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PubMed1990

The GABAergic nigro-collicular pathway is not involved in the inhibitory control of audiogenic seizures in the rat.

Involvement of the GABAergic nigro-collicular pathway in the control of audiogenic seizures was examined in genetically sensitive rats by studying the effects of bilateral injections into the substantia nigra of muscimol, a gamma-Aminobutyric acid (GABA) agonist, and those of bilateral injections into the superior colliculus of picrotoxin, a GABA antagonist, and of muscimol. Microinjections of muscimol (20-80 ng/side) into the substantia nigra and microinjections into the superior colliculus of picrotoxin (20 and 40 ng/side) both failed to suppress audiogenic seizures. Following injections into the superior colliculus, audiogenic seizures were in fact facilitated by picrotoxin and suppressed by muscimol. These results suggest that the nigro-collicular GABAergic pathway is not involved in the inhibitory control over audiogenic seizures. Conversely, a different GABAergic mechanisms may be involved in the superior colliculus in the control of this form of epilepsy.

Acoustic Stimulation↗
PubMed1991

Fall in intracellular pH mediated by GABAA receptors in cultured rat astrocytes.

The influence of muscimol (a specific gamma-aminobutyric acid-A (GABAA) receptor agonist) on intracellular pH (pHi) was studied in cultured rat astrocytes by means of fluorescence spectrophotometry with BCECF as the H+ indicator. In an HCO3(-)-free medium, muscimol had little effect on pHi. In a solution containing 22 mM HCO3-, muscimol produced a reversible, concentration-dependent fall in pHi with a maximum of about 0.1-0.15 units. The muscimol-induced fall in pHi was antagonized by an increase in the external K+ concentration, which suggest that the acidosis is an immediate consequence of a net efflux of HCO3- through GABAA receptor channels rather than an indirect effect caused by a change in membrane potential. The present results raise the possibility that astrocytes may participate in the regulation of extracellular pH at GABAergic synapses and contribute to activity-induced pH changes in nervous tissue.

Animals↗
PubMed1991

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.

Animals↗
PubMed1991

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.

Animals↗
PubMed1994

GABAergic and dopaminergic systems may be involved in seizures induced by pyrimethamine in mice.

1. The effects of some GABAergic and dopaminergic agents on pyrimethamine-induced tonic seizures were investigated in mice. 2. Pyrimethamine dose dependently induced seizures in mice. 3. Muscimol, AOAA and DABA significantly protected mice against pyrimethamine-induced seizures. 4. Bicuculline and picrotoxin effectively potentiated seizures elicited by pyrimethamine and significantly antagonized the protective effect of muscimol against the seizures. 5. Diazepam and phenobarbitone effectively protected mice against seizures elicited by pyrimethamine. 6. L-Dopa significantly potentiated pyrimethamine-induced seizures. 7. Apomorphine and pargyline significantly reduced the latency of seizures induced by pyrimethamine. 8. Haloperidol and pimozide effectively protected mice against pyrimethamine-elicited seizures and also significantly antagonized the potentiating effects of apomorphine and L-dopa on the seizures. 9. Disulfiram significantly potentiated seizures induced by pyrimethamine and also significantly enhanced the seizure-potentiating effect of L-dopa. 10. alpha-Methyl-p-tyrosine effectively protected against seizures induced by pyrimethamine. However, L-dopa significantly potentiated the seizures in alpha-methyl-p-tyrosine-pretreated animals. 11. Muscimol significantly attenuated the potentiating effect of L-dopa on pyrimethamine-induced seizures while bicuculline significantly enhanced the effect of L-dopa. Furthermore, haloperidol significantly potentiated the protective effect of muscimol against pyrimethamine-induced seizures. 12. These results suggest that both GABA and dopamine might be involved in the mechanism(s) of pyrimethamine seizures in mice.

Animals↗
PubMed1983

Role of the ventromedial nucleus of the thalamus in motor behaviour--II. Effects of lesions.

Rotational behaviour was initiated in naive rats by injecting muscimol into one substantia nigra pars reticulata, or in unilaterally 6-hydroxydopamine-treated rats with systemic or intracaudate apomorphine. Electrolytic or kainic acid lesions were made in one or both ventromedial nuclei of the thalamus and their effects on the components of circling studied. A unilateral ventromedial electrolesion imposed a weak ipsilateral posture and occasionally elicited weak ipsiversive circling acutely, but not chronically. Challenging these rats with a large subcutaneous dose of apomorphine invariably provoked ipsiversive circling, however old was the lesion. Bilateral electrolesions caused slight hypoactivity. Kainic acid treatments of one or both ventromedial thalami produced uncontrolled hypermotility initially, with subsequent loss of ventromedial neurones and recovery of normal motor behaviour. No form of ventromedial lesion affected the incidence of stereotypy. Acute (but not chronic) contralateral or ipsilateral ventromedial electrolesions, or both, slowed muscimol and apomorphine-induced circling (often in different ways) through complex changes in posture and/or locomotor drive. Animals lesioned during the course of a circling episode often showed the biggest changes in circling to begin with, only to recover minutes later. Rapidly circling rats were sometimes more readily inhibited than slowly circling rats. Toxin injury of the ventromedial nucleus appeared to suppress muscimol and not apomorphine circling. Any ventromedial lesion (electrical or chemical, acute or chronic), if positioned opposite a contraversive circling stimulus, intensified the associated posture. Ipsilateral lesions tended to abolish posture altogether or, like bilateral treatments, to suppress locomotion. Sham operations had none of these effects. Acute electrical lesions and drug-induced inhibition of one or both ventromedial thalami were more or less identical in their effects on rat circling behaviour, save that bilateral muscimol injection caused profound catalepsy while lesions did not. It is suggested that the ventromedial thalamus is more concerned with the registration of striatal dopamine-mediated behaviours in drug-stimulated than in spontaneously behaving rats, and that other output pathways may rapidly compensate for any impairment of function in the ventromedial nuclei.

Animals↗
PubMed1990

Circling behavior induced by intranigral administration of ruthenium red and 4-aminopyridine in the rat.

We have studied the effects of the unilateral intranigral microinjection of Ruthenium Red and 4-aminopyridine in the rat, as compared with that of muscimol. The three drugs produced contralateral turning when injected into the central nigra reticulata. Muscimol was the most effective but its effect disappeared in 3-4 h, whereas that of Ruthenium Red lasted for up to 3 days. When injected into the caudoventromedial nigra, Ruthenium Red produced intense ipsiversive turning, 4-aminopyridine weak ipsiversive turning and muscimol intense contraversive turning. Pretreatment with haloperidol (i.p.) abolished the effect of Ruthenium Red after injection into the caudoventromedial nigra but only partially reduced it after administration into the central nigra. The effect of muscimol, when injected into either of the nigral regions studied, was only slightly diminished by haloperidol. The release of [3H]GABA in slices of the Ruthenium Red-injected substantia nigra was not altered. Histological examination showed that the microinjected Ruthenium Red was located mainly inside the soma of nigral neurons. It is concluded that alterations of transmitter release are probably responsible for the circling behavior induced by 4-aminopyridine, but the effects of Ruthenium Red seem to be secondary to its penetration into the neuronal somas. Dopaminergic neurons seem to play an important role in the ipsilateral turning induced by Ruthenium Red when injected into the caudoventromedial nigra.

4-Aminopyridine↗
PubMed1994

MK-801 affects cardiovascular responses produced by GABAA agents in area postrema.

The cardiovascular effects of nanoliter microinfusions of muscimol, bicuculline, and MK-801 (dizocilpine) into area postrema (AP) were tested in urethane-anesthetized male Sprague-Dawley rats. Microinfusion of muscimol (10 nl/min/5min, 1 ng/nl) into the AP produced significant hypertension (+29 +/- 8 mmHg), but no significant change in heart rate (HR). Microinfusion of bicuculline (10 nl/min/5 min, 1 ng/nl) into the AP produced significant hypotension (-27 +/- 4 mmHg) and bradycardia (-53 +/- 10 bpm). Treatment of the AP with MK-801 (20 nl/min/5 min, 6 ng/nl) produced no changes in mean arterial pressure or HR by itself, but it completely blocked the hypotension and bradycardia produced by bicuculline infusion, without affecting the hypertension produced by muscimol microinfusion into AP. Following pretreatment of AP with MK-801, microinfusion of muscimol into the AP produced significant tachycardia (+51 +/- 16 bpm). The data suggest that a) GABAergic neurotransmission in the AP affects its cardiovascular functions; b) functional interactions between NMDA receptor-mediated neurotransmission and GABAA receptor-mediated neurotransmission within the AP modulate blood pressure and HR regulation.

Animals↗
PubMed1994

Studies on picrotoxin binding sites of GABAA receptors in rat cortical synaptoneurosomes.

Experiments were performed to characterize [35S]TBPS binding in rat cortical synaptoneurosomes, which have vesicular structures containing both pre- and postsynaptic elements. Scatchard analysis revealed a single component of [35S]TBPS binding sites with KD and Bmax values of 76.1 nM and 1.97 pmoles/mg protein, respectively, under physiological conditions. GABA and muscimol inhibited [35S]TBPS binding in a concentration-dependent manner. IC50 values of these GABAA agonists in displacing synaptoneurosomal [35S]TBPS binding are comparable to previously reported EC50 values of the agonist-stimulated 36Cl- uptake in synaptoneurosomes by these agents. Furthermore, the IC50 values of these GABAA agonists were better correspondence to those determined by [3H]muscimol binding in synaptoneurosomal preparations as reported by Delorey and Brown (3) than those determined in membrane preparations. Although bicuculline increased [35S]TBPS binding in a concentration dependent manner in cortical membranes, it did not affect synaptoneurosomal [35S]TBPS binding. Benzodiazepine agonists and inverse agonists (0.1 to 10 microM) did not show any effects on the binding in the absence of muscimol. However, benzodiazepine agonists potentiated and inverse agonists antagonized muscimol-induced inhibition of synaptoneurosomal [35S]TBPS binding. In addition, an anesthetic steroid, THDOC, and pentobarbital inhibited synaptoneurosomal [35S]TBPS binding in a concentration dependent manner. These results suggest that allosteric modulation of [35S]TBPS binding by various ligands which interact with GABAA supramolecular complexes remain intact in synaptoneurosomes. It appears that this preparation is useful for investigating correlation between functional 36Cl- uptake and individual binding studies of each of the GABAA receptor complex.

Animals↗
PubMedDate not supplied

Functional properties of GABAA receptors in two rat lines selected for high and low alcohol sensitivity.

The effects of lorazepam and sodium barbital on GABAA receptor function were evaluated in rat lines selected for differential sensitivity to the motor-impairing effects of ethanol [alcohol-insensitive (AT) and alcohol-sensitive (ANT) lines]. The effect of GABA on [3H]flunitrazepam and [3H]Ro 15-4513 binding and the effects of lorazepam and sodium barbital on [3H]muscimol binding were measured in cerebellar, cerebrocortical, and hippocampal membrane preparations. The effects of lorazepam and sodium barbital on muscimol-stimulated 36Cl- influx were measured using membrane vesicle suspensions from the same brain areas. No differences were found between the rat lines in the GABA-induced stimulation of [3H]flunitrazepam binding or in the lorazepam and sodium barbital-induced enhancement of either [3]muscimol binding or muscimol-stimulated 36Cl- flux. Neither was desensitization of the 36Cl- flux affected differently by ethanol, lorazepam, and barbital in vitro between the lines. The affinity of cerebellar diazepam-insensitive (DZ-IS) [3H]Ro 15-4513-binding sites for benzodiazepine agonists has been shown to be much greater in the ANT than the AT rats. In the present study, at 0 degrees C, GABA decreased [3H]Ro 15-4513 binding in the presence of diazepam only in ANT rats. Similarly, GABA decreased this binding at 37 degrees C in ANT rats having a high affinity for diazepam, whereas it enhanced the binding in all AT samples in those ANT samples where diazepam had a poor AT-like affinity. The decrease in binding in ANT samples is apparently caused by the enhancing effect of GABA on diazepam binding to DZ-IS [3H]Ro 15-4513-binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Development of GABAergic modulation of mouse locomotor activity and pain sensitivity after prenatal benzodiazepine exposure.

Outbred CD-1 mice were exposed to oxazepam (15 mg/kg PO twice/day) on days 12-16 of fetal life, i.e., at a critical ontogenetic stage of Type II benzodiazepine (BDZ) receptor increase, and fostered at birth to untreated dams. Locomotor activity (single 30-min session in a Varimex apparatus), hot-plate responding, and muscimol (GABAa agonist) effects thereon [see normative data in (16)] were assessed on postnatal day 14, 21, or 28. Prenatal oxazepam did not affect the development of hot-plate responding and muscimol analgesia; however, it reduced activity on day 14 (as in previous studies) and modified the profile of muscimol effects at 21 days (time of first appearance of an adult-like pattern of activity) and at 28 days. Specifically, oxazepam mice showed a faster recovery from the initial depression after 1 mg/kg of muscimol at the former age and a lack of rebound hyperactivity at the latter age. These effects might be explained either 1) by an accelerated development of GABAergic regulatory mechanisms, or 2) by the same monoaminergic system changes which can account for other effects of prenatal BDZ exposure (1,3). In any event, the dissociation phenomena found in the present study strengthen the notion that GABAergic influences contribute to the modulation of locomotor activity and of pain reactivity by mechanisms which are at least in part separate from each other (16).

Analysis of Variance↗
PubMed2006

Effects of medial amygdala inactivation on a panic-related behavior.

In the last years, the role played by the medial nucleus of the amygdala (MeA) in the modulation of fear- and anxiety-related behaviors has been increasingly investigated. This nucleus plays an important role in the processing of predator odor-induced defensive reactions, i.e. freezing and risk-assessment behaviors. Immunohistochemical evidence also indicates that the MeA may be involved in the regulation of escape, a defensive behavior related to panic attacks. In this study, we further addressed this question by investigating the effects of the reversible inactivation of the nucleus on escape behavior generated in male Wistar rats by two different aversive stimuli, electrical stimulation of the dorsal periaqueductal gray matter (dPAG) and exposure to one of the open arms of the elevated T-maze. Results showed that intra-MeA administration of either the reversible sodium channel blocker lidocaine (34 nmol/0.2 microl) or the GABA(A) receptor agonist muscimol (0.22 nmol/0.2 microl) raised the threshold of aversive electrical stimulation, increasing the amount of current that applied to the dPAG evokes escape, an antiaversive effect. Local microinjection of muscimol (0.22 nmol/0.2 microl) inhibited escape behavior in the elevated T-maze, also suggesting an antiaversive effect. In this latter test, muscimol did not affect inhibitory avoidance, a behavior associated with generalized anxiety disorder. Muscimol effect in the elevated T-maze was independent of changes in general exploratory activity as measured in an open-field. Taken together, our data corroborate previous evidences suggesting that the MeA is involved in the modulation of escape. Dysfunction of this regulatory mechanism may be of relevance in the genesis/maintenance of panic disorder.

Amygdala↗
PubMed2004

Inhibition of the activity of the native gamma-aminobutyric acid A receptor by metabolites of thyroid hormones: correlations with molecular modeling studies.

To characterize the direct effects of thyroid hormones on native gamma-aminobutyric acid(A) (GABA(A)) receptors, rapid (5 s) actions of a series of iodothyronines on muscimol-stimulated uptake of (36)Cl(-) were investigated in synaptoneurosomes prepared from rat brain. The results were correlated with molecular modeling of the active compounds. Dose-response curves for muscimol in the presence of 3,3', 5-L-triiodothyronine (L-T3) indicated a noncompetitive inhibition of muscimol-stimulated (36)Cl(-) uptake by the thyroid hormone. Synaptoneurosomes prepared from cerebellum were less sensitive to L-T3 than those from cerebral cortex, in terms of the potency of the hormone. The overall efficacy approached complete inhibition for both brain regions. Muscimol-stimulated (36)Cl(-) uptake was inhibited differentially by iodothyronine derivatives. One group of compounds with IC(50) values of 18-30 microM included L-thyroxine (L-T4), D-thyroxine (D-T4), 3,3', 5,5'-tetraiodothyroacetic acid (Tetrac), and 3,3', 5-triiodothyroacetic acid (Triac). A second group with values of 75-100 microM included 3,3', 5'-l-triiodothyronine (reverse T3; r-T3), 3,3'-diiodo-L-thyronine (3,3'-l-T2) and 3,5-diiodo-L-thyronine (3,5-D-T2). A final group of inactive compounds with IC(50) values greater than 100 microM included 3',5'-diiodo-L-thyronine (3',5'-l-T2), 3-iodo-L-thyronine (L-T1), 3'-iodo-L-thyronine (3'-L-T1), and L-thyronine (L-T0). Molecular modeling of the active iodothyronines using the Gaussian03 series of programs indicated close correspondences with models of the GABA-inhibitory neurosteroid pregnenolone sulfate (PREGS), suggesting common mechanisms of action at the GABA(A) receptor.

Animals↗
PubMed2005

Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro.

Previous studies suggested that the postsynaptic GABA(B) receptors of deep cerebellar nuclear neurons of adult rats were not activated by selective GABA(B) receptor agonist baclofen or endogenous GABA released by cerebellar cortical Purkinje cells, although the receptors have been demonstrated to exist in the deep cerebellar nuclei. In this study, cerebellar slices of adult rats were prepared for testing effects of GABA, baclofen and muscimol (selective GABA(A) receptor agonist) on cerebellar interpositus nucleus (IN) neurons. Perfusing slices with GABA (10-1000 microM), baclofen (1-30 microM) and muscimol (1-100 microM) respectively produced a dose-dependent inhibitory response on the IN neurons (n = 39, 62 and 50), which was not blocked by low-Ca(2+)/high-Mg(2+) medium (n = 5, 6 and 6), supporting a direct postsynaptic action of these GABAergic agonists. Moreover, both selective GABA(B) receptor antagonist CGP35348 and selective GABA(A) receptor antagonist bicuculline were capable of partially blocking the inhibitory response of IN neurons to GABA (n = 14 and 11), suggesting that the GABA-induced inhibition may contain two components, a GABA(B) receptors-mediated component and a GABA(A) receptors-mediated one. Further experiments revealed that not only muscimol (n = 50) but also baclofen (n = 62) suppressed IN cells' activity. The baclofen-induced inhibition was selectively blocked by CGP35348 (n = 12) but not by bicuculline (n = 8), whereas the muscimol-induced inhibition was selectively antagonized by bicuculline (n = 8) instead of CGP35348 (n = 9). These results indicate that GABA(B) receptors in the IN neurons can be activated not only by GABA but also by baclofen, suggesting that besides GABA(A) receptors, GABA(B) receptors may also be involved in mediating the inhibitory effect of GABA on cerebellar IN neurons of adult rats.

Action Potentials↗
PubMed2005

Simultaneous glutamate and GABA(A) receptor agonist administration increases calbindin levels and prevents hippocampal damage induced by either agent alone in a model of perinatal brain injury.

Perinatal brain injury is associated with the release of amino acids, principally glutamate and GABA, resulting in massive increases in intracellular calcium and eventual cell death. We have previously demonstrated that independent administration of kainic acid (KA), an AMPA/kainate receptor agonist, or muscimol, a GABA(A) receptor agonist, to newborn rats results in hippocampal damage [Hilton, G.D., Ndubuizu, A., and McCarthy, M.M., 2004. Neuroprotective effects of estradiol in newborn female rat hippocampus. Dev. Brain Res. 150, 191-198; Hilton, G. D., Nunez, J.L. and McCarthy, M.M., 2003. Sex differences in response to kainic acid and estradiol in the hippocampus of newborn rats. Neuroscience. 116, 383-391; Nunez, J.L. and McCarthy, M.M., 2003. Estradiol exacerbates hippocampal damage in a model of preterm infant brain injury. Endocrinology. 144, 2350-2359; Nunez, J.L., Alt, J.J. and McCarthy, M.M., 2003. A new model for prenatal brain damage. I. GABA(A) receptor activation induces cell death in developing rat hippocampus. Exp. Neurol. 181, 258-269]. We now report that KA or muscimol alone administered to immature hippocampal neurons in culture induces significant cell death as evidenced by TUNEL assay. Surprisingly, simultaneous administration of equimolar quantities of these two agonists blocks the effect of either one alone. Moreover, treatment of newborn pups results in less damage compared to either muscimol or KA alone. We further observed that immunoreactivity for the calcium-binding protein, calbindin D(28K), is increased in the brains of pups simultaneously administered KA and muscimol as compared to either alone.

Animals↗
PubMed2005

Effect of GABA(A) receptor stimulation in the subthalamic nucleus on motor deficits induced by nigrostriatal lesions in the rat.

Inhibition of the subthalamic nucleus by lesions or GABAergic agonists improves motor symptoms in monkeys or humans with a loss of nigrostriatal dopaminergic neurons, a characteristic of Parkinson's disease. In rats, nigrostriatal lesions induce deficits in a variety of motor tests that are ameliorated by dopaminergic agonists. However, the validity of these tests to predict the beneficial effects of subthalamic inhibition is not known. We have examined the effects of an intrasubthalamic injection of the GABA(A) receptor agonist muscimol (0.1 microg/0.1 microL) in intact rats and in rats with a unilateral nigrostriatal lesion. Muscimol induced a mild ipsiversive rotation in sham-operated (control) rats and blocked contraversive rotations induced by apomorphine in lesioned rats. In addition, in the cylinder test of limb use asymmetry, muscimol decreased the ipsilateral bias after lesion without inducing any significant effect in sham-operated controls. In the forced-step test, however, 0.1 microg (but not 0.01 microg) of muscimol into the subthalamic nucleus induced a behavioral bias by markedly decreasing the number of adjusting steps of the contralateral limb in control rats, similar to the effect of a nigrostriatal lesion. Neither dose improved performance in this test in rats with lesions, and the higher dose exacerbated the deficit. The data support a beneficial role of stimulating subthalamic GABA(A) receptors for akinesia but also reveal negative behavioral effects of this treatment and suggest that the cylinder and forced-step tests measure different aspects of behavioral deficits after dopaminergic lesions.

Animals↗
PubMed2006

The role of substantia nigra pars reticulata in modulating clonic seizures is determined by testosterone levels during the immediate postnatal period.

GABAergic activation of substantia nigra pars reticulata (SNR) at postnatal day (PN) 15 has sex-specific features on seizure control in vivo and electrophysiological responses in vitro. In males, the GABA(A)-receptor agonist muscimol has proconvulsant effects and induces depolarizing responses. In females, muscimol has no effect on seizures and evokes hyperpolarizing responses. We determined the time period during which sex hormones must be present to produce the sex-specific muscimol effects on seizures and their influence on SNR GABA(A) receptor-mediated postsynaptic currents. Exposure to testosterone or its metabolites (estrogen or dihydrotestosterone) during PN0-2 in females or males castrated at PN0 was sufficient to produce proconvulsant muscimol effects but did not affect the in vitro GABA responses, which remained hyperpolarizing. The data suggest that the PN0-2 period is critical for the development of the seizure-controlling SNR system; the hormonal effect on seizure control is independent from their effect on GABA conductance.

Animals↗
PubMed2004

Two-photon imaging of spontaneous vesicular release in acute brain slices and its modulation by presynaptic GABAA receptors.

Action potential-independent spontaneous vesicular release of gamma-aminobutyric acid (GABA) in the CNS mediates miniature inhibitory postsynaptic currents (mIPSCs) and exerts an important control on central excitability. Using dual-photon laser scan microscopy and hyperosmotic loading of the readily releasable vesicle pool with the fluorescent styryl dye FM1-43 in hippocampal slice, we demonstrate action potential-independent release of vesicles (fluorescence destaining) from proximal perisomatic, presumed GABAergic terminals and significant inhibition of this release by the specific GABA(A) receptor agonist muscimol in the presence of tetrodotoxin and glutamate receptor antagonists CNQX and AP5. These data agree with reduction of mIPSCs by muscimol in whole-cell recordings from CA3 pyramidal neurons. In contrast, rate of vesicle release from distal, presumably glutamatergic terminals, was significantly lower and not changed by muscimol. The effect of muscimol on mIPSCs was not blocked but rather enhanced in the absence of external calcium. Our data directly demonstrate a potent disinhibitory reduction of GABA release by GABA(A) receptor activation. Those novel methods should be well suited to study pathophysiological changes in inhibition in resections obtained from neurosurgical treatment of epilepsy patients.

Animals↗