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PubMed2004

NPY mediates the feeding elicited by muscimol injections into the nucleus accumbens shell.

Injections of muscimol into the nucleus accumbens shell (AcbSh) induce large increases in food intake in satiated rats and also activate neurons in a number of feeding-related brain regions, including NPY-containing neurons in the arcuate hypothalamic nucleus and cells in the paraventricular hypothalamic nucleus. This suggests that the NPY system may participate in the expression of AcbSh-mediated feeding behavior. Therefore, we examined the effects of intraventricular administration of the Y1 receptor antagonist 1229U91 or the Y5 receptor antagonist L-152,804 on AcbSh-mediated food intake. Intra-AcbSh muscimol elicited a large increase in food intake which was potently suppressed by blocking either central Y1 or Y5 receptors. Our results suggest that the AcbSh influences food intake, in part, through the release of NPY.

Analysis of Variance↗

PubMed2004

Intra-amygdala muscimol injections impair freezing and place avoidance in aversive contextual conditioning.

Rats were trained by shocking them in a closed compartment. When subsequently tested in the same closed compartment with no shock, normal rats showed an increased tendency to freeze. They also showed an increased tendency to actively avoid the compartment when given access to an adjacent neutral compartment for the first time. Amygdala inactivation with bilateral muscimol injections before training attenuated freezing and eliminated avoidance during the test. Rats trained in a normal state and given intra-amygdala muscimol injections before the test did not freeze or avoid the shock-paired compartment. This pattern of effects suggests that amygdala inactivation during training impaired acquisition of a conditioned response (CR) due either to inactivation of a neural substrate essential for its storage or to elimination of a memory modulation effect that facilitates its storage in some other brain region(s). The elimination of both freezing and active avoidance by amygdala inactivation during testing suggests that neither of these behaviors is the CR. The possibility that the CR is a set of internal responses that produces both freezing and avoidance as well as other behavioral effects is discussed.

Amygdala↗

PubMed1983

Muscimol potentiation of acidic amino acid release from cerebellar synaptosomes is chloride dependent.

In previous studies we have shown that the depolarization-induced release of preaccumulated acidic amino acids and newly synthesized glutamate from cerebellar synaptosomal preparations is potentiated by gamma-aminobutyric acid (GABA) agonists through a GABAergic presynaptic mechanism. Here we report a systematic analysis of the ionic requirements of the potentiating effect of muscimol on the high K+-evoked release of D-[3H]aspartate. Our studies show that: Ca2+, Na+, and Mg2+ are not required for muscimol to exert its effect; a depolarizing concentration of K+ is a necessary, but not sufficient, condition to observe the presynaptic effect in question; and a minimal Cl- concentration (50-70 mM) is also required. A possible model based on these findings is proposed.

Animals↗

PubMed1984

Decreased high-affinity binding of [3H]muscimol to cerebral synaptic membranes of scrapie-infected mice.

Scrapie is a transmissible disease that results in progressive degeneration of the central nervous system and death. Although scrapie has been studied histopathologically, relatively little is known concerning neurotransmitter alterations. Specific [3H]muscimol binding to whole brain crude synaptic membranes (CSM) from mice clinically affected with scrapie was significantly (p less than 0.01) reduced, to approximately 73% of that of the controls. Of the brain regions examined, binding to only cerebral CSM was significantly (p less than 0.0001) decreased. Scatchard analyses of saturation curves revealed that the high-affinity (KD = 8 +/- 3 nM) site for muscimol was abolished in cerebral CSM from scrapie-infected mice, while the low-affinity site was unaffected. Binding of [3H]flunitrazepam to cerebral CSM was unaffected by scrapie and was stimulated by GABA to the same extent in both scrapie and control mice. These results suggest that scrapie agent 139A in C57BL/6J mice manifests a portion of its CNS pathology via a high-affinity GABA binding site that is unassociated with the benzodiazepine receptor.

Animals↗

PubMed1988

Increased binding of [3H]muscimol and [3H]flunitrazepam in the rat brain under hypoxia.

We examined the effects of in vivo hypoxia (10% O2/90% N2) on the gamma-aminobutyric acid (GABA)/benzodiazepine receptors and on glutamic acid decarboxylase (GAD) activity in the rat brain. Male Wistar rats were exposed to a mixture of 10% O2 and 90% N2 in a chamber for various periods (3, 6, 12, and 24 h). The control rats were exposed to room air. The brain regions examined were the cerebral cortex, striatum, hippocampus, and cerebellum. GABA and benzodiazepine receptors were assessed using [3H]muscimol and [3H]flunitrazepam, respectively. Compared with control values, GAD activity was decreased significantly following a 6-h exposure to hypoxia in all four regions studied. On the other hand, the numbers of both [3H]muscimol and [3H]flunitrazepam binding sites were increased significantly. The increase in receptor number tended to return to control values after 24 h. Treatment of the membrane preparations with 0.05% Triton X-100 eliminated the increase in the binding capacity. These results may represent an up-regulation of postsynaptically located GABA/benzodiazepine receptors corresponding to the impaired presynaptic activity under hypoxia.

Animals↗

PubMed1990

Dissociation of muscimol, SR 95531, and strychnine from GABAA and glycine receptors, respectively, suggests similar cooperative interactions.

Binding to gamma-aminobutyric acid-A (GABAA) receptors was studied in synaptosomal membranes of rat brain. Dissociation of [3H]muscimol and the GABAA antagonist [3H]2-(3-carboxypropyl)-3-amino-6-p-methoxyphenylpyridazinium bromide ([3H]SR 95531) binding elicited by 100-fold dilution was accelerated by excess of GABA or SR 95531. Control dissociation might be retarded by rebinding. The contribution of a rapid first phase of dissociation of the agonist [3H]muscimol was preferentially enhanced by SR 95531. In contrast, the dissociation of [3H]SR 95531 binding was preferentially accelerated by GABA. These opposite preferential accelerations can be explained by negative heterotropic cooperativity and a reversed affinity relationship of agonists and antagonists to GABAA binding sites with different affinities. Modification of the membranes by p-diazobenzenesulfonic acid (DSA) selectively decreased the accelerating effect of GABA on the dissociation of [3H]SR 95531 binding. [3H]Strychnine binding was studied in a membrane preparation of rat spinal cord. The dissociation of the antagonist [3H]strychnine elicited by dilution was preferentially accelerated by glycine. Again, pretreatment with DSA decreased selectively this negative heterotropic (i.e., allosteric) interaction. Chemical modification by DSA might be attributed to tyrosine residues responsible for similar allosteric interactions for the GABA- and glycine-gated chloride channels.

Animals↗

PubMed1996

Intra-amygdala muscimol decreases operant ethanol self-administration in dependent rats.

Dependence is an important factor motivating continued alcohol use in human alcoholics. Development of a model of ethanol (EtOH) consumption in dependent animals would advance the understanding of reinforcement after chronic EtOH exposure and allow for the investigation of the neuropharmacological mechanisms mediating reinforcement in dependent versus nondependent animals. In the present study, rats were trained to lever press for 10% EtOH, surgically implanted with bilateral guide cannulae in the amygdala, and either made dependent on EtOH by exposure for 2 weeks to EtOH or exposed to air in identical vapor chambers. Upon removal, the rats were placed in operant boxes and allowed to respond on levers for 10% EtOH or water during a 12-hr period. Rats were removed briefly at approximately 6.5 hr for intra-amygdala injections of saline or the GABAA receptor agonist muscimol. After the test period, rats were returned to the vapor chambers for 4 days before retest. EtOH-dependent animals responded more for EtOH across the 12-hr test period than did air control nondependent rats; this difference became more pronounced with repeated test sessions. Intra-amygdala muscimol significantly decreased responding for EtOH in EtOH-dependent rats, but had no effect in nondependent controls. These data suggest that the reinforcing effects of EtOH and neurotransmitter pathways mediating reward are altered after the development of dependence, and they support the use of this paradigm for further investigations into the neuropharmacology of EtOH dependence.

Alcoholism↗

PubMed1986

Topographic studies of the effects of microinjections of muscimol on the hypothalamic control of feed intake in sheep.

Ten sheep were used to define the anatomical basis for the feeding systems sensitive to gamma-aminobutyric acid, by using intrahypothalamic microinjections of the gamma-aminobutyric acid agonist, muscimol. In satiated sheep, 1 microL of muscimol (0.5 nmol/microL) elicited feeding when injected into paraventricular, ventromedial, and anterior hypothalamic areas. Similar injections into 39 sites tested in 6-h fasted sheep failed to decrease feed intake. The data suggest that neurons sensitive to gamma-aminobutyric acid in medial hypothalamus may be involved in the initiation of feeding.

Animals↗

PubMed2001

Muscimol infusions in the brain stem reticular formation reversibly block ingestion in the awake rat.

Previous studies have localized a central pattern generator for mastication to the midline pontomedullary reticular formation (RF) based on cortically induced ororhythmic movements. The present study determined whether this same substrate mediated licking responses evoked by more natural stimuli. Licking in the awake rat was initiated either through an appetitive response to sucrose presented in a bottle or by intraoral (IO) infusions. Oral rejection responses also were obtained by IO infusions of quinine hydrochloride. Small volumes of the GABA(A) agonist muscimol bilaterally infused into the lateral medullary RF significantly reduced licking and oral rejection responses measured electromyographically from the anterior digastric and geniohyoid muscles. Other than the decrement or absence of ororhythmic activity, rats appeared normal and actively approached and probed the water bottle. The suppression was reversible and returned to baseline within 3 h. In contrast, midline infusions of muscimol did not affect licking or rejection responses. We postulate that the lateral medullary RF is an essential final common path for ingestive consummatory responses.

Administration, Oral↗

PubMed2007

Three-dimensional eye-head coordination after injection of muscimol into the interstitial nucleus of Cajal (INC).

The interstitial nucleus of Cajal (INC) is thought to be the "neural integrator" for torsional/vertical eye position and head posture. Here, we investigated the coordination of eye and head movements after reversible INC inactivation. Three-dimensional (3-D) eye-head movements were recorded in three head-unrestrained monkeys using search coils. INC sites were identified by unit recording/electrical stimulation and then reversibly inactivated by 0.3 mul of 0.05% muscimol injection into 26 INC sites. After muscimol injection, the eye and head 1) began to drift (an inability to maintain stable fixation) torsionally: clockwise (CW)/counterclockwise (CCW) after left/right INC inactivation respectively. 2) The eye and head tilted torsionally CW/CCW after left/right INC inactivation, respectively. Horizontal gaze/head drifts were inconsistently present and did not result in considerable position offsets. Vertical eye drift was dependent on both vertical eye position and the magnitude of the previous vertical saccade, as in head-fixed condition. This correlation was smaller for gaze and head drift, suggesting that the gaze and head deficits could not be explained by a first-order integrator model. Ocular counterroll (OC) was completely disrupted. The gain of torsional vestibuloocular reflex (VOR) during spontaneous eye and head movements was reduced by 22% in both CW/CCW directions after either left or right INC inactivation. Our results suggest a complex interdependence of eye and head deficits after INC inactivation during fixation, gaze shifts, and VOR. Some of our results resemble the symptoms of spasmodic torticollis (ST).

Animals↗

PubMed1993

Role of the caudal fastigial nucleus in saccade generation. II. Effects of muscimol inactivation.

1. We studied the effect of temporarily inhibiting neurons in the caudal fastigial nucleus in two rhesus macaques trained to make saccades to jumping targets. We placed injections of the gamma-aminobutyric acid (GABA) agonist muscimol unilaterally or bilaterally at sites in the caudal fastigial nucleus where we had recorded saccade-related neurons a few minutes earlier. 2. Unilateral injections (n = 9) made horizontal saccades to the injected side hypermetric and those to the other side hypometric (mean gain of 1.37 and 0.61, respectively, for 10 degrees target steps, and 1.26 and 0.81 for 20 degrees target steps; normal saccade gain was 0.96). Saccades to vertical targets showed a small but significant hypermetria and curved strongly toward the side of the injection. The trajectories and end points of all targeted saccades were more variable than normal. 3. After unilateral injections, centripetal saccades were slightly larger than centrifugal saccades (mean gains for ipsilateral saccades were 1.42 and 1.31, respectively, for 10 degrees target steps, and 1.37 and 1.15 for 20 degrees target steps). 4. Unilateral injections increased the average acceleration of ipsilateral saccades and decreased the acceleration of contralateral saccades. Injections decreased both the acceleration and deceleration of vertical saccades. 5. After dysmetric saccades, monkeys acquired the target with an abnormally high number of hypometric corrective saccades. Injection increased the average number of corrective saccades from 0.6 to 2.1 after 10 degrees horizontal target steps and from 0.8 to 2.1 after 20 degrees steps. The size of each successive corrective saccade in a series decreased, and the latency from the previous corrective saccade increased. 6. Bilateral injections (n = 2) of muscimol, in which we injected first into the left caudal fastigial nucleus and then, within 30 min, into the right, made all saccades hypermetric (mean gain for 10 degrees right, left, up, and down saccades was 1.18, 1.49, 1.43, and 1.10, respectively). Paradoxically, bilateral injection decreased both saccade acceleration and deceleration. Saccade trajectories and end points were more variable than normal. 7. To account for the effects of our injections, we propose that the activity of caudal fastigial neurons on one side normally helps to decelerate ipsilateral saccades and helps to accelerate contralateral saccades by influencing the feedback loop of the saccade burst generator in the brain stem. Without caudal fastigial activity the brain stem burst generator produces hypermetric, variable saccades. We therefore also propose that the influence of caudal fastigial neurons on the burst generator makes saccades more consistent and accurate.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1997

Participation of caudal fastigial nucleus in smooth pursuit eye movements. II. Effects of muscimol inactivation.

We studied the effect of temporarily inactivating the caudal fastigial nucleus (CFN) in three rhesus macaques trained to make smooth pursuit eye movements. We injected the gamma-aminobutyric acid A agonist muscimol into one or both CFNs where we had recorded pursuit-related neurons a few minutes earlier. Inactivating the CFN on one side impaired pursuit in one monkey so severely that it could not follow step-ramp targets moving at 20 degrees/s, the target velocity that we used to test the other two monkeys. We tested this monkey with targets moving at 10 degrees/s. In all three monkeys, unilateral CFN inactivation either increased the acceleration of ipsilateral step-ramp pursuit (in 2 monkeys, to 144 and 220% of normal) or decreased the acceleration of contralateral pursuit (in 1 monkey, to 71% of normal). Muscimol injected into both CFNs in two of the monkeys left both ipsilateral and contralateral acceleration nearly normal in both monkeys (101% of normal). Unilateral CFN inactivation also impaired the velocity of maintained pursuit as the monkeys tracked a target moving at a constant velocity or oscillating sinusoidally. Averaged across both types of movements in all three monkeys, gains for ipsilateral, contralateral, upward, and downward pursuit were 94, 67, 84, and 73% of normal, respectively. Unilateral CFN inactivation also impaired the monkeys' ability to suppress their vestibuloocular reflex (VOR). Averaged across the two monkeys VOR gain during suppression increased from 0.06 to 0.25 during yaw rotation and from 0.21 to 0.59 during pitch rotation. Bilateral CFN inactivation reduced pursuit gains in all directions more than unilateral injection did. In the two monkeys tested, ipsilateral, contralateral, upward, and downward gains went from 94, 86, 85, and 74% of normal, respectively, after we inactivated one CFN to 88, 73, 80, and 64% of normal after we also inactivated the second CFN. We can explain many, but not all, of the effects of CFN activation on smooth pursuit with the behavior of CFN neurons, and the assumption that the activity of each CFN neuron helps drive pursuit movements in the direction that best activates that neuron. We conclude that the CFN, like the flocculus-ventral paraflocculus, is a cerebellar region involved in control of smooth pursuit.

Animals↗

PubMed1998

Orienting gaze shifts during muscimol inactivation of caudal fastigial nucleus in the cat. I. Gaze dysmetria.

The cerebellar control of orienting behavior toward visual targets was studied in the head-unrestrained cat by analyzing the deficits of saccadic gaze shifts after unilateral injection of muscimol in the caudal part of the fastigial nucleus (cFN). Gaze shifts are rendered strongly inaccurate by muscimol cFN inactivation. The characteristics of gaze dysmetria are specific to the direction of the movement with respect to the inactivated cFN. Gaze shifts directed toward the injected side are hypermetric. Irrespective of their starting position, all these ipsiversive gaze shifts overshoot the target by a constant horizontal error (or bias) to terminate at a "shifted goal" location. In particular, when gaze is directed initially at the future target's location, a response with an amplitude corresponding to the bias moves gaze away from the actual target. Additionally, when gaze is initially in between the target and this shifted goal location, the response again is directed toward the latter. This deficit of ipsiversive gaze shifts is characterized by a consistent increase in the y intercept of the relationship between horizontal gaze amplitude and horizontal retinal error. Slight increases in the slope sometimes are observed as well. Contraversive gaze shifts are markedly hypometric and, in contrast to ipsiversive responses, they do not converge onto a shifted goal but rather underestimate target eccentricity in a proportional way. This is reflected by a decrease in the slope of the relationship between horizontal gaze amplitude and horizontal retinal error, with, for some experiments, a moderate change in the y-intercept value. The same deficits are observed in a different setup, which permits the control of initial gaze position. Correction saccades rarely are observed when visual feedback is eliminated on initiation of the primary orienting response; instead, they occur frequently when the target remains visible. Like the primary contraversive saccades, they are hypometric and the ever-decreasing series of three to five correction saccades reduces the gaze fixation error but often does not completely eliminate it. We measured the position of gaze after the final correction saccade and found that fixation of a visible target is still shifted toward the inactivated cFN by 4.9 +/- 2.4 degrees. This fixation offset is correlated to, but on average 54% smaller than, the hypermetric bias of ipsiversive responses measured in the same experiments. In conclusion, the cFN contributes to the control of saccadic shifts of the visual axis toward a visual target. The hypometria of contraversive gaze shifts suggests a cFN role in adjusting a gain in the translation of retinal signals into gaze motor commands. On the basis of the convergence of ipsiversive gaze shifts onto a shifted goal, the straightness of gaze trajectory during these responses and the production of misdirected or inappropriately initiated responses toward this shifted goal, we propose that the cFN influences the processes that specify the goal of ipsiversive gaze shifts.

Animals↗

PubMed1999

Muscimol-induced inactivation of monkey frontal eye field: effects on visually and memory-guided saccades.

Muscimol-induced inactivation of the monkey frontal eye field: effects on visually and memory-guided saccades. Although neurophysiological, anatomic, and imaging evidence suggest that the frontal eye field (FEF) participates in the generation of eye movements, chronic lesions of the FEF in both humans and monkeys appear to cause only minor deficits in visually guided saccade generation. Stronger effects are observed when subjects are tested in tasks with more cognitive requirements. We tested oculomotor function after acutely inactivating regions of the FEF to minimize the effects of plasticity and reallocation of function after the loss of the FEF and gain more insight into the FEF contribution to the guidance of eye movements in the intact brain. Inactivation was induced by microinjecting muscimol directly into physiologically defined sites in the FEF of three monkeys. FEF inactivation severely impaired the monkeys' performance of both visually guided and memory-guided saccades. The monkeys initiated fewer saccades to the retinotopic representation of the inactivated FEF site than to any other location in the visual field. The saccades that were initiated had longer latencies, slower velocities, and larger targeting errors than controls. These effects were present both for visually guided and for memory-guided saccades, although the memory-guided saccades were more disrupted. Initially, the effects were restricted spatially, concentrating around the retinotopic representation at the center of the inactivated site, but, during the course of several hours, these effects spread to flanking representations. Predictability of target location and motivation of the monkey also affected saccadic performance. For memory-guided saccades, increases in the time during which the monkey had to remember the spatial location of a target resulted in further decreases in the accuracy of the saccades and in smaller peak velocities, suggesting a progressive loss of the capacity to maintain a representation of target location in relation to the fovea after FEF inactivation. In addition, the monkeys frequently made premature saccades to targets in the hemifield ipsilateral to the injection site when performing the memory task, indicating a deficit in the control of fixation that could be a consequence of an imbalance between ipsilateral and contralateral FEF activity after the injection. There was also a progressive loss of fixation accuracy, and the monkeys tended to restrict spontaneous visual scanning to the ipsilateral hemifield. These results emphasize the strong role of the FEF in the intact monkey in the generation of all voluntary saccadic eye movements, as well as in the control of fixation.

Animals↗

PubMed2001

Prefrontal cortical representation of visuospatial working memory in monkeys examined by local inactivation with muscimol.

In primates, dorsolateral areas of the prefrontal cortex (PFC) play a major role in visuospatial working memory. To examine the functional organization of the PFC for representing visuospatial working memory, we produced reversible local inactivation, with the local injection of muscimol (5 microg, 1 microl), at various sites (n = 100) in the dorsolateral PFC of monkeys and observed the behavioral consequences in an oculomotor delayed-response task that required memory-guided saccades for locations throughout both visual fields. At 82 sites, the local injection of muscimol induced deficits in memory-guided saccades to a few specific, usually contralateral, target locations that varied with the location of the injection site. Such deficits depended on the delay length, and longer delays were associated with larger deficits in memory-guided saccades. The injection sites and affected spatial locations of the target showed a gross topographical relationship. No deficits appeared for a control task in which the subject was required to make a visually guided saccade to a visible target. These findings suggest that a specific site in the dorsolateral PFC is responsible for the working memory process for a specific visuospatial coordinate to guide goal-directed behavior. Further, memoranda for specific visuospatial coordinates appear to be represented in a topographical memory map within the dorsolateral PFC to represent visuospatial working memory processes.

Animals↗

PubMed2000

GABA and muscimol as reversible inactivation tools in learning and memory.

Reversible inactivation of brain areas is a useful method for inferring brain-behavior relationships. Infusion of GABA or of the GABA receptor agonist muscimol is considered one interesting reversible inactivation method because it may not affect fibers of passage and may therefore be compared to axon-sparing types of lesions. This article reviews the data obtained with this method in learning and memory experiments. A critical analysis of data, collected in collaboration with Simon Brailowsky, with chronic GABA infusion is presented, together with an illustration of data obtained with muscimol-induced inactivation.

Animals↗

PubMed1988

GABAA receptor sites modulating catecholamine secretion in the rat adrenal gland: evidence from 3H-muscimol autoradiography and in vivo functional studies.

The occurrence and distribution of specific 3H-muscimol binding sites, most probably identical with A type gamma-aminobutyric acid (GABA) receptors, were studied in sections of the rat adrenal gland by light microscope autoradiography. Specific binding was found primarily in the adrenal medulla, in association with chromaffin cells. A limited number of binding sites was also observed within the adrenal cortex. In urethane-anaesthetized hexamethonium-pretreated rats, intravenous GABA produced a set of 'excitatory' cardiovascular effects (increase in heart rate, force of contraction and blood pressure) which were mimicked by intravenous muscimol but not by intravenous baclofen, and were antagonized by pretreatment with bicuculline. The cardiovascular excitatory effects of intravenous GABA were unaffected by reserpine pretreatment, markedly reduced by administration of phentolamine plus propranolol, and almost completely abolished by adrenalectomy. Our findings indicate the presence of GABA receptor sites on adrenal chromaffin cells, whose excitation can produce changes in cardiovascular function.

Adrenal Cortex↗

PubMed1992

Autoradiographic localization of the gamma-aminobutyric acid type A receptor agonist 3H-muscimol in the rat superior cervical ganglion.

The anatomical localization of gamma-aminobutyric acid type A (GABA-A) receptor sites in the rat superior cervical ganglion was studied using combined radioreceptor binding and autoradiographic techniques. 3H-Muscimol was used as a ligand of GABA-A receptor sites. The binding was consistent with the labelling of GABA-A sites. The dissociation constant value was 6.4 nmol/l, and the maximum density of binding sites was 146 +/- 7.8 fmol/mg tissue. Light microscope autoradiography revealed the accumulation of 3H-muscimol mainly in superior portions of the ganglion. Binding sites are located primarily in the neuropil rather than within ganglionic neurons. It is probable that the sites revealed by autoradiography are involved in the inhibition of acetylcholine release from ganglionic neurons.

Animals↗