membranes isolated from mouse cerebral cortex. Pretreatment in vivo with a hypnotic dose of ethanol (but not a subhypnotic dose), or exposure to a corresponding concentration in vitro, was effective. This increase in sensitivity of gamma-aminobutyric acid receptor-operated chloride channels to the actions of DMCM was due to an increase in both the potency and efficacy of DMCM. Sensitization to DMCM was reversible and was not observed 24 hr after a single injection of ethanol. Pretreatment with ethanol (10, 50 and 100 mM) in vitro produced sensitization to DMCM in a concentration-dependent manner, similar to that produced by in vivo exposure; this increase in sensitivity did not develop if the membranes were pretreated with ethanol at 0 degrees C. Similarly, in vitro exposure to pentobarbital (200 microM) or flunitrazepam (1 microM) enhanced the actions of the inverse agonist Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4]BZ-3- carboxylate). Acute ethanol exposure did not alter low-affinity gamma-aminobutyric acidA receptor binding or muscimol action, or the ability of a BZ agonist, flunitrazepam, to augment muscimol-activated chloride flux. Ethanol exposure did not alter [3H]flumazenil (Ro15-1788) binding to central BZ receptors, its displacement by DMCM or allosteric modulation of DMCM binding by muscimol (muscimol-shift).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Neurotransmitter analog tethered to a silicon platform for neuro-BioMEMS applications.

The design of chemically well-defined, machinable surfaces containing neuroactive molecules offers potential for fundamental neuroscience and clinical neural engineering applications. Here we report the assembly and characterization of silicon platforms containing a tethered form of muscimol. Muscimol, an analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), is a potent agonist at postsynaptic GABA(A) and GABA(C) receptors. Surfaces were assembled using covalent avidin conjugation to silanized silicon followed by high-affinity avidin-biotin binding of a biotinylated derivative of muscimol (muscimol-biotin). Contact angle measurements, ellipsometry, and X-ray photoelectron spectroscopy (XPS) were conducted to characterize the wettability, thickness, and chemical composition of progressively deposited surface layers. The data demonstrate successful incorporation of a neurotransmitter analog as part of a layered, silicon-based structure possessing robust and specific biomolecular composition. These findings represent a step toward the design of platforms for applications involving control and modulation of neural signaling.

Avidin↗
PubMed1994

Heterogeneity of GABAA receptor in goldfish retina.

The possibility of GABAA receptor heterogeneity in goldfish retina was studied with immunocytochemical and biochemical approaches: 1) immunoblotted membrane particulates of goldfish retina with mAb 62-3G1; 2) immunoprecipitation of the detergent-solubilized membrane proteins with mAb 62-3G1 followed by the receptor binding assay; 3) photoaffinity labeling of the membrane particulates with 3H-flunitrazepam (FNZ) and visualization of the labeled receptors by SDS-PAGE and fluorography; 4) dry autoradiography of 3H-muscimol and 3H-FNZ binding sites on frozen sections. Immunoblots showed that 62-3G1 reacted with 55-57.5 kDa M(r) polypeptides, similar to the muscimol-binding subunit of the receptor complex in bovine brain; while 3H-FNZ photoaffinity labeled the 52.5 kDa and 41-43 kDa M(r) polypeptides. Immunoprecipitated receptors bound only 3H-muscimol, not 3H-FNZ. An attempt to precipitate the 3H-FNZ photolabeled polypeptides failed. Dry autoradiography showed 3H-FNZ binding only in the inner plexiform layer (IPL); the binding was enhanced with gamma-aminobutyric acid (GABA) and blocked by clonazepam. In contrast, 3H-muscimol was bound in both the outer plexiform layer (OPL) and IPL, similar to that observed with 62-3G1 immunocytochemistry. We suggest that there are two subtypes of GABAA receptor in the goldfish retina: 1) GABAA receptors that are not linked to a benzodiazepine (BZD) receptor are located in the OPL and at amacrine-to-amacrine and amacrine-to-ganglion cell synapses in the IPL and are recognized by 62-3G1; 2) GABAA receptors that are linked to a BZD receptor are located only in the IPL, largely at amacrine-to-bipolar cell synapses and are not recognized by mAb 62-3G1.

Affinity Labels↗
PubMed1999

Partial restoration of striatal GABAA receptor balance by functional mesencephalic dopaminergic grafts in mice with hereditary parkinsonism.

Levels of inhibitory amino acid receptors were studied in the weaver (wv/wv) mouse model of dopamine (DA) deficiency after unilateral intrastriatal transplantation of fetal mesencephalic cell suspensions. Graft integration was verified by turning behavior tests and from the topographical levels of the DA transporter, tagged autoradiographically with 3 nM [3H]GBR 12935. The average increase in [3H]GBR 12935 binding in grafted dorsal striatum compared to nongrafted wv/wv striatum was 60% 3 months after grafting. Autoradiography of 8 nM [3H]flunitrazepam and 12 nM [3H]muscimol binding was carried out to visualize the distribution of GABAA receptors in +/+ mice and in recipient weaver mutants. A 17% increase in [3H]flunitrazepam binding and a 20% increase in [3H]muscimol binding was found in the nongrafted dorsal striatum of weaver mutants compared to +/+. The functional mesencephalic grafts had a partial normalizing effect on both [3H]flunitrazepam and [3H]muscimol binding in the dorsal striatum of the weaver recipients. The normalization brought about by the grafts was around 20% for [3H]flunitrazepam binding and more than 40% for [3H]muscimol binding. The results are discussed in the context of the important interaction between the converging glutamatergic corticostriatal and DAergic nigrostriatal pathways in controlling the functional GABAergic output of the basal ganglia in Parkinson's disease and in experimental models of DA deficiency.

Animals↗
PubMed1995

Opioid modulation of working memory: intraseptal, but not intraamygdaloid, infusions of beta-endorphin impair performance in spatial alternation.

The effect of beta-endorphin on spatial working memory was examined following microinfusions of beta-endorphin into the medial septal area and central amygdaloid nucleus in Long-Evans male rats. Working memory was assessed by spatial alternation in a T-maze. beta-Endorphin, 250 and 1000 ng/site, respectively, and muscimol, 20 ng/site, were infused into the medial septal area or central amygdaloid nucleus prior to behavioral testing. The hippocampal theta rhythm was examined following intraseptal infusions of beta-endorphin and muscimol. In the medial septal area, beta-endorphin and muscimol impaired choice accuracy and reduced the power of hippocampal theta rhythm. The degree of reduction in the power of hippocampal theta rhythm was correlated with the magnitude of behavioral impairment of choice accuracy in spatial alternation. In the central amygdaloid nucleus, beta-endorphin (1000 ng) and muscimol (20 ng) did not affect choice accuracy. The results suggest that septal, but not amygdaloid, opioid, and GABAergic activity modulate spatial working memory and hippocampal physiology.

Amygdala↗