Inhibitory Effect Of Muscimol Research Articles

Inhibitory effect of activation of GABAA receptor in the central nucleus of amygdala on the sodium intake in the sodium-depleted rat

The present study investigated the effects of a microinjection of GABAA receptor agonist (muscimol) and antagonist (bicuculline) into the central nucleus of the amygdala (CeA) in sodium-depleted rats. We measured the sodium intake and identified the neuronal activation in the brainstem induced by activating the GABAA receptors in the CeA using Fos immunohistochemistry. Muscimol (0.20, 0.35 or 0.50nmol, in 0.2μl) that was injected bilaterally into the CeA decreased the 0.3M NaCl and water intake in a dose-dependent manner. Microinjection of 0.02nmol/0.2μl muscimol also decreased the NaCl intake, but had no effect on the water intake. The inhibitory effect of muscimol (0.20nmol) on the sodium and water intake could be blocked by pretreatment with bicuculline intra-CeA microinjection (0.4nmol). However, bilateral injections of bicuculline alone into the CeA did not affect the NaCl or water intake. Furthermore, microinjection of muscimol (0.20nmol) into the CeA increased the number of Fos-like immunoreactive (FLI) neurons in the caudal and intermediate parts of the nucleus of the tractus solitarius (cNTS and iNTS) and the lateral parabrachial nucleus (LPBN). These results suggest that GABAA receptors within the CeA may be involved in mediating the sodium intake in the sodium-depleted rat, and the cNTS, iNTS and LPBN were probably involved in this mechanism.

GABA A receptors in the mediodorsal thalamus play a crucial role in rat shell-specific acetylcholine-mediated, but not dopamine-mediated, turning behaviour

The role of GABA A receptors in the mediodorsal thalamus (mdT) in turning behaviour of rats was studied. Neither the GABA A receptor agonist muscimol (50 ng) nor the antagonist bicuculline (200 ng) unilaterally injected into the mdT elicited any behavioural change. Unilateral injection of the acetylcholine receptor agonist (carbachol, 5 μg) into the nucleus accumbens shell has been found to elicit contraversive circling while unilateral injection of a mixture of dopamine D 1 ((±)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393], 5 μg) and D 2 (quinpirole, 10 μg) receptor agonists into the same site is known to elicit contraversive pivoting. The contraversive circling induced by unilateral injection of carbachol (5 μg) into the nucleus accumbens shell was dose-dependently inhibited by muscimol (25 and 50 ng) injected into the mdT. This inhibitory effect of muscimol (50 ng) was antagonised by co-administration of bicuculline (200 ng), which alone did not modify the contraversive circling induced by carbachol (5 μg). The contraversive pivoting induced by unilateral injection of a mixture of SKF 38393 (5 μg) and quinpirole (10 μg) into the nucleus accumbens shell was inhibited by muscimol (25 and 50 ng) injected into the mdT, whereas bicuculline (200 ng) injected into the mdT did not significantly modify the pivoting. The inhibitory effect of muscimol (50 ng) on the pivoting induced by a mixture of SKF 38393 (5 μg) and quinpirole (10 μg) was not dose-dependent and not antagonised by bicuculline (200 ng). The present study suggests that GABA A receptors in the mdT play a limited role in spontaneously occurring locomotor activity. Secondly, this study demonstrates that GABA A receptors in the mdT transmit accumbens-dependent cholinergic circling, but not accumbens-dependent dopaminergic pivoting, to other brain structures. Finally, the present study shows that muscimol-sensitive, non-GABA A receptors in the mdT influence the accumbens-dependent dopaminergic pivoting. To what extent GABA B receptors in the mdT mediate the muscimol-induced effects upon the dopaminergic pivoting behaviour requires additional research.

Activation of Spinal GABA Receptors Attenuates Chronic Central Neuropathic Pain after Spinal Cord Injury

In this study, we investigated the role of the spinal GABAergic system in central neuropathic painlike outcomes following spinal cord injury (SCI) produced by a spinal hemitransection at T13 of the rat. After SCI, mechanical allodynia develops bilaterally in both hind paws of the rat, lasting longer than 40 days, as evidenced by an increase in paw withdrawal frequency in response to a weak von Frey filament. In naive rats, intrathecal (i.t.) administration in the lumbar spinal cord of GABAA and GABAB receptor antagonists, bicuculline (1-5 microg) and phaclofen (0.1-5 microg), respectively, causes a dose-dependent increase in the magnitude of mechanical allodynia. The SCI-induced mechanical allodynia in both hind-paws is attenuated by i.t. administration in the lumbar spinal cord of GABAA or GABAB receptor agonists, muscimol (1 microg) or baclofen (0.5 microg), respectively. In electrophysiological experiments, rats with SCI show a bilateral increase in hyperexcitability in response to natural stimuli in wide dynamic range (WDR) neurons in the lumbar spinal dorsal horn. The topical application of muscimol (1 microg) or baclofen (0.5 microg) onto the lumbar cord surface reduce the SCIinduced increased responsiveness of WDR neurons. Inhibitory effects of muscimol and baclofen on both the behavioral mechanical allodynia and the hyperexcitability in WDR neuron with SCI compared to controls, were antagonized by pre-treatment of bicuculline (10 microg) and phaclofen (5 microg), respectively. This study provides behavioral and electrophysiological evidence for the important role of the loss of spinal inhibitory tone, mediated by activation of both GABAA and GABAB receptors, in the development of central neuropathic pain following SCI.

GABAA and GABAB receptors in the nucleus accumbens shell differentially modulate dopamine and acetylcholine receptor-mediated turning behaviour

The ability of GABAA and GABAB receptors in the shell of the nucleus accumbens to modulate distinct types of turning behaviour was investigated in freely moving rats, using the unilateral injection technique. The GABAA receptor agonist muscimol and the GABAA receptor antagonist bicuculline did not produce turning behaviour; the same holds for the GABAB agonist baclofen and the GABAB antagonist 2-hydroxysaclofen. A mixture of the dopamine D1 receptor agonist SKF 38393 and the dopamine D2/3 receptor agonist quinpirole has been found to elicit contraversive pivoting, when injected into the shell. This pivoting was dose-dependently inhibited by muscimol, and the inhibitory effect of muscimol was antagonised by bicuculline. Pivoting was also dose-dependently inhibited by baclofen; however, 2-hydroxysaclofen did not antagonise the inhibitory effect. The acetylcholine receptor agonist carbachol has been found to elicit contraversive circling, when injected into the shell. This carbachol-induced circling was inhibited by baclofen, and 2-hydroxysaclofen antagonised the inhibitory effect. Carbachol-induced circling was also partially inhibited by muscimol; however, the inhibitory effect of muscimol was not antagonised by bicuculline. It is concluded that mesolimbic GABAA receptors exert an inhibitory control on dopamine-dependent pivoting that can be elicited from the shell of the nucleus accumbens, and that GABAB receptors exert an inhibitory control on acetylcholine-dependent circling that can be elicited from the shell of the nucleus accumbens. This data extends the earlier reported findings that the neurochemical substrate in the shell of the nucleus accumbens that mediates dopamine-dependent pivoting is fundamentally different from the shell substrate that mediates acetylcholine-dependent circling.

Effects of spinal administration of muscimol on C- and A-fibre evoked neuronal responses of spinal dorsal horn neurones in control and nerve injured rats

Neuropathic pain is a common clinical problem with complex aetiology, mechanisms and symptoms. Alterations in spinal γ-aminobutyric acid (GABA) receptors may contribute to persistent pain states. The aim of the present study is to investigate potential changes of spinal GABA A-receptor function following peripheral nerve injury. Effects of spinal administration of the GABA A-receptor agonist muscimol (0.1–30 μg/50 μl) on electrically-evoked responses of spinal neurones in control, spinal nerve ligated and sham operated halothane-anaesthetised rats were studied. Spinal muscimol significantly (10 μg/50 μl) reduced evoked Aβ-, Aδ- and C-fibre responses of spinal neurones in control rats (58±22% of control, P<0.05; 3±2% of control, P<0.001; and 8±7% of control, P<0.001; respectively). Muscimol produced significantly greater inhibition of Aδ- and C-fibre evoked neuronal responses compared to Aβ-fibre evoked neuronal responses in control rats ( P<0.001). C-fibre mediated post-discharge responses and the non-potentiated C-fibre evoked responses were significantly inhibited by muscimol in control rats. Inhibitory effects of muscimol (10 μg/50 μl) were blocked by pre-application of spinal bicuculline (10 μg/50 μl). Following either sham surgery, or spinal nerve ligation, spinal muscimol inhibited Aβ-, Aδ- and C-fibre evoked responses of spinal neurones to a similar extent, however significant inhibitory effects on the post-discharge response were not observed in nerve injured rats. Our data demonstrate that GABA A-receptor control of Aβ- and Aδ-fibre evoked responses are not altered in nerve injured or sham operated rats, compared to control. However, following nerve injury we report a reduction in GABA A-receptor control of C-fibre responses, in particular in relation to post-discharge responses.

AMPA-evoked acetylcholine release from cultured spinal cord motoneurons and its inhibition by GABA and glycine

The release of [ 3H]acetylcholine evoked by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and its inhibition mediated by GABA A and glycine receptors were studied in superfused cultured rat embryo spinal cord motoneurons prelabeled with [ 3H]choline. AMPA elicited tritium release, possibly representing [ 3H]acetylcholine release in a concentration-dependent manner. The release was external Ca 2+-dependent and was sensitive to Cd 2+ ions, ω-conotoxin GVIA and ω-conotoxin MVIIC, but not to nifedipine, suggesting the involvement of N-, P/Q-, but not L-type Ca 2+ channels. The AMPA effect was insensitive to tetrodotoxin. The glutamate receptors involved are AMPA type since the AMPA-evoked [ 3H]acetylcholine release was blocked by LY303070 and was potentiated by the antidesensitizing agent cyclothiazide. Muscimol inhibited completely the AMPA effect on [ 3H]acetylcholine release; muscimol was potentiated by diazepam and antagonized by SR95531, indicating the involvement of benzodiazepine-sensitive GABA A receptors. Glycine, acting at strychnine-sensitive receptors, also inhibited the effect of AMPA, but only in part. The inhibitory effects of muscimol and glycine are additive. We conclude that glutamate can act at AMPA receptors sited on spinal motoneurons to evoke release of acetylcholine. GABA and glycine, possibly released as cotransmitters from spinal interneurons, inhibit glutamate-evoked acetylcholine release by activating GABA A and glycine receptors on motoneurons.

Benzodiazepine-sensitive GABA(A) receptors limit the activity of the NMDA/NO/cyclic GMP pathway: a microdialysis study in the cerebellum of freely moving rats.

In the cerebellum, infusion of NMDA (200 microM) for 20 min evoked a marked (200%) increase of extracellular cyclic GMP (cGMP) levels. The selective GABA(A) receptor agonist muscimol (0.01-100 microM) was able to counteract the NMDA effect with an EC(50) of 0.65 microM; the inhibitory effect of muscimol (10 microM) was prevented by bicuculline (50 microM). Diazepam (10 microM) significantly potentiated the muscimol (1 microM) inhibition; furthermore, when coinfused with 0.1 microM muscimol (a concentration not affecting, on its own, the cGMP response to NMDA), diazepam (10 microM) reduced the NMDA effect. Similar results were obtained with zolpidem (0.1-1 microM). Finally, local infusion of the benzodiazepine site antagonist flumazenil (10 microM), together with muscimol and diazepam, almost completely restored the effect of NMDA on extracellular cGMP levels. It is concluded that GABA(A) receptors potently control the NMDA/nitric oxide/cGMP pathway in the cerebellum in vivo. In terms of the alpha subunit composition, we can deduce that the cerebellar GABA(A) receptor does not contain alpha(6) or beta(4) subunits because it is diazepam-sensitive. Moreover, the observation that zolpidem is active at a rather low concentration, in combination with localization studies present in the literature, tend to exclude the presence of alpha(5) subunits in the receptor composition and suggest the involvement of an alpha(1) subunit.

Reversal in concentrations of actived CaMKII and calcineurin for long lasting stimulation

The release of [3H]acetylcholine evoked by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and its inhibition mediated by GABAA and glycine receptors were studied in superfused cultured rat embryo spinal cord motoneurons prelabeled with [3H]choline. AMPA elicited tritium release, possibly representing [3H]acetylcholine release in a concentration-dependent manner. The release was external Ca2+-dependent and was sensitive to Cd2+ ions, ω-conotoxin GVIA and ω-conotoxin MVIIC, but not to nifedipine, suggesting the involvement of N-, P/Q-, but not L-type Ca2+ channels. The AMPA effect was insensitive to tetrodotoxin. The glutamate receptors involved are AMPA type since the AMPA-evoked [3H]acetylcholine release was blocked by LY303070 and was potentiated by the antidesensitizing agent cyclothiazide. Muscimol inhibited completely the AMPA effect on [3H]acetylcholine release; muscimol was potentiated by diazepam and antagonized by SR95531, indicating the involvement of benzodiazepine-sensitive GABAA receptors. Glycine, acting at strychnine-sensitive receptors, also inhibited the effect of AMPA, but only in part. The inhibitory effects of muscimol and glycine are additive.We conclude that glutamate can act at AMPA receptors sited on spinal motoneurons to evoke release of acetylcholine. GABA and glycine, possibly released as cotransmitters from spinal interneurons, inhibit glutamate-evoked acetylcholine release by activating GABAA and glycine receptors on motoneurons.

Interaction among alfaxalone, pregnenolone sulfate, and two GABAA agonists on hippocampal slices.

GABAA agonists do not respond to the same degree to allosteric modulators of the GABAA receptor complex such as benzodiazepines. We report there the effects of two steroids (alfaxalone and pregnenolone sulfate) on the inhibition induced by two GABAA agonists, 3-amino propane sulphonic acid (3-APS) and muscimol, on the extracellular evoked potentials obtained in CA1 of mice hippocampi. Alfaxalone (1 microM) potentiates the effects of both agonists, although incubation times longer than 15 minutes are required to potentiate the inhibitory effect of muscimol. Lower doses of pregnenolone sulfate at shorter incubation periods are able to inhibit the effects produced by single doses of 3-APS as compared to muscimol (15 microM during 5 min vs 30 microM during 5 min). Our results confirm the possibility that there might be differences in the interaction between GABAA agonists and modulatory steroids.

Central inhibitory effects of muscimol and bicuculline on the milk ejection reflex in the anaesthetized rat

Central inhibitory effects of muscimol and bicuculline on the milk ejection reflex in the anaesthetized rat

Pharmacological modulation of the pontine micturition center

Previous studies have indicated that an area of the rostral pontine tegmentum known as the ‘pontine micturition center’ (PMC) plays an essential role in the regulation of lower urinary tract function. The present pharmacologic experiments were conducted on either decerebrate unanesthetized or chloralose anesthetized cats to identify the location of the PMC and to examine the neurotransmitter mechanism controlling micturition. Microinjections of excitatory and inhibitory amino acids were made at stereotaxic coordinates P1 to P3, L2 to L3, H0 to H-4 where electrical stimulation with trains of pulses (2–30 V, 80–120 Hz and 50–300 ms train duration) elicited short latency (< 2s) bladder contractions or voiding. Injections of L-glutamate (L-GLUT) (20–130 nmol) or DL-homocysteic acid (DLH) (20–100 nmol) into the region of the locus coeruleus or parabrachial nucleus elicited voiding as well as an increase in the frequency or amplitude of isovolumetric bladder contractions. In some anesthetized animals, L-GLUT and DLH also had mixed excitatory-inhibitory or pure inhibitory effects. Injections of muscimol (9–70 nmol) depressed rhythmic bladder activity, increased the bladder volume for inducing micturition or completely abolished the voiding induced by bladder filling. The inhibitory effects of muscimol were reversed by microinjections of bicuculine methiodide (BCMI) (3–22 nmol). Injections of BCMI (1–1.5 nmol) into untreated cats stimulated bladder activity and lowered the bladder volume for inducing micturition. It is concluded that: (1) neurons in the rostral pons are an essential component of the micturition reflex pathway, (2) several populations of neurons located in the region of the locus coeruleus complex and parabrachial nucleus contribute to the functions of the PMC, and (3) PMC neurons are under a tonic GABAergic inhibitory control which regulates the micturition threshold and in turn regulates bladder capacity.

Evidence for GABA involvement in stress-induced inhibition of male amphibian sexual behavior

The behavioral effects of GABA analogs were investigated to determine whether GABAergic neurotransmission is involved in the stress-induced inhibition of masculine sexual behaviors in rough-skinned newts ( Taricha granulosa). Injections of bicuculline, a GABA antagonist, stimulated male sexual behaviors in a dose-dependent fashion, and the minimum effective dose was 40-fold less when administered centrally rather than systemically, suggesting a central nervous system site of action. Injections of muscimol, a GABA agonist, suppressed reproductive behaviors in male newts, and this inhibition lasted at least 5 hr and was proportional to the dose of muscimol administered. The inhibitory effects of muscimol on newt sexual behaviors could be reversed by a single 100-μg ip injection of arginine vasotocin. The inhibitory effects of confinement stress or corticosterone (CS) injections on newt sexual behaviors were blocked by pre-treatment of newts with mercaptopropionic acid, a blocker of GABA synthesis. As well, bicuculline prevented the inhibition of sexual behavior induced by CS injection. These results support the conclusion that, in a male amphibian, the GABAergic system is involved in the inhibitory mechanisms regulating sexual behaviors and that CS mediates the stress-induced inhibition of sexual behaviors through the GABAergic system.

GABA receptors are involved in the modulation of the release of 5-hydroxytryptamine from the vascularly perfused small intestine of the guinea-pig

Isolated small intestinal segments of the guinea-pig were perfused arterially and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) into the portal venous effluent was determined by HPLC with electrochemical detection. Test substances were applied intraarterially. Muscimol (1 μM) time dependently first increased then decreased the release of 5-HT and 5-HIAA. The stimulatory effect was prevented by tetrodotoxin (TTx) or scopolamine, indicating that it was mediated by the release of acetylcholine. Bicuculline concentration dependently decreased (1 μM) or increased (10, 50 μM) the release of 5-HT and 5-HIAA, indicating that endogenous GABA also activates stimulatory and inhibitory GABA A receptors. Bicuculline antagonized the stimulatory and inhibitory effect of muscimol. (-)-Baclofen, but not its (+) enantiomer, inhibited the release of 5-HT in the absence and presence of TTx. It was concluded that the release of 5-HT from enterochromaffin cells is directly inhibited by GABA A and GABA B receptors. In addition, acetylcholine released after activation of GABA A receptors stimulates 5-HT release.

Functional maturation of the GABAergic inhibition on dopamine-mediated behaviours during the neonatal period in the mouse

Previous works have indicated that systemic injection of GABA-agonists depress motoric behaviours in neonatal murids, suggesting an early maturation of GABAergic inhibitory processes. In this paper, the inhibitory effects of muscimol, a postsynaptic GABAA-agonist, on D-amphetamine-induced enhancement of locomotion, wall-climbing and head-raising were examined in neonatal 5-, 8- and 11-day-old mouse pups, using a direct observational procedure. The results show that muscimol can selectively attenuate high levels of locomotion, wall-climbing and head-raising produced by the indirect dopamine agonist in 8- as well as 11-day-old pups. However, while muscimol is able to moderate amphetamine-induced wall-climbing and head-rising in 5-day-old pups, no GABAergic inhibition was seen for locomotion at this age. Licking episodes elicited by amphetamine in 11-day-old pups can be magnified by muscimol if the dosage of the former is relatively too potent. It is suggested that the GABAergic inhibitory processes on dopaminergic functioning have reached good levels of functional maturation in the neonatal murid.

Evidence that clomethiazole interacts with the macromolecular GABA A-receptor complex in the central nervous system and in the anterior pituitary gland

Clomethiazole (CLOM) is known to be an anticonvulsant drug and has been also reported to decrease serum prolactin (PRL) in humans. Both effects may be mediated by an enhancement of gabaergic transmission. In order to determine if (CLOM) interacts with GABA metabolism and/or at the GABA receptor level, we studied its effect on PRL release and on the binding of various compounds that interact with the GABAA-benzodiazepine-receptor complex. Intraperitoneal (IP) administration of CLOM to rats significantly decreased PRL levels, and this effect was antagonized by IP administration of bicuculline, an antagonist of the GABAA receptor. In vitro, the inhibitory effect of muscimol on PRL release from rat hemiadenohypophysis was potentiated in a dose-dependent manner by preincubation with CLOM. This effect was antagonized by picrotoxin (10(-6) M). On the other hand, CLOM had no effect on GABA metabolism and did not compete with GABAA, GABAB or benzodiazepine binding sites in cortical membranes. CLOM competed, however, with the picrotoxin binding site labelled with [35S]-butylbicyclophosphorothionate (TBPS), at an IC50 value of 1.2 x 10(-4) M, which is in the same range as some barbiturates. These results concerning PRL release and binding experiments with cortical membranes suggest that CLOM interacts with the picrotoxin/barbiturate site of the GABAA-receptor-chloride channel complex.

Effect of GABAergic transmission in the subpallidal region on the hypermotility response to the administration of excitatory amino acids and picrotoxin into the nucleus accumbens

Excitatory amino acids and picrotoxin have been shown to produce an intense stimulation of co-ordinated locomotor activity after bilateral administration into the nucleus accumbens of rats. The objective of this study was to determine the role of GABAergic neurotransmission in the substantia innominata/lateral preoptic area in the hypermotility responses to excitatory amino acids and picrotoxin. It was found that the bilateral administration of muscimol into the substantia innominata/lateral preoptic area almost completely inhibited the stimulation of locomotor activity induced by the administration of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), kainic acid, N- methyl- d-aspartic acid and picrotoxin into the n. accumbens. In contrast, muscimol did not inhibit locomotor activity or induce catalepsy in control animals injected with saline into the nucleus accumbens. The inhibitory effect of muscimol on the hypermotility responses to excitatory amino acids and picrotoxin was not due to diffusion to the nucleus accumbens and the activation of GABAergic receptors at this site. This conclusion is supported by the finding that the doses of muscimol injected into the substantia innominata/lateral preoptic area, which effectively inhibited the responses to AMPA and picrotoxin, were either much less effective or not effective in inhibiting these responses when injected into the nucleus aecumbens. These observations suggest that the stimulation of locomotor activity produced by the injection of excitatory amino acids or picrotoxin into the nucleus accumbens may be mediated by the inhibition of a GABAergic neuronal pathway projecting from the nucleus accumbens to the substantia innominata/lateral preoptic area.

Regulation of [3H]GABA release from strips of guinea pig urinary bladder.

The presence of receptors that regulate the release of gamma-aminobutyric acid (GABA) was studied in strips of the guinea pig urinary bladder. GABA (10(-8)-10(-5) M) and muscimol (10(-8)-10(-5) M), but not baclofen (10(-5) M), reduced the Ca2+-dependent, tetrodotoxin-resistant release of [3H]GABA evoked by high K+ from the urinary bladder strips preloaded with [3H]GABA. The inhibitory effect of muscimol was antagonized by bicuculline and potentiated by diazepam, clonazepam, and pentobarbital sodium. The potentiating effect of clonazepam was antagonized by Ro 15-1788. Acetylcholine (ACh) inhibited the high K+-evoked release of [3H]GABA. The inhibitory effect of ACh was antagonized by atropine sulfate and pirenzepine but not by hexamethonium. Norepinephrine (NE) inhibited the evoked release of [3H]GABA. The inhibitory effect of NE was mimicked by clonidine, but not by phenylephrine, and was antagonized by yohimbine but not by prazosin. These results provide evidence that the release of GABA from strips of guinea pig urinary bladder is regulated via the bicuculline-sensitive GABAA receptor, M1-muscarinic, and alpha 2-adrenergic receptors.

Effects of GABA-Mimetic Drugs on Turnover of Histamine in the Mouse Brain

AbstractThe effect of GABA-mimetics on histaminergic activity in the mouse brain was investigated. Systemic administration of muscimol (2 and 5 mg/kg). THIP (5–15 mg/kg) and aminooxyacetic acid (AOAA) (25 mg/kg) but not baclofen (2.5–15 mg/kg) inhibited the pargylme (65 mg/kg)-mduced accumulation of tele-methylhistamine (t-MH). There was no regional difference in the inhibitory effect of muscimol on the t-MH accumulation by pargyline treatment. Muscimol and AOAA also inhibited decrease in the histamine (HA) level induced by α-fluoromethylhistidme (50 mg/kg). a specific inhibitor of histidine decarboxylase. These results suggest that these GABA-mimetics reduce the HA turnover in the mouse bram.

Suppression of a somatosympathetic reflex by the gamma-aminobutyric acid agonist muscimol and by clonidine.

gamma-Aminobutyric acid (GABA) and GABA agonists, e.g., muscimol, reduce blood pressure and sympathetic outflow and inhibit the "carotid occlusion reflex." In contrast, muscimol exerted only marginal effects on postural reflexes in a prior study. The somatosympathetic reflex, i.e., potentials evoked in sympathetic nerves in response to sensory nerve stimulation, is a useful model for studying centrally acting drugs. Effects of muscimol on the reflex were examined in anesthetized normotensive rats. At doses which had previously been shown to reduce blood pressure but to produce only minimal attenuation of postural reflexes in conscious hypertensive rats, muscimol, administered intracerebroventricularly, reduced blood pressure and inhibited the somatosympathetic reflex in the present study. The time course of the evoked potential was not altered. Baroreceptor activation and intracerebroventricular clonidine also suppressed the reflex. The inhibitory effect of muscimol but not that of clonidine was prevented by pretreatment with the GABA antagonist bicuculline. Thus, the marked suppression of the somatosympathetic reflex by muscimol and by clonidine, in contrast to minimal effects on postural reflexes, point to the selectivity of their central inhibitory actions.

Presynaptic GABA autoreceptors on gabaergic nerve endings of the rat substantia nigra

The release of 3H-GABA evoked by exposure to 30 mM potassium during 1 min was found to be calcium independent in the rat occipital cortex and calcium dependent in the substantia nigra. Exposure to either muscimol 1 μM or GABA 1 μM inhibited the potassium-evoked release release of 3H-GABA from the substantia nigra but not from the occipital cortex. The inhibitory effect of muscimol 1 μM on the pitassium-evoked release of 3H-GABA from the substantia nigra was significantly antagonized by picrotoxin 10 μM. Exposure to either 10 or 100 μM pricotoxin alone did not affect the potassium-evoked release of 3H-GABA. These results are compatible with the presence of a negative feedback mechanism in gabaergic nerve terminals of the rat substantia nigra which is mediated by presynaptic GABA autoreceptors. In addition, these results emphasize the importance of the calcium-dependent dependent nature of the release of the neurotransmitter for demonstrating the modulation of transmitter release through presynaptic receptors.