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British Journal of Pharmacology Aug 19881. The modulation of the gamma-aminobutyric acidA (GABAA) receptor by reduced metabolites of progesterone and deoxycorticosterone has been compared with that produced by...
1. The modulation of the gamma-aminobutyric acidA (GABAA) receptor by reduced metabolites of progesterone and deoxycorticosterone has been compared with that produced by depressant barbiturates in: (a) voltage-clamp recordings from bovine enzymatically isolated chromaffin cells in cell culture, and (b) an assay of the specific binding of [3H]-muscimol to a preparation of porcine brain membranes. 2. The progesterone metabolites 5 alpha- and 5 beta-pregnan-3 alpha-ol-20-one (greater than or equal to 30 nM) reversibly and dose-dependently enhanced the amplitude of membrane currents elicited by locally applied GABA (100 microM), and over the concentration range 30 nM-100 microM stimulated the binding of [3H]-muscimol. In contrast, 5 alpha- and 5 beta-pregnan-3 beta-ol-20-one (30 nM-100 microM) had little effect in either assay, indicating a marked stereoselectivity of steroid action. 3. Scatchard analysis of the ligand binding data suggested an apparent increase in the number, rather than the affinity, of detectable [3H]-muscimol binding sites as the principle action of the active steroid isomers. 4. GABA-evoked currents were also potentiated by androsterone (1 microM) and the deoxycorticosterone metabolite 5 alpha-pregnane-3 alpha,21-diol-20-one (100 nM). 5. Secobarbitone (10-100 microM), pentobarbitone (10-300 microM) and phenobarbitone (100-500 microM) reversibly and dose-dependently potentiated the amplitude of GABA-evoked currents in the absence of any change in their reversal potential. 6. At relatively high concentrations (greater than or equal to 30 microM) secobarbitone and pentobarbitone directly elicited a membrane current. It is concluded that such currents result from GABAA receptor-channel activation since they share a common reversal potential with GABA-evoked responses (approximately 0 mV), are reversibly antagonized by bicuculline (3 microM), and potentiated by either diazepam (1 microM) or 5 beta-pregnan-3 alpha-ol-20-one (500 nM). 7. Secobarbitone (1 microM-1 mM) dose-dependently enhanced the binding of [3H]-muscimol. In common with the active steroids, an increase in the apparent number of binding sites was responsible for this effect. 8. A saturating concentration (1 mM) of secobarbitone in the ligand binding assay did not suppress the degree of enhancement of control binding produced by 5 beta-pregnan-3 alpha-ol-20-one (30 nM-100 microM). Similarly the steroid, at a concentration of 100 microM, did not influence the enhancement of [3H]-muscimol binding by secobarbitone (1 microM-1 mM). In all combinations of concentrations tested, the effects of secobarbitone and 5#-pregnan-3a-ol-20-one on [3H]-muscimol binding were additive. 9. In conjunction with previously published observations, the present data indicate close similarities in the GABA-mimetic and potentiating actions of barbiturates and steroids. However, the results obtained with combinations of steroids and barbiturates in the ligand binding assay appear inconsistent with the two classes of compound interacting with a common site to modulate the GABAA receptor activity.
Topics: Animals; Barbiturates; Cattle; Chromaffin System; In Vitro Techniques; Muscimol; Pentobarbital; Pregnanes; Receptors, GABA-A; Secobarbital; Swine
PubMed: 2850060
DOI: 10.1111/j.1476-5381.1988.tb11646.x -
Scientific Reports Jun 2018Despite many years of intense research, there is no strong consensus about the role of the lateral intraparietal area (LIP) in decision making. One view of LIP function...
Despite many years of intense research, there is no strong consensus about the role of the lateral intraparietal area (LIP) in decision making. One view of LIP function is that it guides spatial attention, providing a "saliency map" of the external world. If this were the case, it would contribute to target selection regardless of which action would be performed to implement the choice. On the other hand, LIP inactivation has been shown to influence spatial selection and oculomotor metrics in free-choice decisions, which are made using eye movements, arguing that it contributes to saccade decisions. To dissociate between a more general attention role and a more effector specific saccade role, we reversibly inactivated LIP while non-human primates freely selected between two targets, presented in the two hemifields, with either saccades or reaches. Unilateral LIP inactivation induced a strong choice bias to ipsilesional targets when decisions were made with saccades. Interestingly, the inactivation also caused a reduction of contralesional choices when decisions were made with reaches, albeit the effect was less pronounced. These findings suggest that LIP is part of a network for making oculomotor decisions and is largely effector-specific in free-choice decisions.
Topics: Animals; Decision Making; GABA-A Receptor Agonists; Haplorhini; Muscimol; Parietal Lobe; Saccades
PubMed: 29872059
DOI: 10.1038/s41598-018-26366-9 -
Journal of the American Chemical Society Dec 2006Functionalization of highly fluorescent CdSe/ZnS core-shell nanocrystals (quantum dots, qdots) is an emerging technology for labeling cell surface proteins. We have...
Functionalization of highly fluorescent CdSe/ZnS core-shell nanocrystals (quantum dots, qdots) is an emerging technology for labeling cell surface proteins. We have synthesized a conjugate consisting of approximately 150-200 muscimols (a GABA receptor agonist) covalently joined to the qdot via a poly(ethylene glycol) (PEG) linker (approximately 78 ethylene glycol units) and investigated the binding of this muscimol-PEG-qdot conjugate to homomeric rho1 GABAC receptors expressed in Xenopus oocytes. GABAC receptors mediate inhibitory synaptic signaling at multiple locations in the central nervous system (CNS). Binding of the conjugate was analyzed quantitatively by determining the fluorescence intensity of the oocyte surface membrane in relation to that of the surrounding incubation medium. Upon 5- to 10-min incubation with muscimol-PEG-qdots (34 nM in qdot concentration), GABAC-expressing oocytes exhibited a fluorescent halo at the surface membrane that significantly exceeded the fluorescence of the incubation medium. This halo was absent following muscimol-PEG-qdot treatment of oocytes lacking GABAC receptors. Incubation of the oocyte with free muscimol (100 microM-5 mM), PEG-muscimol (500 microM), or GABA (100 microM - 5 mM) substantially reduced or eliminated the fluorescence halo produced by muscimol-PEG-qdots, and the removal of GABA or free muscimol led to a recovery of muscimol-PEG-qdot binding. Unconjugated qdots and PEG-qdots that lacked conjugated muscimol neither exhibited significant binding activity nor diminished the subsequent binding of muscimol-PEG-qdots. The results indicate that muscimol joined to qdots via a long-chain PEG linker exhibits specific binding activity at the ligand-binding pocket of expressed GABAC receptors, despite the presence of both the long PEG linker and the sterically bulky qdot.
Topics: Animals; Binding Sites; Cadmium Compounds; Cells, Cultured; Coated Materials, Biocompatible; Fluorescent Dyes; GABA Agonists; Gene Expression Regulation; Models, Chemical; Muscimol; Nanoparticles; Oocytes; Polyethylene Glycols; Quantum Dots; Receptors, Cell Surface; Receptors, GABA; Selenium Compounds; Spectrometry, Fluorescence; Sulfides; Zinc Compounds
PubMed: 17147380
DOI: 10.1021/ja064324k -
Behavioral Neuroscience Jun 2022The present study investigated immediate versus delayed effects of estrogen replacement in ovariectomized (OVX) rats on hyperphagia elicited by gamma-aminobutyric acid...
The present study investigated immediate versus delayed effects of estrogen replacement in ovariectomized (OVX) rats on hyperphagia elicited by gamma-aminobutyric acid (GABA)-A-agonist (muscimol) infusions into the nucleus accumbens shell (AcbSh). First, because intra-AcbSh muscimol-induced feeding has never been explored in OVX rats, a dose-effect curve was generated and compared to sham-operated males, the current point of reference in the literature. Muscimol (5, 10, 25, and 50 ng) increased food intake in both sexes, and both sexes reached the same asymptotic level of intake. Nevertheless, slopes of the linearized dose-effect functions for males and OVX females differed significantly, with females starting at a lower baseline and exhibiting a steeper slope. Next, the behavioral profiles of a behaviorally active, but nonmaximal intra-AcbSh muscimol dose (25 ng), were examined in a separate group of OVX females at two time-points: immediately after injecting 17β-estradiol 3-benzoate (EB) subcutaneously (5 μg), and 24 hr post-EB. Delayed, but not immediate, EB pretreatment suppressed, but did not eliminate, muscimol-driven food intake. However, EB did not change nonfood-directed behaviors such as locomotion or rearing. These results demonstrate that feeding mediated by intra-AcbSh GABA-A receptors is delimited by delayed, but not rapid, effects of estradiol. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
Topics: Animals; Eating; Estrogens; Feeding Behavior; Male; Muscimol; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; gamma-Aminobutyric Acid
PubMed: 35389677
DOI: 10.1037/bne0000511 -
The Journal of Neuroscience : the... Feb 1996Both the dorsomedial hypothalamic nucleus (DMH) and the paraventricular hypothalamic nucleus (PVN) have been implicated in the neural control of the cardiovascular...
Both the dorsomedial hypothalamic nucleus (DMH) and the paraventricular hypothalamic nucleus (PVN) have been implicated in the neural control of the cardiovascular response to stress. We used the GABAA agonist muscimol to inhibit neuronal activation and attempted to identify hypothalamic nuclei required for the cardiovascular response to air stress. Chronically instrumented rats received bilateral injections of either 80 pmol of muscimol or 100 nl of saline vehicle into the DMH, the PVN, or an intermediate area (including the rostral edge of the DMH and the region between the two nuclei) and were placed immediately in a restraining tube and subjected to 20 min of air stress. In all rats, air stress after vehicle injections caused marked increases in heart rate (137 +/- 6 beats/min) and blood pressure (26 +/- 2 mmHg). Microinjection of muscimol into the DMH suppressed the heart rate and blood pressure response by 85 and 68%, respectively. Identical microinjection of muscimol into the intermediate area between the DMH and the PVN attenuated the increases in heart rate by only 46% and in blood pressure by 52%. In contrast, similar injections into the vicinity of the PVN failed to alter the cardiovascular response to air stress. These findings demonstrate that muscimol-induced inhibition of neuronal activity in the region of the DMH blocks air stress-induced increases in heart rate and arterial pressure, whereas similar treatment in the area of the PVN has no effect.
Topics: Air; Animals; Blood Pressure; Cardiovascular System; GABA Agonists; GABA-A Receptor Agonists; Heart Rate; Hypothalamus, Anterior; Male; Microinjections; Muscimol; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Stress, Physiological
PubMed: 8558246
DOI: 10.1523/JNEUROSCI.16-03-01173.1996 -
Sleep Mar 2013Gamma-aminobutyric acid (GABA) causes phasic inhibition via synaptic GABAA receptors and tonic inhibition via extrasynaptic GABAA receptors. GABA levels in the...
STUDY OBJECTIVES
Gamma-aminobutyric acid (GABA) causes phasic inhibition via synaptic GABAA receptors and tonic inhibition via extrasynaptic GABAA receptors. GABA levels in the extracellular space regulate arousal state and cognition by volume transmission via extrasynaptic GABAA receptors. GABAergic transmission in the pontine reticular formation promotes wakefulness. No previous studies have determined whether an agonist at extrasynaptic GABAA receptors administered into the pontine reticular formation alters sleep and wakefulness. Therefore, this study used gaboxadol (THIP; agonist at extrasynaptic GABAA receptors that contain a δ subunit) to test the hypothesis that extrasynaptic GABAA receptors within the pontine reticular formation modulate sleep and wakefulness.
DESIGN
Within/between subjects.
SETTING
University of Michigan.
PATIENTS OR PARTICIPANTS
Adult male Crl:CD*(SD) (Sprague-Dawley) rats (n = 10).
INTERVENTIONS
Microinjection of gaboxadol, the nonsubtype selective GABAA receptor agonist muscimol (positive control), and saline (negative control) into the rostral pontine reticular formation.
MEASUREMENTS AND RESULTS
Gaboxadol significantly increased wakefulness and decreased both nonrapid eye movement sleep and rapid eye movement sleep in a concentration-dependent manner. Relative to saline, gaboxadol did not alter electroencephalogram power. Microinjection of muscimol into the pontine reticular formation of the same rats that received gaboxadol increased wakefulness and decreased sleep.
CONCLUSION
Tonic inhibition via extrasynaptic GABAA receptors that contain a δ subunit may be one mechanism by which the extracellular pool of endogenous GABA in the rostral pontine reticular formation promotes wakefulness.
CITATION
Vanini G; Baghdoyan HA. Extrasynaptic GABAA receptors in rat pontine reticular formation increase wakefulness. SLEEP 2013;36(3):337-343.
Topics: Animals; Electroencephalography; GABA Agonists; GABA-A Receptor Agonists; Isoxazoles; Male; Microinjections; Muscimol; Pons; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Reticular Formation; Sleep; Sodium Chloride; Wakefulness
PubMed: 23450652
DOI: 10.5665/sleep.2444 -
Science Progress 2022Numbers are one of the three basic concepts of human abstract thinking. When human beings count, they often point to things, one by one, and read numbers in a positive...
Numbers are one of the three basic concepts of human abstract thinking. When human beings count, they often point to things, one by one, and read numbers in a positive integer column. The prefrontal cortex plays a wide range of roles in executive functions, including active maintenance and achievement of goals, adaptive coding and exertion of general intelligence, and completion of time complexity events. Nonhuman animals do not use number names, such as "one, two, three," or numerals, such as "1, 2, 3" to "count" in the same way as humans do. Our previous study established an animal model of counting in monkeys. Here, we used this model to determine whether the prefrontal cortex participates in counting in monkeys. Two 5-year-old female rhesus monkeys (macaques), weighing 5.0 kg and 5.5 kg, were selected to train in a counting task, counting from 1 to 5. When their counting task performance stabilized, we performed surgery on the prefrontal cortex to implant drug delivery tubes. After allowing the monkeys' physical condition and counting performance to recover, we injected either muscimol or normal saline into their dorsal and ventral prefrontal cortex. Thereafter, we observed their counting task performance and analyzed the error types and reaction time during the counting task. The monkeys' performance in the counting task decreased significantly after muscimol injection into the ventral prefrontal cortex; however, it was not affected after saline injection into the ventral prefrontal cortex, or after muscimol or saline injection into the dorsal prefrontal cortex. The ventral prefrontal cortex of the monkey is necessary for counting performance.
Topics: Animals; Female; Humans; Adult; Macaca mulatta; Muscimol; Prefrontal Cortex; Executive Function; Disease Models, Animal
PubMed: 36443989
DOI: 10.1177/00368504221141660 -
Neuron Jan 2020Neocortical sensory areas are thought to act as distribution hubs, transmitting information about the external environment to downstream areas. Within primary visual...
Neocortical sensory areas are thought to act as distribution hubs, transmitting information about the external environment to downstream areas. Within primary visual cortex, various populations of pyramidal neurons (PNs) send axonal projections to distinct targets, suggesting multiple cellular networks may be independently engaged during behavior. We investigated whether PN subpopulations differentially support visual detection by training mice on a novel eyeblink conditioning task. Applying 2-photon calcium imaging and optogenetic manipulation of anatomically defined PNs, we show that layer 5 corticopontine neurons strongly encode sensory and motor task information and are selectively necessary for performance. Our findings support a model in which target-specific cortical subnetworks form the basis for adaptive behavior by directing relevant information to distinct brain areas. Overall, this work highlights the potential for neurons to form physically interspersed but functionally segregated networks capable of parallel, independent control of perception and behavior.
Topics: Animals; Arousal; Cerebral Cortex; Conditioning, Eyelid; Corpus Striatum; Mice; Muscimol; Neuroanatomical Tract-Tracing Techniques; Neurons; Photic Stimulation; Pons; Visual Cortex; Visual Pathways
PubMed: 31757603
DOI: 10.1016/j.neuron.2019.10.014 -
The Journal of Neuroscience : the... Feb 2018Fast-spiking interneurons (FSIs) exert powerful inhibitory control over the striatum and are hypothesized to balance the massive excitatory cortical and thalamic input...
Fast-spiking interneurons (FSIs) exert powerful inhibitory control over the striatum and are hypothesized to balance the massive excitatory cortical and thalamic input to this structure. We recorded neuronal activity in the dorsolateral striatum and globus pallidus (GP) concurrently with the detailed movement kinematics of freely behaving female rats before and after selective inhibition of FSI activity using IEM-1460 microinjections. The inhibition led to the appearance of episodic rest tremor in the body part that depended on the somatotopic location of the injection within the striatum. The tremor was accompanied by coherent oscillations in the local field potential (LFP). Individual neuron activity patterns became oscillatory and coherent in the tremor frequency. Striatal neurons, but not GP neurons, displayed additional temporal, nonoscillatory correlations. The subsequent reduction in the corticostriatal input following muscimol injection to the corresponding somatotopic location in the primary motor cortex led to disruption of the tremor and a reduction of the LFP oscillations and individual neuron's phase-locked activity. The breakdown of the normal balance of excitation and inhibition in the striatum has been shown previously to be related to different motor abnormalities. Our results further indicate that the balance between excitatory corticostriatal input and feedforward FSI inhibition is sufficient to break down the striatal decorrelation process and generate oscillations resulting in rest tremor typical of multiple basal ganglia disorders. Fast-spiking interneurons (FSIs) play a key role in normal striatal processing by exerting powerful inhibitory control over the network. FSI malfunctions have been associated with abnormal processing of information within the striatum that leads to multiple movement disorders. Here, we study the changes in neuronal activity and movement kinematics following selective inhibition of these neurons. The injections led to the appearance of episodic rest tremor, accompanied by coherent oscillations in neuronal activity, which was reversed following corticostriatal inhibition. These results suggest that the balance between corticostriatal excitation and feedforward FSI inhibition is crucial for maintaining the striatal decorrelation process, and that its breakdown leads to the formation of oscillations resulting in rest tremor typical of multiple basal ganglia disorders.
Topics: Adamantane; Animals; Basal Ganglia Diseases; Cerebral Cortex; Corpus Striatum; Evoked Potentials; Female; Globus Pallidus; Interneurons; Microinjections; Motor Cortex; Muscimol; Rats; Rats, Long-Evans; Tremor
PubMed: 29330326
DOI: 10.1523/JNEUROSCI.2821-17.2018 -
The European Journal of Neuroscience Oct 2015Cognitive flexibility is a hallmark of prefrontal cortical (PFC) function yet little is known about downstream area involvement. The medial dorsal striatum (mDS)...
Cognitive flexibility is a hallmark of prefrontal cortical (PFC) function yet little is known about downstream area involvement. The medial dorsal striatum (mDS) receives major projections from the PFC and is uniquely situated to perform the integration of responses with rule information. In this study, we use a novel rule shifting task in rats that mirrors non-human primate and human studies in its temporal precision and counterbalanced responses. We record activity from single neurons in the mDS while rats switch between different rules for reward. Additionally, we pharmacologically inactivate mDS by infusion of a baclofen/muscimol cocktail. Inactivation of mDS impaired the ability to shift to a new rule and increased the number of regressive errors. While recording in mDS, we identified neurons modulated by direction whose activity reflected the conflict between competing rule information. We show that a subset of these neurons was also rule selective, and that the conflict between competing rule cues was resolved as behavioural performance improved. Other neurons were modulated by rule, but not direction. These neurons became selective before behavioural performance accurately reflected the current rule. These data provide an additional locus for investigating the mechanisms underlying behavioural flexibility. Converging lines of evidence from multiple human psychiatric disorders have implicated dorsal striatum as an important and understudied neural substrate of flexible cognition. Our data confirm the importance of mDS, and suggest a mechanism by which mDS mediates abstract cognition functions.
Topics: Action Potentials; Animals; Baclofen; Catheters, Indwelling; Corpus Striatum; Electrodes, Implanted; Executive Function; GABA-A Receptor Agonists; GABA-B Receptor Agonists; Male; Muscimol; Neurons; Psychomotor Performance; Rats, Long-Evans; Reward
PubMed: 26275165
DOI: 10.1111/ejn.13042