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

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: closed (31 December 2021) | Viewed by 22080

Special Issue Editor

Prof. Dr. M. Bruce MacIver

E-Mail Website
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

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Published Papers (6 papers)

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Research

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19 pages, 4655 KiB  
Article
A Comparison of Brain-State Dynamics across Common Anesthetic Agents in Male Sprague-Dawley Rats
by Rachel Ward-Flanagan, Alto S. Lo, Elizabeth A. Clement and Clayton T. Dickson
Int. J. Mol. Sci. 2022, 23(7), 3608; https://doi.org/10.3390/ijms23073608 - 25 Mar 2022
Cited by 8 | Viewed by 3016
Abstract
Anesthesia is a powerful tool in neuroscientific research, especially in sleep research where it has the experimental advantage of allowing surgical interventions that are ethically problematic in natural sleep. Yet, while it is well documented that different anesthetic agents produce a variety of [...] Read more.
Anesthesia is a powerful tool in neuroscientific research, especially in sleep research where it has the experimental advantage of allowing surgical interventions that are ethically problematic in natural sleep. Yet, while it is well documented that different anesthetic agents produce a variety of brain states, and consequently have differential effects on a multitude of neurophysiological factors, these outcomes vary based on dosages, the animal species used, and the pharmacological mechanisms specific to each anesthetic agent. Thus, our aim was to conduct a controlled comparison of spontaneous electrophysiological dynamics at a surgical plane of anesthesia under six common research anesthetics using a ubiquitous animal model, the Sprague-Dawley rat. From this direct comparison, we also evaluated which anesthetic agents may serve as pharmacological proxies for the electrophysiological features and dynamics of unconscious states such as sleep and coma. We found that at a surgical plane, pentobarbital, isoflurane and propofol all produced a continuous pattern of burst-suppression activity, which is a neurophysiological state characteristically observed during coma. In contrast, ketamine-xylazine produced synchronized, slow-oscillatory activity, similar to that observed during slow-wave sleep. Notably, both urethane and chloral hydrate produced the spontaneous, cyclical alternations between forebrain activation (REM-like) and deactivation (non-REM-like) that are similar to those observed during natural sleep. Thus, choice of anesthesia, in conjunction with continuous brain state monitoring, are critical considerations in order to avoid brain-state confounds when conducting neurophysiological experiments. Full article
(This article belongs to the Special Issue The Cellular, Synaptic and Molecular Mechanisms of Action of Central Nervous System Drugs)
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22 pages, 3148 KiB  
Article
Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus
by Paulina Kazmierska-Grebowska, Marcin Siwiec, Joanna Ewa Sowa, Bartosz Caban, Tomasz Kowalczyk, Renata Bocian and M. Bruce MacIver
Int. J. Mol. Sci. 2021, 22(24), 13604; https://doi.org/10.3390/ijms222413604 - 19 Dec 2021
Cited by 8 | Viewed by 4895
Abstract
Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with brain disorders, including epilepsy and Alzheimer’s disease. [...] Read more.
Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with brain disorders, including epilepsy and Alzheimer’s disease. Theta rhythm generation involves a specific interplay between cellular (ion channel) and network (synaptic) mechanisms. HCN channels are theta modulators, and several medications are known to enhance their activity. We investigated how different doses of lamotrigine (LTG), an HCN channel modulator, and antiepileptic and neuroprotective agent, would affect HPC theta rhythms in acute HPC slices (in vitro) and anaesthetized rats (in vivo). Whole-cell patch clamp recordings revealed that LTG decreased GABAA-fast transmission in CA3 cells, in vitro. In addition, LTG directly depressed CA3 and CA1 pyramidal neuron excitability. These effects were partially blocked by ZD 7288, a selective HCN blocker, and are consistent with decreased excitability associated with antiepileptic actions. Lamotrigine depressed HPC theta oscillations in vitro, also consistent with its neuronal depressant effects. In contrast, it exerted an opposite, enhancing effect, on theta recorded in vivo. The contradictory in vivo and in vitro results indicate that LTG increases ascending theta activating medial septum/entorhinal synaptic inputs that over-power the depressant effects seen in HPC neurons. These results provide new insights into LTG actions and indicate an opportunity to develop more precise therapeutics for the treatment of dementias, memory disorders and epilepsy. Full article
(This article belongs to the Special Issue The Cellular, Synaptic and Molecular Mechanisms of Action of Central Nervous System Drugs)
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14 pages, 3268 KiB  
Article
Ketamine Produces a Long-Lasting Enhancement of CA1 Neuron Excitability
by Grace Jang and M. Bruce MacIver
Int. J. Mol. Sci. 2021, 22(15), 8091; https://doi.org/10.3390/ijms22158091 - 28 Jul 2021
Cited by 9 | Viewed by 2582
Abstract
Ketamine is a clinical anesthetic and antidepressant. Although ketamine is a known NMDA receptor antagonist, the mechanisms contributing to antidepression are unclear. This present study examined the loci and duration of ketamine’s actions, and the involvement of NMDA receptors. Local field potentials were [...] Read more.
Ketamine is a clinical anesthetic and antidepressant. Although ketamine is a known NMDA receptor antagonist, the mechanisms contributing to antidepression are unclear. This present study examined the loci and duration of ketamine’s actions, and the involvement of NMDA receptors. Local field potentials were recorded from the CA1 region of mouse hippocampal slices. Ketamine was tested at antidepressant and anesthetic concentrations. Effects of NMDA receptor antagonists APV and MK-801, GABA receptor antagonist bicuculline, and a potassium channel blocker TEA were also studied. Ketamine decreased population spike amplitudes during application, but a long-lasting increase in amplitudes was seen during washout. Bicuculline reversed the acute effects of ketamine, but the washout increase was not altered. This long-term increase was statistically significant, sustained for >2 h, and involved postsynaptic mechanisms. A similar effect was produced by MK-801, but was only partially evident with APV, demonstrating the importance of the NMDA receptor ion channel block. TEA also produced a lasting excitability increase, indicating a possible involvement of potassium channel block. This is this first report of a long-lasting increase in excitability following ketamine exposure. These results support a growing literature that increased GABA inhibition contributes to ketamine anesthesia, while increased excitatory transmission contributes to its antidepressant effects. Full article
(This article belongs to the Special Issue The Cellular, Synaptic and Molecular Mechanisms of Action of Central Nervous System Drugs)
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Review

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13 pages, 1611 KiB  
Review
Thalamic T-Type Calcium Channels as Targets for Hypnotics and General Anesthetics
by Tamara Timic Stamenic and Slobodan M. Todorovic
Int. J. Mol. Sci. 2022, 23(4), 2349; https://doi.org/10.3390/ijms23042349 - 21 Feb 2022
Cited by 8 | Viewed by 3273
Abstract
General anesthetics mainly act by modulating synaptic inhibition on the one hand (the potentiation of GABA transmission) or synaptic excitation on the other (the inhibition of NMDA receptors), but they can also have effects on numerous other proteins, receptors, and channels. The effects [...] Read more.
General anesthetics mainly act by modulating synaptic inhibition on the one hand (the potentiation of GABA transmission) or synaptic excitation on the other (the inhibition of NMDA receptors), but they can also have effects on numerous other proteins, receptors, and channels. The effects of general anesthetics on ion channels have been the subject of research since the publication of reports of direct actions of these drugs on ion channel proteins. In particular, there is considerable interest in T-type voltage-gated calcium channels that are abundantly expressed in the thalamus, where they control patterns of cellular excitability and thalamocortical oscillations during awake and sleep states. Here, we summarized and discussed our recent studies focused on the CaV3.1 isoform of T-channels in the nonspecific thalamus (intralaminar and midline nuclei), which acts as a key hub through which natural sleep and general anesthesia are initiated. We used mouse genetics and in vivo and ex vivo electrophysiology to study the role of thalamic T-channels in hypnosis induced by a standard general anesthetic, isoflurane, as well as novel neuroactive steroids. From the results of this study, we conclude that CaV3.1 channels contribute to thalamocortical oscillations during anesthetic-induced hypnosis, particularly the slow-frequency range of δ oscillations (0.5–4 Hz), by generating “window current” that contributes to the resting membrane potential. We posit that the role of the thalamic CaV3.1 isoform of T-channels in the effects of various classes of general anesthetics warrants consideration. Full article
(This article belongs to the Special Issue The Cellular, Synaptic and Molecular Mechanisms of Action of Central Nervous System Drugs)
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13 pages, 1012 KiB  
Review
General Anesthesia and the Young Brain: The Importance of Novel Strategies with Alternate Mechanisms of Action
by Stefan Maksimovic, Nemanja Useinovic, Nidia Quillinan, Douglas F. Covey, Slobodan M. Todorovic and Vesna Jevtovic-Todorovic
Int. J. Mol. Sci. 2022, 23(3), 1889; https://doi.org/10.3390/ijms23031889 - 8 Feb 2022
Cited by 7 | Viewed by 2327
Abstract
Over the past three decades, we have been grappling with rapidly accumulating evidence that general anesthetics (GAs) may not be as innocuous for the young brain as we previously believed. The growing realization comes from hundreds of animal studies in numerous species, from [...] Read more.
Over the past three decades, we have been grappling with rapidly accumulating evidence that general anesthetics (GAs) may not be as innocuous for the young brain as we previously believed. The growing realization comes from hundreds of animal studies in numerous species, from nematodes to higher mammals. These studies argue that early exposure to commonly used GAs causes widespread apoptotic neurodegeneration in brain regions critical to cognition and socio-emotional development, kills a substantial number of neurons in the young brain, and, importantly, results in lasting disturbances in neuronal synaptic communication within the remaining neuronal networks. Notably, these outcomes are often associated with long-term impairments in multiple cognitive-affective domains. Not only do preclinical studies clearly demonstrate GA-induced neurotoxicity when the exposures occur in early life, but there is a growing body of clinical literature reporting similar cognitive-affective abnormalities in young children who require GAs. The need to consider alternative GAs led us to focus on synthetic neuroactive steroid analogues that have emerged as effective hypnotics, and analgesics that are apparently devoid of neurotoxic effects and long-term cognitive impairments. This would suggest that certain steroid analogues with different cellular targets and mechanisms of action may be safe alternatives to currently used GAs. Herein we summarize our current knowledge of neuroactive steroids as promising novel GAs. Full article
(This article belongs to the Special Issue The Cellular, Synaptic and Molecular Mechanisms of Action of Central Nervous System Drugs)
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Other

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9 pages, 1111 KiB  
Hypothesis
Many Drugs of Abuse May Be Acutely Transformed to Dopamine, Norepinephrine and Epinephrine In Vivo
by Paul J. Fitzgerald
Int. J. Mol. Sci. 2021, 22(19), 10706; https://doi.org/10.3390/ijms221910706 - 2 Oct 2021
Cited by 13 | Viewed by 5189
Abstract
It is well established that a wide range of drugs of abuse acutely boost the signaling of the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis, where norepinephrine and epinephrine are major output molecules. This stimulatory effect is accompanied by such symptoms as [...] Read more.
It is well established that a wide range of drugs of abuse acutely boost the signaling of the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis, where norepinephrine and epinephrine are major output molecules. This stimulatory effect is accompanied by such symptoms as elevated heart rate and blood pressure, more rapid breathing, increased body temperature and sweating, and pupillary dilation, as well as the intoxicating or euphoric subjective properties of the drug. While many drugs of abuse are thought to achieve their intoxicating effects by modulating the monoaminergic neurotransmitter systems (i.e., serotonin, norepinephrine, dopamine) by binding to these receptors or otherwise affecting their synaptic signaling, this paper puts forth the hypothesis that many of these drugs are actually acutely converted to catecholamines (dopamine, norepinephrine, epinephrine) in vivo, in addition to transformation to their known metabolites. In this manner, a range of stimulants, opioids, and psychedelics (as well as alcohol) may partially achieve their intoxicating properties, as well as side effects, due to this putative transformation to catecholamines. If this hypothesis is correct, it would alter our understanding of the basic biosynthetic pathways for generating these important signaling molecules, while also modifying our view of the neural substrates underlying substance abuse and dependence, including psychological stress-induced relapse. Importantly, there is a direct way to test the overarching hypothesis: administer (either centrally or peripherally) stable isotope versions of these drugs to model organisms such as rodents (or even to humans) and then use liquid chromatography-mass spectrometry to determine if the labeled drug is converted to labeled catecholamines in brain, blood plasma, or urine samples. Full article
(This article belongs to the Special Issue The Cellular, Synaptic and Molecular Mechanisms of Action of Central Nervous System Drugs)
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