Differential anesthetic activity of ketamine and the GABAergic
neurosteroid allopregnanolone in mice lacking progesterone receptor
A and B subtypes

Reddy, Doodipala Samba; Zeng, Yong-Chun

doi:10.1358/mf.2007.29.10.1147766

Cited by 11 publications

(10 citation statements)

References 26 publications

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“…Another potential source of variance is sex difference, since differences in hormones in males and females may affect the metabolism of anesthetics (8). However, most studies have not found significant sex differences (10,15). We also did not find any sex differences.…”

Section: Discussioncontrasting

confidence: 50%

Best anesthetics for assessing left ventricular systolic function by echocardiography in mice

Pachon

Scharf

Vatner

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Our review of the literature of the major cardiovascular journals for the past three years showed that for all studies using anesthesia for mouse echocardiography, the predominant anesthetic was isoflurane, which was used in 76% of the studies. The goal of this investigation was to determine if isoflurane is indeed the best anesthetic. Accordingly, we compared isoflurane with 2,2,2-tribromoethanol (Avertin), ketamine-xylazine, and ketamine on different days in the same 14 mice, also studied in the conscious state without anesthesia. A randomized crossover study design was employed to compare the effects on left ventricular (LV) systolic function and heart rate of the four different anesthetic agents assessed by transthoracic echocardiography. As expected, each anesthetic depressed LV ejection fraction and heart rate when compared with values in conscious mice. Surprisingly, isoflurane was not the best, but actually second to last in maintaining normal LV function and heart rate. The anesthetic with the least effect on LV function and heart rate was ketamine alone at a dose of 150 mg/kg, followed by Avertin at 290 mg/kg, isoflurane at 3% induction and 1 to 2% maintenance, and lastly ketamine-xylazine at 100 and 10 mg/kg, respectively. In summary, these results indicate that ketamine alone exerts the least depressant effects on LV function and heart rate, with Avertin second, suggesting that these anesthetics should be used when it is not feasible to study the animals in the conscious state as opposed to the most commonly used anesthetic, isoflurane.echocardiography; mice; conscious state; anesthetics TRANSTHORACIC ECHOCARDIOGRAPHY is an essential noninvasive tool for the assessment of cardiovascular function in mice. Currently, echocardiography is either performed consciously or under anesthesia. As a general rule, the conscious study is preferred because it eliminates the complicating influences of anesthesia on cardiac function and regulation by the autonomic nervous system. The concept of the superiority of studies in conscious animals as opposed to anesthetized animals are largely based on studies of chronically instrumented animals that were recorded in the conscious state without being touched or manipulated by the investigators (10, 12). While echocardiography also has these advantages in patients, who understand that the transducer is harmless, conscious rodents are wary of a transducer touching their skin. Accordingly, it is possible to argue that light anesthesia affects the rodent's cardiovascular system less than the application of the echocardiographic transducer in the conscious state. Therefore, it becomes important not only to compare echocardiographic studies in mice in the conscious state or during anesthesia but also to compare the effects of the different anesthetics that have been used in mouse echocardiography, which were the goals of the current investigation.To address these goals, we first reviewed the frequency of mouse echocardiography studies in conscious versus anesthetized animals an...

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Section: Discussioncontrasting

confidence: 50%

Best anesthetics for assessing left ventricular systolic function by echocardiography in mice

Pachon

Scharf

Vatner

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…Consistent with potentiation effects at the cellular level, endogenous neurosteroids like allopregnanolone and THDOC are capable of sedative, anxiolytic, and anticonvulsant behavioral effects on the CNS (Reddy and Kulkarni, 1997; Reddy, 2003a; Reddy and Zeng, 2007; Reddy, 2011). It is appropriate to consider the system-wide pharmacological effects of treatments that involve neuromodulatory agents.…”

Section: Neurosteroid Modulation Of Gabaa Receptorsmentioning

confidence: 82%

Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

2013

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Rationale Neurosteroids are steroids synthesized within the brain with rapid effects on neuronal excitability. Allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are three widely explored prototype endogenous neurosteroids. They have very different targets and functions compared to conventional steroid hormones. Neuronal GABAa receptors are one of the prime molecular targets of neurosteroids. Objective This review provides a critical appraisal of recent advances in the pharmacology of endogenous neurosteroids that interact with GABAa receptors in the brain. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance of the neuron, mainly via potentiation of GABAa receptors at low concentrations and direct activation of receptor chloride channel at higher concentrations. The GABAa receptor mediates two types of inhibition, now characterized as synaptic (phasic) and extrasynaptic (tonic) inhibition. Synaptic release of GABA results in the activation of low-affinity γ2-containing synaptic receptors, while high-affinity δ-containing extrasynaptic receptors are persistently activated by the ambient GABA present in the extracellular fluid. Neurosteroids are potent positive allosteric modulators of synaptic and extrasynaptic GABAa receptors and therefore enhance both phasic and tonic inhibition. Tonic inhibition is specifically more sensitive to neurosteroids. The resulting tonic conductance generates a form of shunting inhibition that controls neuronal network excitability, seizure susceptibility, and behavior. Conclusion The growing understanding of the mechanisms of neurosteroid regulation of the structure and function of the synaptic and extrasynaptic GABAa receptors provide many opportunities to create improved therapies for sleep, anxiety, stress, epilepsy, and other neuropsychiatric conditions.

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“…The PRs are expressed widely in the brain, including areas relevant to epilepsy such as the hippocampus, amygdala, and neocortex (Brinton et al, 2008). We have previously demonstrated that the seizure protection conferred by progesterone is not due to its interaction with PRs (Reddy et al, 2004), and PRs are not required for the anxiolytic effects of allopregnanolone and related neurosteroids (Reddy et al, 2005; Reddy and Zeng, 2007b). The key observation in this study is that the neurosteroid withdrawal-induced upregulation of α4-subunit transcription is undiminished in PR knockout mice, thus clearly proving that the PR is not involved in neurosteroid withdrawal regulation of α4-subunit expression.…”

Section: Discussionmentioning

confidence: 99%

Neurosteroid withdrawal regulates GABA-A receptor α4-subunit expression and seizure susceptibility by activation of progesterone receptor-independent early growth response factor-3 pathway

Gangisetty

Reddy

2010

Neuroscience

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Neurosteroids regulate GABA-A receptor plasticity. Neurosteroid withdrawal occurs during menstruation and is associated with a marked increase in expression of GABA-A receptor α4-subunit, a key subunit linked to enhanced neuronal excitability, seizure susceptibility and benzodiazepine resistance. However, the molecular mechanisms underlying the upregulation of α4-subunit expression remain unclear. Here we utilized the progesterone receptor (PR) knockout mouse to investigate molecular pathways of PR and the transcription factor early growth response factor-3 (Egr3) in regulation of the GABA-A receptor α4-subunit expression in the hippocampus in a mouse neurosteroid withdrawal paradigm. Neurosteroid withdrawal induced a threefold increase in α4-subunit expression in wild-type mice, but this upregulation was unchanged in PR knockout mice. The expression of Egr3, which controls α4-subunit transcription, was increased significantly following neurosteroid withdrawal in wild-type and PR knockout mice. Neurosteroid withdrawal-induced α4-subunit upregulation was completely suppressed by antisense Egr3 inhibition. In the hippocampus kindling model of epilepsy, there was heightened seizure activity, significant reduction in the antiseizure sensitivity of diazepam (a benzodiazepine insensitive at α4βγ-receptors) and conferral of increased seizure protection of flumazenil (a low-affinity agonist at α4βγ-receptors) in neurosteroid-withdrawn wild-type and PR knockout mice. These observations are consistent with enhanced α4-containing receptor abundance in vivo. Neurosteroid withdrawal-induced seizure exacerbation, diazepam insensitivity, and flumazenil efficacy in the kindling model were reversed by inhibition of Egr3. These results indicate that neurosteroid withdrawal-induced upregulation of GABA-A receptor α4-subunit expression is mediated by the Egr3 via a PR-independent signaling pathway. These findings help advance our understanding of the molecular basis of catamenial epilepsy, a neuroendocrine condition that occurs around the perimenstrual period and is characterized by neurosteroid withdrawal-linked seizure exacerbations in women with epilepsy.

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Differential anesthetic activity of ketamine and the GABAergic neurosteroid allopregnanolone in mice lacking progesterone receptor A and B subtypes

Cited by 11 publications

References 26 publications

Best anesthetics for assessing left ventricular systolic function by echocardiography in mice

Best anesthetics for assessing left ventricular systolic function by echocardiography in mice

Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

Neurosteroid withdrawal regulates GABA-A receptor α4-subunit expression and seizure susceptibility by activation of progesterone receptor-independent early growth response factor-3 pathway

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