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PubMed1988

Modulation of the GABAA receptor by depressant barbiturates and pregnane steroids.

1. The modulation of the gamma-aminobutyric acidA (GABAA) receptor by reduced metabolites of progesterone and deoxycorticosterone has been compared with that produced by depressant barbiturates in: (a) voltage-clamp recordings from bovine enzymatically isolated chromaffin cells in cell culture, and (b) an assay of the specific binding of [3H]-muscimol to a preparation of porcine brain membranes. 2. The progesterone metabolites 5 alpha- and 5 beta-pregnan-3 alpha-ol-20-one (greater than or equal to 30 nM) reversibly and dose-dependently enhanced the amplitude of membrane currents elicited by locally applied GABA (100 microM), and over the concentration range 30 nM-100 microM stimulated the binding of [3H]-muscimol. In contrast, 5 alpha- and 5 beta-pregnan-3 beta-ol-20-one (30 nM-100 microM) had little effect in either assay, indicating a marked stereoselectivity of steroid action. 3. Scatchard analysis of the ligand binding data suggested an apparent increase in the number, rather than the affinity, of detectable [3H]-muscimol binding sites as the principle action of the active steroid isomers. 4. GABA-evoked currents were also potentiated by androsterone (1 microM) and the deoxycorticosterone metabolite 5 alpha-pregnane-3 alpha,21-diol-20-one (100 nM). 5. Secobarbitone (10-100 microM), pentobarbitone (10-300 microM) and phenobarbitone (100-500 microM) reversibly and dose-dependently potentiated the amplitude of GABA-evoked currents in the absence of any change in their reversal potential. 6. At relatively high concentrations (greater than or equal to 30 microM) secobarbitone and pentobarbitone directly elicited a membrane current. It is concluded that such currents result from GABAA receptor-channel activation since they share a common reversal potential with GABA-evoked responses (approximately 0 mV), are reversibly antagonized by bicuculline (3 microM), and potentiated by either diazepam (1 microM) or 5 beta-pregnan-3 alpha-ol-20-one (500 nM). 7. Secobarbitone (1 microM-1 mM) dose-dependently enhanced the binding of [3H]-muscimol. In common with the active steroids, an increase in the apparent number of binding sites was responsible for this effect. 8. A saturating concentration (1 mM) of secobarbitone in the ligand binding assay did not suppress the degree of enhancement of control binding produced by 5 beta-pregnan-3 alpha-ol-20-one (30 nM-100 microM). Similarly the steroid, at a concentration of 100 microM, did not influence the enhancement of [3H]-muscimol binding by secobarbitone (1 microM-1 mM). In all combinations of concentrations tested, the effects of secobarbitone and 5#-pregnan-3a-ol-20-one on [3H]-muscimol binding were additive. 9. In conjunction with previously published observations, the present data indicate close similarities in the GABA-mimetic and potentiating actions of barbiturates and steroids. However, the results obtained with combinations of steroids and barbiturates in the ligand binding assay appear inconsistent with the two classes of compound interacting with a common site to modulate the GABAA receptor activity.

Animals↗
PubMed1995

Peripheral GABAA receptor-mediated effects of sodium valproate on dural plasma protein extravasation to substance P and trigeminal stimulation.

1. The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine. Its mechanism of action is unknown. We tested the effects of sodium valproate and GABAA-agonist muscimol on dural plasma protein ([125I]-bovine serum albumin) extravasation evoked by either unilateral trigeminal ganglion stimulation (0.6 mA, 5 ms, 5 Hz, 5 min) or substance P (SP) administration (1 nmol kg-1,i.v.) in anaesthetized Sprague-Dawley rats. 2. Intraperitoneal (i.p.) injection of sodium valproate or muscimol, but not baclofen (< or = 10 mg kg-1, i.p.) dose-dependently reduced dural plasma protein extravasation caused either by electrical trigeminal stimulation (ED50: 6.6 +/- 1.4 mg kg-1, i.p., and 58 +/- 18 micrograms kg-1, i.p. for valproate or muscimol, respectively) or by intravenous substance P administration (ED50: 3.2 +/- 1.4 mg kg-1, i.p. and 385 +/- 190 micrograms kg-1, i.p. for valproate or muscimol, respectively). 3. Valproate (6.6 mg kg-1, i.p.) or muscimol (58 micrograms kg-1, i.p.) had no effect on mean arterial blood pressure or heart rate when measured for 30 min after i.p. administration. 4. The GABAA-antagonist bicuculline (0.01 mg kg-1, i.p.) completely reversed the effect of valproate and muscimol on plasma extravasation following electrical stimulation or substance P administration, whereas the GABAB-receptor antagonist, phaclofen (0.01-1 mg kg-1, i.p.) did not. Bicuculline or phaclofen, given alone, did not alter the plasma extravasation response after either electrical stimulation or SP administration. 5. Valproate decreased plasma extravasation following substance P administration in adult animals, neonatally treated with capsaicin by a bicuculline-reversible mechanism. This suggests that GABAA receptors are not found primarily on those afferent neurones or fibres which are sensitive to capsaicin treatment in neonatal rats.6. We conclude that sodium valproate blocks plasma extravasation in the meninges through GABAA mediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinically. Agonists and modulators at the GABAA receptor may become useful for the development of selective therapeutic agents for migraine and cluster headache.

Animals↗
PubMed1997

Ethanol, flunitrazepam, and pentobarbital modulation of GABAA receptors expressed in mammalian cells and Xenopus oocytes.

GABAA receptors composed of human alpha 1 beta 2 gamma 2L, alpha 1 beta 2 gamma 2S, alpha 1 beta 3 gamma 2S, alpha 6 beta 3 gamma 2S, and alpha 5 beta 3 gamma 3 subunits as well as bovine alpha 1 beta 1 gamma 2L and alpha 1 beta 1 subunits were stably expressed in mammalian L(tk-) cells and transiently expressed in Xenopus oocytes. Effects of muscimol, ethanol, flunitrazepam, and pentobarbital on receptor function were compared for the two expression systems using a 36Cl- flux assay for cells and an electrophysiological assay for oocytes. Muscimol activated all receptors in both expression systems but was more potent for L(tk-) cells than oocytes; this difference ranged from 2.6-to 26-fold, depending upon subunit composition. The most pronounced differences between receptors and expression systems were found for ethanol. In L(tk-) cells, low (5-50 mM) concentrations of ethanol potentiated muscimol responses only with receptors containing the gamma 2L subunit. In oocytes, concentrations of 30-100 mM produced small enhancements for most subunit combinations. Flunitrazepam enhanced muscimol responses for all receptors except alpha 6 beta 3 gamma 2S and alpha 1 beta 1, and this enhancement was similar for both expression systems. Pentobarbital also enhanced muscimol responses for all receptors, and this enhancement was similar for L(tk-) cells and oocytes, except for alpha 6 beta 3 gamma 2S where the pentobarbital enhancement was much greater in oocytes than cells. The alpha 6 beta 3 gamma 2S receptors were also distinct in that pentobarbital produced direct activation of chloride channels in both expression systems. Thus, the type of expression/assay system markedly affects the actions of ethanol on GABAA receptors and also influences the actions of muscimol and pentobarbital on this receptor. Differences between these expression systems may reflect posttranslational modifications of receptor subunits.

Animals↗
PubMed1980

Effect of GABA analogues on blood pressure and central GABA metabolism in the rat.

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

3-Mercaptopropionic Acid↗
PubMed2005

Effects of chronic infusion of a GABAA receptor agonist or antagonist into the vestibular nuclear complex on vestibular compensation in the guinea pig.

The aim of this study was to determine the effects of chronic infusion of a GABA(A) receptor agonist/antagonist into the ipsilateral or contralateral vestibular nuclear complex (VNC) on vestibular compensation, the process of behavioral recovery that occurs after unilateral vestibular deafferentation (UVD). This was achieved by a mini-osmotic pump that infused, over 30 h, muscimol or gabazine into the ipsilateral or contralateral VNC. Spontaneous nystagmus (SN), yaw head tilt (YHT), and roll head tilt (RHT) were measured. Infusion of muscimol or gabazine into either the ipsilateral or the contralateral VNC had little effect on SN compensation. In contrast, infusion of muscimol (250, 500, and 750 ng) into the contralateral VNC and gabazine (31.25, 62.5, and 125 ng) into the ipsilateral VNC significantly affected YHT and RHT (p < 0.05), but not their rate of compensation (p > 0.05). Interestingly, the effects of muscimol and gabazine on YHT and RHT were consistent throughout the first 30 h post-UVD. Infusion of muscimol (62.5, 125, and 250 ng) into the ipsilateral VNC and gabazine (125, 375, and 750 ng) into the contralateral VNC had little effect on YHT and RHT or their rate of compensation. These results suggest that the ipsilateral gabazine and contralateral muscimol infusions are modifying the expression of the symptoms without altering the mechanism of compensation. Furthermore, the neurochemical mechanism responsible for vestibular compensation can cope with the both the GABA(A) receptor-mediated and the UVD-induced decrease in resting activity.

Animals↗
PubMed1992

Medullary pathways for adrenocorticotropic hormone and vasopressin secretion in rabbits.

We determined, in urethan-anesthetized rabbits, whether pharmacological alteration of neuronal function in the ventrolateral medulla oblongata, including the A1 area, and in the nucleus tractus solitarii (NTS), alters plasma adrenocorticotropic hormone (ACTH) and vasopressin and whether inhibition of neuronal function in the ventrolateral medulla impairs the secretion of ACTH normally observed in response to hemorrhage or constriction of the inferior vena cava. We also tested whether the increase in plasma ACTH and vasopressin after pharmacological inhibition of neuronal function in the NTS is dependent on a pathway that synapses in the A1 area of the ventrolateral medulla. Activation of the A1 area with bicuculline increased both ACTH and vasopressin. Inhibition of the NTS with muscimol increased levels of both hormones, as did hemorrhage and constriction of the inferior vena cava. Inhibition of neuronal function within the A1 area with muscimol eliminated the secretion of vasopressin but did not significantly alter the secretion of ACTH, obtained by injecting muscimol into the NTS. Injection of muscimol into the A1 area eliminated the secretion of both ACTH and vasopressin in response to constriction of the inferior vena cava and, in the case of vasopressin, in response to hemorrhage. Although hemorrhage-initiated secretion of ACTH was significantly reduced by injection of muscimol into the A1 area, it was not completely eliminated by these injections or by injections of muscimol into a more rostrocaudally extensive region of the medulla oblongata. We conclude that the net output from the NTS tonically inhibits secretion of both ACTH and vasopressin, reflecting tonic baroreceptor tone. For vasopressin, the pathway from the NTS to the hypothalamus is dependent on a synapse in the A1 area. For ACTH, there are pathways to the hypothalamus that do not synapse in the A1 area, but neurons in this region do have an excitatory effect on secretion of ACTH.

2-Amino-5-phosphonovalerate↗
PubMed1997

Neurosteroid inhibition of cell death.

Diverse gamma-aminobutyric acid (GABAA) receptor modulators exhibited novel cytoprotective effects and mechanisms of action in rabbit renal proximal tubules subjected to mitochondrial inhibition (antimycin A) or hypoxia. Cytoprotective potencies (50% effective concentration, EC50) were 0.3 nM allopregnanolone (AP) > 0.4 nM 17 alpha-OH-allopregnanolone (17 alpha-OH-AP) > 30 nM dehydroepiandrosterone sulfate (DHEAS) = 30 nM pregnenolone sulfate (PS) > 500 nM pregnenolone (PREG) > 30 microM muscimol > 10 mM GABA following antimycin A exposure. Maximal protection with AP and 17 alpha-OH-AP was 70%, whereas DHEAS, PS, PREG, and muscimol produced 100% cytoprotection. Experiments with AP, PS, and muscimol revealed the return of mitochondrial function and active Na+ transport following hypoxia/reoxygenation. Muscimol inhibited the antimycin A-induced influx of both extracellular Ca2+ and Cl- that occurs during the late phase of cell injury, whereas the neurosteroids only inhibited influx of Cl-. Radioligand binding studies with AP and PS did not reveal a specific binding site; however, structural requirements were observed for cytoprotective potency and efficacy. In conclusion, we suggest that the GABAA receptor modulators muscimol and neurosteroids are cytoprotective at different cellular sites in the late phase of cell injury; muscimol inhibits Ca2+ and subsequent Cl- influx, whereas the neurosteroids inhibit Cl- influx.

Alkaloids↗
PubMed2003

Estradiol exacerbates hippocampal damage in a model of preterm infant brain injury.

We have developed a model for prenatal hypoxia-ischemia in which muscimol, a selective gamma-aminobutyric acid A (GABA(A)) receptor agonist, administered to newborn rats, induces hippocampal damage. In the neonatal rat brain, activation of GABA(A) receptors leads to membrane depolarization and neuronal excitation. Because of our previous detection of sex differences in this model and the considerable interest in the neuroprotective effects of estradiol in the adult brain, we now investigate the effect of pretreatment with high physiological levels of estradiol in our model of prenatal hypoxia-ischemia. We used unbiased stereology to assess neuron number in the hippocampal formation of control, muscimol-treated, and estradiol- plus muscimol-treated animals. Muscimol decreased neuron number in the hippocampus, with damage exacerbated by pretreatment with estradiol. A hippocampal culture paradigm was developed to mirror the in vivo investigation. We observed elevated cytotoxicity (using the lactate dehydrogenase assay) by 48 h after treatment with estradiol plus muscimol, but decreased cytotoxicity between 2 and 24 h after treatment. To determine whether the actions of estradiol on muscimol-induced damage were via the estrogen receptor, hippocampal cultures were pretreated with ICI 182,780, a selective estrogen receptor antagonist. Treatment with ICI 182,780 blocked the potentiating effect of estradiol on the late period of cytotoxicity, but had no effect on the protective actions of estradiol during the early period of cytotoxicity. There appears to be a biphasic action of estradiol in our model of neonatal brain injury that involves early nongenomic, nonreceptor-mediated protection, followed by late deleterious receptor-mediated effects.

Animals↗
PubMed1994

Effects of Kamikihito, a traditional Chinese medicine, on neurotransmitter receptor binding in the aged rat brain determined by in vitro autoradiography (2): changes in GABAA and benzodiazepine receptor binding.

We investigated the effects of the long-term administration of Kamikihito (KKT) on the specific binding of [3H]muscimol and [3H]flunitrazepam in the brains of young and aged rats using in vitro quantitative autoradiography. Specific [3H]muscimol binding in aged rats was decreased in all brain regions examined compared with that in young rats, whereas [3H]flunitrazepam binding did not change in any of the brain regions. Scatchard analysis revealed that the maximal number of [3H]muscimol binding sites in the cortex and thalamus was significantly decreased in aged rats compared with young rats, while its affinity remained unchanged. Long-term administration of KKT in young rats had no effect on either [3H]muscimol or [3H]flunitrazepam binding. In contrast, the same treatment in aged rats produced a significant increase in [3H]flunitrazepam binding to the cortex, caudate/putamen and accumbens, and it tended to decrease the [3H]muscimol binding. These results suggest that the selective reduction of specific [3H]muscimol binding in the brain may be responsible, at least in part, for anxiety-related behavior in aged rats. Furthermore, it appears that the significant increase in specific [3H]flunitrazepam binding produced in the brains of aged rats by the long-term administration of KKT may be responsible for the anxiolytic effects of this agent.

Aging↗
PubMed2004

Acute neurosteroid modulation and subunit isolation of the gamma-aminobutyric acidA receptor in the bullfrog, Rana catesbeiana.

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has multiple receptors. In mammals, the GABA(A) receptor subtype is modulated by neurosteroids. However, whether steroid interaction with the GABA(A) receptor is unique to mammals or a conserved feature in vertebrates is unknown. Thus, neurosteroid modulation of the GABA(A) receptor was investigated in the brain of the bullfrog (Rana catesbeiana) using the mammalian GABA(A) receptor agonist [(3)H]muscimol. Two neurosteroids, allopregnanolone and pregnenolone sulfate, affected [(3)H]muscimol specific binding in bullfrog brain membrane preparations. Allopregnanolone significantly increased [(3)H]muscimol specific binding in a dose- and time-dependent manner. The pattern of allopregnanolone modulation supports the hypothesis that the bullfrog brain possesses both high-affinity and low-affinity [(3)H]muscimol binding sites. Unlike allopregnanolone, pregnenolone sulfate showed biphasic modulation with increased [(3)H]muscimol specific binding at low nanomolar concentrations and decreased specific binding at micromolar concentrations. Additionally, three cDNA fragments with significant homology to mammalian GABA(A) receptor subunits were isolated from the bullfrog brain. These fragments belong to the alpha1, beta1, and gamma2 subunit families. In mammals, GABA(A) receptors composed of these specific subunit isoforms are effectively modulated by neurosteroids, including allopregnanolone. Neurosteroid modulation of the amphibian brain GABA(A) receptor is therefore supported by both [(3)H]muscimol binding studies and subunit sequences. Allopregnanolone and pregnenolone sulfate modulation of this receptor may thus represent a significant mechanism for steroid influence on amphibian brain and behavior.

Amino Acid Sequence↗
PubMed1999

[Antinociceptive effects of intrathecally administered GABA agonists at the spinal cord level].

The present study was designed to investigate antinociceptive effect of GABA agonists regarding visceral as well as somatic noxious stimuli. Following the approval by the institutional animal care committee, an intrathecal catheter was implanted in the subarachnoid space at the L 4/5 level in male Sprague-Dawley rats. The tail flick (TF) test and the colorectal distension test (CD) were used to measure responses to somatic and visceral stimuli, respectively. Threshold in TF test and CD test were measured at 5, 10, 15, 20, 30, 60, 90, 120 and 180 min after the intrathecal injection of 0.1, 1, 5, 20 micrograms of muscimol, 0.01, 0.1, 0.3, 1 microgram of baclofen or normal saline. Percent of maximum possible effect (%MPE) and %area under the curve (%AUC) were calculated by transforming response threshold in TF and CD tests. Repeated measure ANOVA followed by Fisher's PLSD test were used for statistical analysis. Muscimol 0.1 microgram increased mean %MPE in TF test at 10 min to 15% but not in CD test. Muscimol 1, 5 and 20 micrograms significantly increased %MPE at 5 min in TF and CD tests. Muscimol 20 micrograms produced 100%MPE for 180 min after drug injection. Baclofen 0.1, 0.3 and 1 microgram significantly increased %MPE at 5 min in TF and CD test. Antinociceptive effect in TF test seems to be greater than that in CD test. Muscimol caused motor disturbance but baclofen did not. It is concluded that intrathecally administered muscimol and baclofen produced somatic and visceral antinociception in a dose dependent fashion.

Analgesics↗
PubMed2001

The role of cortical activity in experience-dependent potentiation and depression of sensory responses in rat barrel cortex.

The role of cortical activity in experience-dependent cortical plasticity was studied in the rat barrel cortex. Plasticity was induced by depriving every other whisker in a chessboard pattern, which is known to cause depression of responses to deprived whisker stimulation and potentiation of responses to spared whisker stimulation. Postsynaptic activity was blocked by muscimol released from elvax slow-release polymer located under the dura and over the barrel field. Spared whisker responses potentiated 2.5-fold in layer II/III and 2.9-fold in layer IV of the near-neighbor barrel in animals implanted with saline-elvax. In contrast, in whisker-deprived animals implanted with muscimol-elvax, responses were indistinguishable from those in undeprived animals. Similarly, in the spared barrel itself, spared whisker responses potentiated 1.3-fold in layer IV in animals implanted with saline-elvax but not at all in muscimol-treated animals. Whiskers that were deprived and then allowed to regrow showed depressed responses in saline-elvax-treated animals, in which 40% of the cells in layer II/III and 26% in layer IV were unresponsive to their principal whisker. These values fell to 17 and 3% for layers II/III and IV, respectively, in muscimol-treated animals, and the response magnitude distributions were indistinguishable from undeprived cases. Cortical activity block had no acute effect on the ventroposteriomedial nucleus responses and had a transient facilitatory effect after 4 d of muscimol treatment, which returned to baseline as the muscimol treatment wore off. We conclude from these studies that cortical activity is required for potentiation and depression of sensory responses in barrel cortex.

Animals↗
PubMed1983

Medullary gamma-aminobutyric acid (GABA) receptors and the regulation of blood pressure in the rat.

The cardiovascular effects of a GABAergic agonist (muscimol) and antagonist (bicuculline methiodide) were determined after microinjection (100 nl) into ventrolateral vasodepressor and vasopressor neuron pools. In urethane-anesthetized rats, these neuron pools were identified bilaterally by observing pressor or depressor responses after the microinjection of L-glutamate (333 ng). The bilateral microinjection of muscimol (0.1-10 ng/site) into vasodepressor sites caused a dose-related (0.1-10.0 ng/site) increase in the blood pressure, heart rate and pulse pressure. In ventrolateral vasopressor sites, muscimol (0.1-10.0 ng/site) caused a marked fall in blood pressure, heart rate and pulse pressure. The depressor response elicited by aortic nerve stimulation (2 V, 25 HZ, 3 msec) was blocked and reversed by muscimol microinjections into vasodepressor sites. In these sites, muscimol also caused a similar reversal of the depressor response induced by stimulation of pulmonary C-fibers (J-receptors) after the right atrial administration of phenyldiguanide (30 micrograms/kg). All the effects of muscimol were blocked or reversed by the bilateral microinjection of bicuculline methiodide into the vasodepressor and vasopressor sites. These results demonstrate the importance of ventrolateral vasodepressor and vasopressor neuron pools in the maintenance and reflex regulation of blood pressure and suggest that intrinsic GABAergic systems may serve to modulate activity in these neuron pools.

Animals↗
PubMed1990

Effects of GABA antagonists, SR 95531 and bicuculline, on GABAA receptor-regulated chloride flux in rat cortical synaptoneurosomes.

Synaptoneurosomes isolated from cerebral cortices of male Sprague-Dawley rats were used for studying GABAA receptor-regulated chloride influx. The in vitro effects of GABA antagonists, SR 95531 (a pyridazinyl GABA derivative) and bicuculline, on pentobarbital-stimulated, muscimol-stimulated or flunitrazepam-enhanced, muscimol-stimulated chloride uptake were studied. The chloride uptake was determined at 30 degrees C, for 5 sec. Pentobarbital and muscimol produced a maximal stimulation of chloride uptake in cortical synaptoneurosomes at 500 microM and 50 microMs, respectively. SR 95531 as well as bicuculline had no effect on the basal uptake of chloride. Whereas, SR 95531 (0.3 - 30 microM) and bicuculline (0.1 - 100 microM), when added 5 min before muscimol (50 microM), produced a significant concentration-dependent inhibition of muscimol (50 microM)-stimulated chloride uptake (IC50S of 0.89 +/- 0.11 microM and 13.45 +/- 2.10 microM, respectively). In studies of the inhibitory effects of SR 95531 and bicuculline on pentobarbital (500 microM)-stimulated chloride uptake, the IC50S were 0.81 +/- 0.12 microM and 3.86 +/- 1.14 microM, respectively. SR 95531 exhibited a more potent inhibitory effect than bicuculline on flunitrazepam-enhanced, muscimol-stimulated chloride uptake. The results revealed that SR 95531 has a more potent antagonistic effect than bicuculline on GABAA-regulated chloride flux.

Animals↗
PubMed1986

Influence of environment on GABA receptors in muricidal rats.

The influence of environment (isolation) on GABA receptor numbers ( [3H]-muscimol binding sites) and affinities was investigated in specific limbic areas known to be involved with the development of muricide. Olfactory bulbs of isolated rats were found to have identical numbers of [3H]-muscimol binding sites whether or not they were muricidal. However, in the olfactory bulbs of the aggregated animals a greater than two-fold increase was found in numbers of [3H]-muscimol binding sites in those rats that were muricidal. In the amygdala muricidal rats had a 32-34% increase in [3H]-muscimol binding sites over non-muricidal rats regardless of environment. In the septum non-muricidal rats had fewer [3H]-muscimol binding sites than muricidal rats and although the trend was evident, statistical vigor was seen only in the aggregated animals. Neither muricide nor isolation significantly influenced [3H]-muscimol binding numbers in the hypothalamus. GABA Ki values were examined in all brain regions and found to be the same in the isolated and aggregated animals whether or not they were muricidal. We concluded that environment appears to influence apparent GABA receptor numbers in the olfactory bulbs and septum whereas muricidal behavior correlates well with an increase in apparent number of GABA receptors in the amygdala. GABA receptors in the hypothalamus were not influenced by either environment or aggression.

Aggression↗
PubMed2005

Antidepressant-like actions of intra-accumbens infusions of allopregnanolone in ovariectomized Wistar rats.

This study was aimed to verify the role of the nucleus accumbens (NAcc) in the antidepressant-like effects of allopregnanolone in ovariectomized rats forced to swim. The interaction between infusions of allopregnanolone (intra-NAcc) with systemic administrations of allopregnanolone, muscimol, fluoxetine and GABA-A antagonists was assessed. Results showed that allopregnanolone (intra-NAcc; 1.5 microg, p < 0.05; 2.0 microg, p < 0.05) or systemic injections of allopregnanolone (1.5 mg/kg, p < 0.05; 2.0 mg/kg, p < 0.05; s.c.) or muscimol (0.3 mg/kg, p < 0.05; 0.6 mg/kg, p < 0.05; i.p.) reduced immobility by increasing climbing in the forced swimming task (FST), whereas fluoxetine (1.0 mg/kg, p < 0.05; 2.0 mg/kg, p < 0.05; i.p.) reduced immobility by increasing swimming. Allopregnanolone (intra-NAcc; 0.5 microg/side) synergized with systemic doses of allopregnanolone (0.5 mg/kg; p < 0.05), muscimol (0.1 mg/kg; p < 0.05) or fluoxetine (0.5 mg/kg; p < 0.05) and reduced immobility by increasing climbing. Picrotoxin (0.125 mg/kg; i.p.) attenuated the synergism of the combination allopregnanolone (intra-NAcc; 0.5 microg/side) plus fluoxetine (i.p.) or allopregnanolone (s.c.) and the effects of allopregnanolone (intra-NAcc; 1.5 microg/side). Bicuculline (2.0 mg/kg; i.p.) attenuated the synergism between the combination allopregnanolone (intra-NAcc; 0.5 microg/side) plus muscimol (i.p.), but not the synergism of the combination allopregnanolone (intra-NAcc; 0.5 microg/side) plus allopregnanolone (s.c.). In conclusion, allopregnanolone (systemic injections or intra-NAcc), fluoxetine or muscimol produced antidepressant-like effects in the FST. Subthreshold doses of allopregnanolone (intra-NAcc) synergized with systemic subthreshold doses of fluoxetine, muscimol or allopregnanolone. Antagonists of the GABA-A receptor canceled the synergism.

Animals↗
PubMedDate not supplied

Regulation of melatonin and dopamine biosynthesis in chick retina: the role of GABA.

Melatonin biosynthesis in chick retina occurs as a circadian rhythm. Biosynthesis of the neurohormone is highest at night in darkness, and is suppressed by light. The role of gamma-aminobutyric acid (GABA) in the nocturnal regulation of melatonin synthesis was examined. Systemic or intravitreal administration of muscimol, a GABA-A receptor agonist, to light-exposed chicks at the beginning of the dark phase of the light/dark cycle increased retinal melatonin levels and the activity of serotonin N-acetyltransferase (NAT), a key regulatory enzyme of the melatonin biosynthetic pathway. Baclofen, a GABA-B receptor agonist, also increased NAT activity of light-exposed retinas, but muscimol was approximately 40-fold more potent than baclofen. Effects of both muscimol and baclofen on NAT activity were inhibited by GABA-A antagonists, bicuculline and picrotoxin, and the effect of baclofen was unaffected by the GABA-B selective antagonist, CGP 35348. Thus, activation of GABA-A receptors appears to be associated with increased melatonin biosynthesis. The GABA-uptake inhibitor, nipecotic acid, and the GABA-transaminase inhibitor, aminooxyacetic acid, also increased NAT activity of light-exposed retinas. The high levels of NAT activity associated with exposure to darkness were unaffected by either muscimol or baclofen, but picrotoxin and bicuculline significantly inhibited retinal NAT activity in darkness. The rate of dopamine synthesis, estimated from in situ tyrosine hydroxylase activity, was higher in light-exposed retinas than in darkness. Muscimol inhibited dopamine synthesis in light, and picrotoxin stimulated dopamine synthesis in darkness. The stimulation of melatonin synthesis by muscimol in light-exposed retinas appears to be related to inhibition of retinal dopamine neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Seizures in the developing brain.

PURPOSE: Development and sex hormones are important determinants of seizure susceptibility. Seizures develop in the immature brain more readily than in the mature brain. Male children experience a higher incidence of epilepsy or unprovoked seizures than do female children. Sex-specific differences in the development of seizure-suppressing neuronal networks may account, at least in part, for this increased age- and sex-related susceptibility to seizures. The control of seizures can be influenced by the substantia nigra pars reticulata (SNR) in an age- and sex-specific manner. In the adult male rat SNR, two topographically discrete regions (SNRanterior and SNRposterior) mediate distinct effects on seizures, by using divergent output networks in response to localized infusions of gamma-aminobutyric acid (GABA)A agents, such as muscimol. The GABAA-sensitive "anticonvulsant" region is located in the SNRanterior, whereas the GABAA-sensitive "proconvulsant region is in the SNRposterior. In immature postnatal day (PN)15-21 male rats, the SNR is not topographically segregated, and GABAAergic drug infusions produce similar effects when applied in the SNRanterior or SNRposterior. Only a GABAA-sensitive proconvulsant network is evident. By contrast, female SNR does not contain any region that mediates muscimol-related proconvulsant effects. As with the adult, immature female rats do not develop a proconvulsant SNR region at any age. METHODS: We measured the effects of SNR muscimol infusions on seizures in male rats castrated at birth to better understand the effects of testosterone on the formation of age- and sex-specific features of the SNR. RESULTS: Neonatal castration permanently alters the maturation of the muscimol-sensitive SNR effect on seizures. The SNR of neonatally castrated rats develops functionally like the "female" SNR. The "proconvulsant" SNR region does not develop in the absence of testosterone in the immediate postnatal period. The "male" type of SNR effects can be induced in neonatally castrated rats by restoration of testosterone levels or in female rats by artificially increasing testosterone levels. Dihydrotestosterone and estrogen, produced by the reduction and aromatization of testosterone, respectively, are the direct mediators of testosterone actions. At PN0, only beta estrogen receptors are equally expressed in the SNRs of males and females and may be responsible for testosterone-mediated effects in both sexes. CONCLUSIONS: The phenotype of SNR GABAergic neurons, as characterized by GABAA-receptor subunit composition, by muscimol-induced electrophysiologic responses, and by connectivity of output networks each may be altered by the presence of testosterone. Higher KCC2 messenger RNA (mRNA) expression in female PN15 SNR neurons compared with males may be responsible for sex-related differences in muscimol-induced electrophysiologic responses. In summary, a growing body of compelling evidence identifying sex-related differences in the SNR implicates postnatal testosterone as a critical factor in the development of pro- or anticonvulsant circuits. The recognition of sex- and age-related features in the SNR holds the promise that these findings can be translated into the development of specific and effective treatments for seizure disorders.

Age Factors↗