An integrative view on the cell-type-specific mechanisms of ketamine's antidepressant actions.

Over the past six decades, the use of ketamine has evolved from an anesthetic and recreational drug to the first non-monoaminergic antidepressant approved for treatment-resistant major depressive disorder (MDD). Subanesthetic doses of ketamine and its enantiomer (S)-ketamine (esketamine) directly bind to several neurotransmitter receptors [including N-methyl-d-aspartic acid receptor (NMDAR), κ and µ opioid receptor (KOR and MOR)] widely distributed in the brain and across different cell types, implicating several potential molecular mechanisms underlying the action of ketamine as an antidepressant. This review examines preclinical studies investigating cell-type-specific mechanisms underlying the effects of ketamine on behavior and synapses. Cell-type-specific approaches are crucial for disentangling the critical mechanisms involved in the therapeutic effect of ketamine.

Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action.

Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2A receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1A and 5-HT2C receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action.

A non-hallucinogenic LSD analog with therapeutic potential for mood disorders.

Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT2A, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT2A ß-arrestin recruitment and internalization in vitro and does not induce tolerance in vivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT2A-selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications.

Translational control by ketamine and its implications for comorbid cognitive deficits in depressive disorders.

Ketamine has shown antidepressant effects in patients with major depressive disorder (MDD) resistant to first-line treatments and approved for use in this patient population. Ketamine induces several forms of synaptic plasticity, which are proposed to underlie its antidepressant effects. However, the molecular mechanism of action directly responsible for ketamine's antidepressant effects remains under active investigation. It was recently demonstrated that the effectors of the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, namely, eukaryotic initiation factor 4E (eIF4E) binding proteins 1 and 2 (4E-BP1 and 4E-BP2), are central in mediating ketamine-induced synaptic plasticity and behavioural antidepressant-like effect. 4E-BPs are a family of messenger ribonucleic acid (mRNA) translation repressors inactivated by mTORC1. We observed that their expression in inhibitory interneurons mediates ketamine's effects in the forced swim and novelty suppressed feeding tests and the long-lasting inhibition of GABAergic neurotransmission in the hippocampus. In addition, another effector pathway that regulates translation elongation downstream of mTORC1, the eukaryotic elongation factor 2 kinase (eEF2K), has been implicated in ketamine's behavioural effects. We will discuss how ketamine's rapid antidepressant effect depends on the activation of neuronal mRNA translation through 4E-BP1/2 and eEF2K. Furthermore, given that these pathways also regulate cognitive functions, we will discuss the evidence of ketamine's effect on cognitive function in MDD. Overall, the data accrued from pre-clinical research have implicated the mRNA translation pathways in treating mood symptoms of MDD. However, it is yet unclear whether the pro-cognitive potential of subanesthetic ketamine in rodents also engages these pathways and whether such an effect is consistently observed in the treatment-resistant MDD population.

Transcriptomic signature of extinction learning in the brain of the fire-bellied toad, Bombina orientalis.

Insight into the molecular and cellular mechanisms of learning and memory from a diverse array of taxa contributes to our understanding of the evolution of these processes. The fire-bellied toad, Bombina orientalis, is a basal anuran amphibian model species who could help us describe shared and divergent characteristics of learning and memory mechanisms between amphibians and other vertebrates, and hence answer questions about the evolution of learning. Utilizing next generation sequencing techniques, we profiled gene expression patterns associated with the extinction of prey-catching conditioning in the brain of the fire-bellied toad. For this purpose, gene expression was at first compared between toads sacrificed after acquisition and extinction of the conditioned response. A second comparison was done between toads submitted to extinction following either short or long acquisition training, which results in toads displaying response extinction or resistance to extinction, respectively. We analyzed brain tissue transcription profiles common to both acquisition and extinction learning, or unique to extinction learning and resistance to extinction, and found significant overlap in gene expression related to molecular pathways involving neuronal plasticity (e.g. structural modification, transcription). However, extinction learning induced a unique GABAergic transcriptomic signal, which may be responsible for suppression of the original response memory. Further, when comparing extinction learning in short- and long-trained groups, short training engaged many pathways related to neuronal plasticity, as expected, but long training engaged molecular pathways related to the suppression of learning through epigenetic mediated transcriptional suppression and inhibitory neurotransmission. Overall, gene expression patterns associated with extinction learning in the fire-bellied toad were similar to those found in mammals submitted to extinction, although some divergent profiles highlighted potential differences in the mechanisms of learning and memory among tetrapods.

Temporal Profile of Brain Gene Expression After Prey Catching Conditioning in an Anuran Amphibian.

A key goal in modern neurobiology is to understand the mechanisms underlying learning and memory. To that end, it is essential to identify the patterns of gene expression and the temporal sequence of molecular events associated with learning and memory processes. It is also important to ascertain if and how these molecular events vary between organisms. In vertebrates, learning and memory processes are characterized by distinct phases of molecular activity involving gene transcription, structural change, and long-term maintenance of such structural change in the nervous system. Utilizing next generation sequencing techniques, we profiled the temporal expression patterns of genes in the brain of the fire-bellied toad Bombina orientalis after prey catching conditioning. The fire-bellied toad is a basal tetrapod whose neural architecture and molecular pathways may help us understand the ancestral state of learning and memory mechanisms in tetrapods. Differential gene expression following conditioning revealed activity in molecular pathways related to immediate early genes (IEG), cytoskeletal modification, axon guidance activity, and apoptotic processes. Conditioning induced early IEG activity coinciding with transcriptional activity and neuron structural modification, followed by axon guidance and cell adhesion activity, and late neuronal pruning. While some of these gene expression patterns are similar to those found in mammals submitted to conditioning, some interesting divergent expression profiles were seen, and differential expression of some well-known learning-related mammalian genes is missing altogether. These results highlight the importance of using a comparative approach in the study of the mechanisms of leaning and memory and provide molecular resources for a novel vertebrate model in the relatively poorly studied Amphibia.

Behavioural evidence for a sleep-like quiescent state in a pulmonate mollusc, Lymnaea stagnalis (Linnaeus).

The objective of this study was to determine whether the great pond snail, Lymnaea stagnalis, expresses a sleep-like behavioural state. We found that snails spontaneously enter a relatively brief (22±1 min) quiescent state characterized by postural relaxation of the foot, mantle and tentacles, and cessation of radula rasping. Quiescence was reversed ('aroused') by appetitive (sucrose solution) and aversive (tactile) stimuli. Responsiveness to both stimuli was significantly lower in quiescent snails than in active snails. However, tactile stimuli evoked a more sustained defensive response in quiescent snails. Quiescence bouts were consolidated into 'clusters' over an infradian timescale and were only weakly affected by time of day. Clusters contained 7±0.5 bouts, lasted 13±1 h and were separated by long (37±4 h) intervals of almost continuous activity. Analysis of Kaplan-Meier survival curves revealed that the quiescent bout duration was described by an exponential probability distribution (time constant 15±1 min). Active bout duration was described by a bi-exponential probability distribution (time constants 62±4 and 592±48 min). We found no evidence for a 'sleep rebound' mechanism and quiescence expression appeared to be regulated through stochastic processes causing state transitions to resemble a Markovian random walk. We conclude that Lymnaea is a potentially valuable model system for studies of cellular function in sleep.