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The Cellular, Synaptic and Molecular Mechanisms of Action of Central Nervous System Drugs 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 20 October 2024 | Viewed by 7242

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Special Issue Editor

Prof. Dr. M. Bruce MacIver

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Guest Editor

Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA 94304, USA
Interests: sedatives; anesthetics; higher nervous system; neuropharmacology; central nervous system drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The past few years have seen remarkable progress in understanding drug effects on the Central Nervous System. Advances in molecular, cellular and systems level knowledge together with an array of new analytical approaches and tools have increased our breadth and depth of understanding how drugs alter brain activity to impact memory, learning, sensory perception and consciousness. The current special interest series brings leading scientists from across the globe together to share their insights and new findings regarding drug actions at numerous levels in the nervous system. Many major neurotransmitter classes are represented and correlates between molecular actions and changes in higher level brain functions are being discovered, some for the very first time. This new knowledge is being used to design better, more efficacious and safer pharmaceuticals. A new era in neuropharmacology is beginning and promises to provide treatments for many of the most debilitating and expensive diseases facing modern man. Our goal with this special issue of the journal is to document and facilitate an ongoing and exciting time of discovery for the brain sciences.

Prof. Dr. M. Bruce MacIver
Guest Editor

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Keywords

CNS
drug
addiction
memory
consciousness
loss of consciousness
recovery of consciousness
coma
anesthesia, anaesthesia
anesthetic
inhalant
abuse
GABA
glutamate
5-HT
adrenaline, noradrenaline
serotonin
dopamine
adenosine
reanimation
electrical stimulation

Published Papers (4 papers)

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Research

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10 pages, 1852 KiB

Open AccessCommunication

Learning in the Single-Cell Organism Physarum polycephalum: Effect of Propofol

by Stefan Kippenberger, Gordon Pipa, Katja Steinhorst, Nadja Zöller, Johannes Kleemann, Deniz Özistanbullu, Roland Kaufmann and Bertram Scheller

Int. J. Mol. Sci. 2023, 24(7), 6287; https://doi.org/10.3390/ijms24076287 - 27 Mar 2023

Cited by 2 | Viewed by 1943

Abstract

Propofol belongs to a class of molecules that are known to block learning and memory in mammals, including rodents and humans. Interestingly, learning and memory are not tied to the presence of a nervous system. There are several lines of evidence indicating that single-celled organisms also have the capacity for learning and memory which may be considered as basal intelligence. Here, we introduce a new experimental model for testing the learning ability of Physarum polycephalum, a model organism frequently used to study single-celled “intelligence”. In this study, the impact of propofol on Physarum’s “intelligence” was tested. The model consists of a labyrinth of subsequent bifurcations in which food (oat flakes soaked with coconut oil-derived medium chain triglycerides [MCT] and soybean oil-derived long chain triglycerides [LCT]) or propofol in MCT/LCT) is placed in one of each Y-branch. In this setting, it was tested whether Physarum memorized the rewarding branch. We saw that Physarum was a quick learner when capturing the first bifurcations of the maze; thereafter, the effect decreased, perhaps due to reaching a state of satiety. In contrast, when oat flakes were soaked with propofol, Physarum’s preference for oat flakes declined significantly. Several possible actions, including the blocking of gamma-aminobutyric acid (GABA) receptor signaling, are suggested to account for this behavior, many of which can be tested in our new model. Full article

(This article belongs to the Special Issue The Cellular, Synaptic and Molecular Mechanisms of Action of Central Nervous System Drugs 2.0)

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15 pages, 1435 KiB

Open AccessArticle

Changes in Memory, Sedation, and Receptor Kinetics Imparted by the β2-N265M and β3-N265M GABA_A Receptor Point Mutations

by Alifayaz Abdulzahir, Steven Klein, Chong Lor, Mark G. Perkins, Alyssa Frelka and Robert A. Pearce

Int. J. Mol. Sci. 2023, 24(6), 5637; https://doi.org/10.3390/ijms24065637 - 15 Mar 2023

Cited by 1 | Viewed by 982

Abstract

Point mutations in the β2 (N265S) and β3 (N265M) subunits of γ-amino butyric acid type A receptors (GABA_ARs) that render them insensitive to the general anesthetics etomidate and propofol have been used to link modulation of β2-GABA_ARs to sedation and β3-GABA_ARs to surgical immobility. These mutations also alter GABA sensitivity, and mice carrying the β3-N265M mutation have been reported to have impaired baseline memory. Here, we tested the effects of the β2-N265M and β3-N265M mutations on memory, movement, hotplate sensitivity, anxiety, etomidate-induced sedation, and intrinsic kinetics. We found that both β2-N265M and β3-N265M mice exhibited baseline deficits in the Context Preexposure Facilitation Effect learning paradigm. Exploratory activity was slightly greater in β2-N265M mice, but there were no changes in either genotype in anxiety or hotplate sensitivity. β2-N265M mice were highly resistant to etomidate-induced sedation, and heterozygous mice were partially resistant. In rapid solution exchange experiments, both mutations accelerated deactivation two- to three-fold compared to wild type receptors and prevented modulation by etomidate. This degree of change in the receptor deactivation rate is comparable to that produced by an amnestic dose of etomidate but in the opposite direction, indicating that intrinsic characteristics of GABA_ARs are optimally tuned under baseline conditions to support mnemonic function. Full article

(This article belongs to the Special Issue The Cellular, Synaptic and Molecular Mechanisms of Action of Central Nervous System Drugs 2.0)

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16 pages, 2939 KiB

Open AccessArticle

Opioid-Induced Reductions in Amygdala Lateral Paracapsular GABA Neuron Circuit Activity

by Joakim W. Ronström, Natalie L. Johnson, Stephen T. Jones, Sara J. Werner, Hillary A. Wadsworth, James N. Brundage, Valerie Stolp, Nicholas M. Graziane, Yuval Silberman, Scott C. Steffensen and Jordan T. Yorgason

Int. J. Mol. Sci. 2023, 24(3), 1929; https://doi.org/10.3390/ijms24031929 - 18 Jan 2023

Cited by 2 | Viewed by 1790

Abstract

Opioid use and withdrawal evokes behavioral adaptations such as drug seeking and anxiety, though the underlying neurocircuitry changes are unknown. The basolateral amygdala (BLA) regulates these behaviors through principal neuron activation. Excitatory BLA pyramidal neuron activity is controlled by feedforward inhibition provided, in part, by lateral paracapsular (LPC) GABAergic inhibitory neurons, residing along the BLA/external capsule border. LPC neurons express µ-opioid receptors (MORs) and are potential targets of opioids in the etiology of opioid-use disorders and anxiety-like behaviors. Here, we investigated the effects of opioid exposure on LPC neuron activity using immunohistochemical and electrophysiological approaches. We show that LPC neurons, and other nearby BLA GABA and non-GABA neurons, express MORs and δ-opioid receptors. Additionally, DAMGO, a selective MOR agonist, reduced GABA but not glutamate-mediated spontaneous postsynaptic currents in LPC neurons. Furthermore, in LPC neurons, abstinence from repeated morphine-exposure in vivo (10 mg/kg/day, 5 days, 2 days off) decrease the intrinsic membrane excitability, with a ~75% increase in afterhyperpolarization and ~40–50% enhanced adenylyl cyclase-dependent activity in LPC neurons. These data show that MORs in the BLA are a highly sensitive targets for opioid-induced inhibition and that repeated opioid exposure results in impaired LPC neuron excitability. Full article

(This article belongs to the Special Issue The Cellular, Synaptic and Molecular Mechanisms of Action of Central Nervous System Drugs 2.0)

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Review

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12 pages, 725 KiB

Open AccessReview

Cannabinoids in Treating Chemotherapy-Induced Nausea and Vomiting, Cancer-Associated Pain, and Tumor Growth

by Pavana P. Bathula and M. Bruce Maciver

Int. J. Mol. Sci. 2024, 25(1), 74; https://doi.org/10.3390/ijms25010074 - 20 Dec 2023

Viewed by 2046

Abstract

Cannabis has been used as an herbal remedy for thousands of years, and recent research indicates promising new uses in medicine. So far, some studies have shown cannabinoids to be safe in helping mitigate some cancer-associated complications, including chemotherapy-induced nausea and vomiting, cancer-associated pain, and tumor growth. Researchers have been particularly interested in the potential uses of cannabinoids in treating cancer due to their ability to regulate cancer-related cell cycle pathways, prompting many beneficial effects, such as tumor growth prevention, cell cycle obstruction, and cell death. Cannabinoids have been found to affect tumors of the brain, prostate, colon and rectum, breast, uterus, cervix, thyroid, skin, pancreas, and lymph. However, the full potential of cannabinoids is yet to be understood. This review discusses current knowledge on the promising applications of cannabinoids in treating three different side effects of cancer—chemotherapy-induced nausea and vomiting, cancer-associated pain, and tumor development. The findings suggest that cannabinoids can be used to address some side effects of cancer and to limit the growth of tumors, though a lack of supporting clinical trials presents a challenge for use on actual patients. An additional challenge will be examining whether any of the over one hundred naturally occurring cannabinoids or dozens of synthetic compounds also exhibit useful clinical properties. Currently, clinical trials are underway; however, no regulatory agencies have approved cannabinoid use for any cancer symptoms beyond antinausea. Full article

(This article belongs to the Special Issue The Cellular, Synaptic and Molecular Mechanisms of Action of Central Nervous System Drugs 2.0)

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