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PubMed2000

GABAergic contribution to rat bladder hyperactivity after middle cerebral artery occlusion.

To evaluate the influences of gamma-aminobutyric acid (GABA) mechanisms on bladder hyperactivity after left middle cerebral artery occlusion, cystometric recordings were obtained from unanesthetized female rats. Intracerebroventricular administration of both muscimol (GABA(A) receptor agonist; 0.1-10 nmol) and baclofen (GABA(B) receptor agonist; 0.1-3 nmol) produced dose-dependent inhibitions of micturition with increases in bladder capacity (BC). The effects of high doses (1-10 nmol) were similar in sham-operated (SO) and cerebral-infarcted (CI) rats. However, lower doses of muscimol (0.1 or 0.3 nmol) and baclofen (0.1 nmol) reduced BC in CI rats. After bicuculline (GABA(A) receptor antagonist; 1 or 3 nmol) administration, BC in both SO and CI rats first decreased and subsequently increased. An increase in urethral pressure was observed after administration of bicuculline (3 nmol) but not with either muscimol or baclofen. Infarct volumes in muscimol-, bicuculline-, or baclofen-treated rats were not significantly different from those of vehicle-treated rats. These results suggest that GABAergic mechanisms inhibit the micturition reflex at the supraspinal level but that this can change as a result of CI.

Animals↗
PubMed2003

Involvement of the dorsolateral prefrontal cortex of monkeys in visuospatial target selection.

To examine the involvement of the dorsolateral prefrontal cortex (PFC) in visuospatial target selection, we induced local, reversible inactivation with muscimol at various sites in the dorsolateral PFC of two rhesus monkeys while they performed oculomotor visual search (OVS) and oculomotor detection (OD) tasks. The OVS task required the subject to select a target stimulus from among distractors and to make a saccade to the target location (target selection was required for correct performance), whereas the OD task only required a saccade to the target (target selection was not required for correct performance). The local injection of muscimol (5 microg, 1 microl) into the dorsolateral PFC induced a specific deficit in the OVS task but not in the OD task. The deficit in the OVS task was characterized by the disordering of saccades for some (mostly a few) particular target locations as well as by prolongation of the time required for the visual search in most cases. The target locations affected by muscimol were biased to the contralateral visual field. Further, the OVS task with "pop-out" and "non-pop-out" conditions was similarly impaired by muscimol injection. These results suggest that the dorsolateral PFC plays a role in target selection in visual space to guide goal-directed motor acts and particular sites are involved in target selection for a particular visuospatial coordinate. Further, this function of the dorsolateral PFC appears to involve both top-down (active) and bottom-up (passive) target-selection/selective attention processes to control interfering information (distractors).

Animals↗
PubMed1998

Effects of cerebellar nuclear inactivation on the learning of a complex forelimb movement in cats.

The purpose of this study was to determine the effects of inactivating concurrently the cerebellar interposed and dentate nuclei on the capacity of cats to acquire and retain a complex, goal-directed forelimb movement. To assess the effects on acquisition, cats were required to learn to move a vertical manipulandum bar through a two-segment template with a shape approximating an inverted "L" after the injection of muscimol (saline for the control group) in the interposed and dentate cerebellar nuclei. During training periods, they were exposed progressively to more difficult templates, which were created by decreasing the angle between the two segments of the template. After determining the most difficult template the injected animals could learn within the specified time and performance constraints, the retraining phase of the experiment was initiated in which the cats were required to execute the same sequence of templates in the absence of any injection. This stage of the experiment assessed retention and determined the extent of any relearning required to execute the task at criterion levels. Next, the animals were overtrained without any injection on the most difficult template they could perform. Finally, to determine the effects of nuclear inactivation on retention after extensive retraining, their capacity to perform the same template was determined after muscimol injection in the interposed and dentate nuclei. The findings show that during the inactivation of the dentate and interposed nuclei the animals could learn to execute the more difficult templates. However, when required to execute the most difficult template learned under muscimol on the day after injections were discontinued, the cats had to "relearn" (reacquire) the movement. Finally, when the cerebellar nuclei were inactivated after the animals learned the task in the absence of any injections during the retraining phase, retention was not blocked. The data indicate that the intermediate and lateral cerebellum are not required either for learning this type of complex voluntary movement or for retaining the capacity to perform the task once it is learned. Nevertheless, when the cerebellum becomes available for executing a task learned in the absence of this structure, reacquisition of the behavior usually is necessary. It is hypothesized that the relearning observed after acquisition during muscimol inactivation reflects the tendency of the system to incorporate the cerebellum into the interactions responsible for the learning and performance of a motor sequence that is optimal for executing the task.

Animals↗
PubMed1999

Evidence for chloride ions as intracellular messenger substances in astrocytes.

Cultured rat hippocampal astrocytes were used to investigate the mechanism underlying the suppression of Ba2+-sensitive K+ currents by GABAA receptor activation. Muscimol application had two effects on whole cell currents: opening of the well-known Cl- channel of the GABAA receptor and a secondary longer-lasting blockade of outward K+ currents displaying both peak and plateau phases. This blockade was independent of both Na+ (inside and outside) and ATP in the pipette. It also seemed to be independent of muscimol binding to the receptor because picrotoxin application showed no effect on the K+ conductance. The effect is blocked when anion efflux is prevented by replacing Cl- with gluconate (both inside and out) and is enhanced with more permeant anions such as Br- and I-. Moreover, the effect is reproduced in the absence of muscimol by promoting Cl- efflux via lowering of extracellular Cl- levels. These results, along with the requirement for Cl- efflux in muscimol experiments, show a strong dependency of the secondary blockade on Cl- efflux through the Cl- channel of the GABAA receptor. We therefore conclude that changes in the intracellular Cl- concentration alter the outward K+ conductances of astrocytes. Such a Cl--mediated modulation of an astrocytic K+ conductance will have important consequences for the progression of spreading depression through brain tissue and for astrocytic swelling in pathological situations.

Animals↗
PubMed1999

Impaired reaching and grasping after focal inactivation of globus pallidus pars interna in the monkey.

The purpose of this study was to test the hypothesis that the basal ganglia output from globus pallidus pars interna (GPi) contributes to inhibition of competing motor patterns to prevent them from interfering with a volitional movement. To test this hypothesis, the kinematics of a natural reach, grasp, and retrieval task were measured in the monkey before and after focal inactivation in GPi with the GABA(A) agonist muscimol. Two rhesus monkeys were trained to reach in a parasagittal plane to grasp a 1-cm cube of apple and retrieve it. Reflective markers were applied to the shoulder, elbow, wrist, and index finger. Movements were videotaped at 60 fields/s, digitized, and analyzed off-line. In each session the monkey performed 12-15 reaches before and 12-15 reaches after injection of 0.5 microl of 8.8 mM muscimol. Muscimol was injected into 22 separate locations in the "arm" area of GPi. Inactivation of the GPi with muscimol produced movement deficits in a reach-grasp-retrieve task that can be summarized as follows: 1) decreased peak wrist velocity during the reach to target; 2) decreased elbow and shoulder angular velocities, with elbow angular velocity relatively more impaired than shoulder angular velocity; resulting in 3) higher maximum vertical wrist and index finger positions at the apex of the reach; 4) prolonged latency from the end of the reach to the completion of grasp; and 5) less impairment of retrieval than reach, with inactivation at the majority of sites causing no impairment and some actually speeding up retrieval despite slow reaching. The results of this study show that reaching movements are impaired in a specific way after focal inactivation of GPi in previously normal monkeys. The slowing of the reach with normal (or fast) retrieval suggests that there is difficulty inhibiting the posture holding mechanisms that were active before the reach, but that assist the retrieval. The nature of the impairment supports the hypothesis that GPi lesions disrupt the ability to inhibit competing motor mechanisms to prevent them from interfering with desired voluntary movement.

Animals↗
PubMed2000

Impairments in prehension produced by early postnatal sensory motor cortex activity blockade.

This study examined the effects of blocking neural activity in sensory motor cortex during early postnatal development on prehension. We infused muscimol, either unilaterally or bilaterally, into the sensory motor cortex of cats to block activity continuously between postnatal weeks 3-7. After stopping infusion, we trained animals to reach and grasp a cube of meat and tested behavior thereafter. Animals that had not received muscimol infusion (unilateral saline infusion; age-matched) reached for the meat accurately with small end-point errors. They grasped the meat using coordinated digit flexion followed by forearm supination on 82.7% of trials. Performance using either limb did not differ significantly. In animals receiving unilateral muscimol infusion, reaching and grasping using the limb ipsilateral to the infusion were similar to controls. The limb contralateral to infusion showed significant increases in systematic and variable reaching end-point errors, often requiring subsequent corrective movements to contact the meat. Grasping occurred on only 14.8% of trials, replaced on most trials by raking without distal movements. Compensatory adjustments in reach length and angle, to maintain end-point accuracy as movements were started from a more lateral position, were less effective using the contralateral limb than ipsilateral limb. With bilateral inactivations, the form of reaching and grasping impairments was identical to that produced by unilateral inactivation, but the magnitude of the reaching impairments was less. We discuss these results in terms of the differential effects of unilateral and bilateral inactivation on corticospinal tract development. We also investigated the degree to which these prehension impairments after unilateral blockade reflect control by each hemisphere. In animals that had received unilateral blockade between postnatal weeks (PWs) 3 and 7, we silenced on-going activity (after PW 11) during task performance using continuous muscimol infusion. We inactivated the right (previously active) and then the left (previously silenced) sensory motor cortex. Inactivation of the ipsilateral (right) sensory motor cortex produced a further increase in systematic error and less frequent normal grasping. Reinactivation of the contralateral (left) cortex produced larger increases in reaching and grasping impairments than those produced by ipsilateral inactivation. This suggests that the impaired limb receives bilateral sensory motor cortex control but that control by the contralateral (initially silenced) cortex predominates. Our data are consistent with the hypothesis that the normal development of skilled motor behavior requires activity in sensory motor cortex during early postnatal life.

Age Factors↗
PubMed2001

Activation of GABA(A) receptors in subthalamic neurons in vitro: properties of native receptors and inhibition mechanisms.

The subthalamic nucleus (STN) influences the output of the basal ganglia, thereby interfering with motor behavior. The main inputs to the STN are GABAergic. We characterized the GABA(A) receptors expressed in the STN and investigated the response of subthalamic neurons to the activation of GABA(A) receptors. Cell-attached and whole cell recordings were made from rat brain slices using the patch-clamp technique. The newly identified epsilon subunit confers atypical pharmacological properties on recombinant receptors, which are insensitive to barbiturates and benzodiazepines. We tested the hypothesis that native subthalamic GABA(A) receptors contain epsilon proteins. Applications of increasing concentrations of muscimol, a selective GABA(A) agonist, induced Cl(-) and HCO currents with an EC(50) of 5 microM. Currents induced by muscimol were fully blocked by the GABA(A) receptor antagonists, bicuculline and picrotoxin. They were strongly potentiated by the barbiturate, pentobarbital (+190%), and by the benzodiazepines, diazepam (+197%) and flunitrazepam (+199%). Spontaneous inhibitory postsynaptic currents were also significantly enhanced by flunitrazepam. Furthermore, immunohistological experiments with an epsilon subunit-specific antibody showed that the epsilon protein was not expressed within the STN. Native subthalamic GABA(A) receptors did not, therefore, display pharmacological or structural properties consistent with receptors comprising epsilon. Burst firing is a hallmark of Parkinson's disease. Half of the subthalamic neurons have the intrinsic capacity of switching from regular-firing to burst-firing mode when hyperpolarized by current injection. This raises the possibility that activation of GABA(A) receptors might trigger the switch. Statistical analysis of spiking activity established that 90% of intact neurons in vitro were in single-spike firing mode, whereas 10% were in burst-firing mode. Muscimol reversibly stopped recurrent electrical activity in all intact neurons. In neurons held in whole cell configuration, membrane potential hyperpolarized by -10 mV whilst input resistance decreased by 50%, indicating powerful membrane shunting. Muscimol never induced burst firing, even in neurons that exhibited the capacity of switching from regular- to burst-firing mode. These molecular and functional data indicate that native subthalamic GABA(A) receptors do not contain the epsilon protein and activation of GABA(A) receptors induces membrane shunting, which is essential for firing inhibition but prevents switching to burst-firing. They suggest that the STN, like many other parts of the brain, has the physiological and structural features of the widely expressed GABA(A) receptors consisting of alphabetagamma subunits.

Animals↗
PubMed2001

Honokiol and magnolol selectively interact with GABAA receptor subtypes in vitro.

Honokiol and magnolol have been identified as modulators of the GABAA receptors in vitro. Our previous study suggested a possible selectivity of honokiol and magnolol on GABAA receptor subtypes. This possibility was examined in the current study by 3H-muscimol and 3H-flunitrazepam binding assays on various rat brain membrane preparations and human recombinant GABA(A) receptor subunit combinations expressed by the Sf-9/baculovirus system. Generally, honokiol and magnolol have a similar enhancing effect on (3)H-muscimol binding to various membrane preparations in nonsaturation binding assays. Honokiol and magnolol preferentially increased (3)H-muscimol binding to hippocampus compared to cortex and cerebellum (with a maximum enhancement of 400% of control). As for subunit combinations, honokiol and magnolol have a more potent enhancing effect on alpha2 subunit containing combinations (with a maximum enhancement of 400-450% of control). This action was independent of the gamma subunit. In saturation binding assays, magnolol affected either the number of binding sites (ca. 4-fold on alpha2 containing combinations) or the binding affinity (on alpha1 containing combinations) of (3)H-muscimol binding to various GABAA receptor subunit combinations. In contrast, honokiol increased only binding sites on alpha2beta3gamma2s and alpha2beta3 combinations, but both the number of binding sites and the binding affinity on alpha1beta2gamma2S and alpha(1)beta2 combinations. These results indicate that honokiol and magnolol have some selectivity on different GABAA receptor subtypes. The property of interacting with GABAA receptors and their selectivity could be responsible for the reported in vivo effects of these two compounds.

Animals↗
PubMed1981

Biochemical development of the human brain. II. Some parameters of the GABA-ergic system.

The development of the gamma-aminobutyrate (GABA)-ergic system in the human cerebral cortex and cerebellum was studied in post mortem specimens, by estimating the activity of glutamate decarboxylase (GAD) and the binding capacity for muscimol as markers of GABA-ergic nerve terminals and GABA receptors respectively. The age periods studied were as follows (number of specimens in parentheses): fetal period, 17--24 and 28 weeks, gestational age (GA) (15); perinatal period, 26--42 weeks GA (9); postnatal period, 43--56 and 74 weeks GA (11); adult life, 26, 47, 57--73 years (9). Total protein and DNA were estimated in all specimens. Differences between the cerebral cortex and the cerebellum in the ontogenesis of the GABA-ergic system were revealed. In the cerebral cortex, GAD-specific activity increased progressively during development, but at term had only reached approximately 20% of the adult value, and the trend in the postnatal specimens indicated that the adult level is not reached until some time after 60 weeks GA. The concentration of muscimol binding sites, on the other hand, rose more rapidly than GAD activity with age in the cerebral cortex, attaining adult values by 60 weeks GA and being already at term approximately 45% of the mean adult figure. In the cerebellum, the relative development of pre- and postsynaptic markers was the reverse of that in the cerebral cortex: GAD specific activity had reached the adult value by 60 weeks GA and approximately 40% of this adult level was attained at term, while the muscimol binding site concentration was only about 10% of the adult value at term and was still increasing at 60 weeks GA. The affinity of the receptor for [3H]-muscimol did not change during development, and was the same in cerebral cortex and cerebellum.

Adult↗
PubMed1989

Regulation of high-affinity GABAa receptors in specific brain regions by ovarian hormones.

The regulation of 3H-muscimol binding to high-affinity GABAa receptors by estradiol (E) and by progesterone (P) was studied within discrete brain regions using in vitro quantitative autoradiography. Treatment of ovariectomized and adrenalectomized female rats with E resulted in a decrease of muscimol binding only in specific estrogen-sensitive brain regions like the ventromedial nuclei (VMN) of the hypothalamus, the arcuate nucleus (ARC), the medial amygdala and the midbrain central grey (MCG). When administered alone, P had no effect. However, in estrogen-primed females, P increased muscimol binding in both VMN and MCG to levels seen in control animals. Thus, E and P exert opposite effects on the GABAa receptor within these two nuclei. As both hormones facilitate female reproductive behavior as well as the release of luteinizing hormone, present results suggest that E and P affect muscimol binding by different mechanisms.

Adrenalectomy↗
PubMed1990

On the relationship between noradrenergic stimulatory and GABAergic inhibitory systems in the control of luteinizing hormone secretion in female rats.

The relationship between noradrenergic (NA) stimulatory and gamma-aminobutyric acid (GABA)-mediated inhibitory systems in the control of luteinizing hormone (LH) secretion was examined in ovariectomized rats. Stimulation of the GABAA receptor by an intraventricular (i.c.v.) administration of a GABAA agonist, muscimol, significantly attenuated the LH secretory response to the subsequent i.c.v. injection of NA in estrogen-primed rats. On the other hand, blockade of alpha-adrenergic receptors by phenoxybenzamine did not interfere with the stimulatory effect of an i.c.v. injection of a GABAA antagonist bicuculline. In a different series of experiments, ovariectomized animals had been treated with i.c.v. injections of 6-hydroxydopamine (6-OHDA) or its vehicle. An i.c.v. injection of muscimol or phentolamine significantly inhibited the estrogen-induced surge of LH secretion in vehicle-treated rats. Muscimol also inhibited the existing pulsatile LH secretion in vehicle-treated, estrogen-unprimed animals. In animals in which hypothalamic NA terminals were presumed to be destroyed by 6-OHDA, the inhibitory effect of phentolamine was significantly diminished while that of muscimol was unaltered. These results permit the following conclusions: (1) the central GABAergic system inhibits LH secretion via GABAA receptors; (2) this inhibitory GABA system operates without mediation by the NA system, and (3) the GABAergic non-NA-mediated system can affect physiological patterns of pituitary LH secretion in female rats.

Animals↗
PubMed1990

Predominant epithelial localization of type A gamma-aminobutyric acid receptor sites within rat seminal vesicles and prostate glands.

In order to understand the role of the gamma-aminobutyric acid (GABA)-ergic system in the reproductive organs of the male, the biochemical characteristics and the autoradiographic localization of GABA type A (GABAA) receptor sites were studied in sections of the rat epididymis, seminal vesicles and prostate gland (lateral lobe) using 3H-muscimol as a ligand. No specific 3H-muscimol binding occurred in the epididymis. 3H-muscimol was bound to sections of seminal vesicles and prostate glands in a manner consistent with the labeling of specific GABAA receptors. Binding was saturable, reversible, with Kd values of 27.5 +/- 2.0 and 26.0 +/- 1.9 nmol/l and Bmax values of 230 +/- 21 and 160 +/- 13 fmol/mg protein for seminal vesicles and prostate glands, respectively. The rank order of potency of GABAergic drugs in inhibiting 3H-muscimol binding to sections of seminal vesicles and prostate glands was also consistent with the labeling of GABAA receptors. Autoradiography demonstrated the predominant accumulation of silver grains in the epithelium of seminal vesicles and prostatic glandular tissue. These findings further support the suggestion of a possible role of GABA in the male reproductive function. The predominant epithelial localization of GABAA receptors in the seminal vesicles and in the prostate gland allows us to hypothesize that GABA may be involved in the secretory activities of these glands.

Animals↗
PubMed1989

Hypothalamic GABA and sympathetic regulation in spontaneously hypertensive rats.

The posterior hypothalamus contains a sympathoexcitatory system that can be modulated by changes in GABAergic tone. We tested the hypothesis that the GABAergic mechanism in the posterior hypothalamus is altered in spontaneously hypertensive rats (SHR) compared with the Wistar-Kyoto (WKY) control rats. Blood pressure and heart rate were continuously measured in the conscious state; blood samples were obtained for determination of plasma catecholamine concentrations. Bilateral microinjections of the GABAA receptor antagonist bicuculline methiodide into the posterior hypothalamus increased heart rate and blood pressure in a dose-related fashion and increased plasma catecholamine concentrations in both SHR and WKY rats. The responses were not significantly different between the two strains of rats. Microinjections of the GABAA receptor agonist muscimol in this same region caused dose-related decreases in both heart rate and blood pressure in SHR and WKY rats. Although the decreases in heart rate caused by muscimol were not significantly different between the SHR and WKY rats, the decreases in blood pressure were significantly greater in SHR compared with WKY rats. Further, microinjection of muscimol caused a significant decrease in plasma catecholamines in SHR but not in WKY rats. These data indicate that in SHR and WKY rats the posterior hypothalamus contains a sympathoexcitatory mechanism that is tonically inhibited by GABA. The ability of muscimol to decrease plasma catecholamines selectively in SHR and to cause greater decreases in blood pressure, suggests that the GABAergic mechanisms in the posterior hypothalamus of the SHR and WKY rats may differ.

Animals↗
PubMed1992

Protective effect of synaptic inhibition during cerebral ischemia in rats and rabbits.

BACKGROUND: Excitatory neurotransmitters appear to cause cell death during ischemia by inducing depolarization, influx of ions, and metabolic failure in the postsynaptic neuron. If this hypothesis is correct, then postsynaptic membrane hyperpolarization and inhibition of metabolism may be protective. Antagonists of the excitotoxic amino acid glutamate protect neurons in culture and in animal models of stroke but appear to cause unacceptable side effects in humans. We propose an alternative strategy of protection using agonists of the inhibitory neurotransmitter gamma-aminobutyric acid. METHODS: We caused multifocal cerebral ischemia in rats and rabbits by injecting microspheres into the carotid circulation. We administered saline, muscimol, or MK-801 within 5 minutes of stroke onset. We used a bioassay to measure outcome. In rats, we also used learning to assess cortical function, and we performed detailed quantitative brain morphometry 3 months after infarction. RESULTS: Using the bioassay, we found that muscimol exerted a protective effect in rats (p less than 0.01). There was a dose-response effect seen in muscimol-treated rabbits. Rats treated with muscimol or MK-801 exhibited significantly better visual-spatial learning compared with saline-treated subjects (p less than 0.001). Hemisphere volume after ischemia was comparable in all groups. CONCLUSIONS: Agonists of gamma-aminobutyric acid and antagonists of glutamate appear to protect brain during ischemia. Since agonists of gamma-aminobutyric acid are known to have fewer side effects in humans, they may prove more useful in the clinical setting as neuroprotective agents.

Animals↗
PubMedDate not supplied

Examination of the mechanisms of action of diverse cytoprotectants in renal cell death.

Glycine, strychnine, muscimol, allopregnanolone, and pregnenolone sulfate act in the late phase of renal cell injury, block Cl- influx and cell lysis induced by the mitochondrial inhibitor antimycin A, and promote the recovery of respiration and ion transport following hypoxia/reoxygenation. However, the mechanism of action of these compounds has not been completely elucidated. Recently, we have shown that calpains are critical mediators of renal cell death produced by diverse toxicants and that antimycin A exposure results in calpain translocation from the cytosol to the membrane fraction that is temporally associated with Cl- influx and precedes cell death/lysis. The current study examined the effects of a group of diverse cytoprotectants on calpain activity and determined if calpain inhibition plays a role in the cytoprotection produced by these compounds. The cytoprotection produced by glycine, strychnine, muscimol, allopregnanolone, and pregnenolone sulfate in rabbit renal proximal tubules exposed to antimycin A was associated with the inhibition of antimycin A-induced calpain translocation. None of the cytoprotectants had a direct effect on calpain activity. All of the cytoprotectants decreased calcium-ionophore-induced cell death. Glycine, strychnine, and muscimol also blocked antimycin A mediated extracellular Ca2+ influx. These data suggest that the cytoprotective mechanism of action of glycine, strychnine, and muscimol involves the inhibition of antimycin A mediated extracellular Ca2+ influx as well as calpain translocation and associated Cl- influx. In contrast, the mechanism of action of the neurosteroids results only from the blockade of calpain translocation and associated Cl- influx.

Animals↗
PubMed2002

Effect of intracerebroventricular injection of GABA receptor agents on morphine-induced antinociception in the formalin test.

In the present study, the effects of gamma-aminobutyric acid (GABA) receptor agonists and antagonists on antinociception induced by morphine in the formalin test were investigated in rats. Intraperitoneal (i.p.) injection of different doses of morphine (1, 3, 6 and 9 mg/kg) and intracerebroventricular (i.c.v.) injection of different doses of muscimol (0.5, 1 and 2 microg per rat) or baclofen (0.25, 0.5 and 1 microg per rat) induced a dose-related antinociception in the both first and second phases of the formalin test. The responses induced by muscimol or baclofen in both phases were reduced by bicuculline or CGP35348 [p-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid], respectively. Bicuculline alone has produced antinociception in the second phase and CGP35348 alone has had antinociception in both phases of the formalin test. Morphine in combination with different doses of muscimol or baclofen did not elicit potentiation. The opioid receptor antagonist naloxone reduced the response induced by muscimol in the second phase and baclofen in both phases of the formalin test. It may be concluded that central GABA(A) and GABA(B) receptor stimulation induces antinociception in the formalin test. However, the antinociception induced by GABA receptor agonists may be mediated partly through supraspinal opioid receptor mechanisms and, for the GABA(B) receptor agonist, through spinal and supraspinal opioid receptor mechanisms.

Analgesics, Opioid↗
PubMed2002

Effects of intrahippocampal injection of GABAergic drugs on memory retention of passive avoidance learning in rats.

The effect of post-training intrahippocampal injection of gamma-aminobutyric acid (GABA) receptor agonists and antagonists, immediately after a training session on memory retention of passive avoidance learning in rats, was measured in the presence and absence of physostigmine. Post-training treatments were carried out in all the experiments. The different doses of the GABAA receptor agonist muscimol (2, 4 and 6 microg/rat) decreased memory retention in rats dose-dependently. The higher response was obtained with 6 microg/rat of the drug. When the GABAA receptor antagonist bicuculline (0.5, 1, 2 and 4 microg/rat) was administered, only one dose of the drug (1 microg/rat) increased memory retention; however, the antagonist reduced the effect of muscimol. The GABAB receptor agonist, baclofen (0.25, 0.5, 1 and 2 microg/rat) also reduced memory retention in the animals. Intrahippocampal injection of lower doses of the GABAB receptor antagonist CGP35348 (P-[3-aminopropyl]-p-diethoxymethyl-phosphinic acid) (2.5, 5, 10 microg/rat) did not effect memory retention, although the higher doses of the drug (25 and 50 microg/rat) decreased memory retention. The doses of antagonist (2.5, 5 and 10 microg/rat), which did not elicit any response alone, reduced the effect of baclofen. The inhibitory response of CGP35348 was also decreased by bicuculline. In another series of experiments, physostigmine improved memory retention. The GABA receptor agonists, muscimol and baclofen, as well as the GABA receptor antagonists bicuculline and CGP35348, decreased the effect of physostigmine. Atropine decreased memory retention by itself and potentiated the response of muscimol and baclofen. It is concluded that GABAA and GABAB receptor activation may be involved in the impairment of memory retention.

Animals↗
PubMed2000

Luteinizing hormone-releasing hormone (LHRH) biosynthesis and secretion in embryonic LHRH.

Evidence indicates that LH-releasing hormone (LHRH) neurons can exhibit neuroendocrine secretory properties before entrance into the central nervous system. In this study, we evaluated LHRH biosynthesis and secretion in embryonic LHRH neurons maintained in nasal explants. Using ELISA and calcium imaging techniques, peptide content and single neuron activities were examined. LHRH neurons maintained for 7-10 days in vitro were found to possess a similar amount of LHRH/cell as the equivalent aged LHRH cells in vivo (postnatal day 1). LHRH peptide was measured in the medium of these relatively young cultures, and 40 mM KCl stimulated a 4-fold increase in LHRH secretion. KCl enhanced medium also resulted in a significant increase in LHRH content per culture (24.5 pg vs. 32.3). A similar effect was observed after muscimol-enhanced media (32.2 pg). Both agents also stimulated a substantial rise in intracellular calcium. Pretreatment of cultures with tetrodotoxin partially blocked the affects of muscimol on both peptide content and calcium activity, but not KCl. Calcium-depleted medium blocked the effects of KCl yet only attenuated the effects of muscimol. Treatment of cultures with cycloheximide blocked the effects of both muscimol and KCl. These results indicate that developing LHRH neurons are capable of synthesizing, secreting, and rapidly replenishing stores of LHRH peptide.

Animals↗