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Special Issue "Psychoactive Substances in Neuronal Development"

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

Deadline for manuscript submissions: closed (31 August 2020).

Special Issue Editors

Dr. João Pedro Silva
E-Mail Website
Guest Editor
UCIBIO-REQUIMTE, Toxicology Lab, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
Interests: molecular toxicology; developmental neurotoxicology; new psychoactive substances; cannabinoids; oxidative stress
Special Issues, Collections and Topics in MDPI journals
Prof. Helena Carmo
E-Mail Website
Guest Editor
UCIBIO-REQUIMTE, Toxicology Lab, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
Interests: toxicology; in vitro methods; drug of abuse
Dr. Diana Dias da Silva
E-Mail Website
Guest Editor
UCIBIO-REQUIMTE, Toxicology Lab, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Portugal
Interests: Neurotoxicology; Psychoactive Substances; Cannabinoids; Amphetamines; Cocaine
Prof. Dr. Félix Carvalho
E-Mail Website
Guest Editor
UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira nº 228, 4050-313 Porto, Portugal
Interests: toxicology; Drugs of abuse; pesticides; antidotes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Psychoactive substances comprise a diverse range of licit and illicit substances capable of affecting the mind, emotions, and behavior. In view of their highly prevalent use among specific risk groups, including pregnant women/women of childbearing potential (due to the harmful potential to the offspring) and adolescents (in whom the central nervous system is not fully developed), understanding how psychoactive substances may affect the developing brain has become a hot research topic. In fact, there is accumulating evidence associating medically prescribed drugs like antidepressants (e.g., SSRIs) and anticonvulsants (e.g., valproic acid) with neurodevelopment impairment, and the widespread recreational use of psychoactive drugs of abuse (e.g., cannabis, cocaine, amphetamines, opioids) is of particular concern in view of their ability to interfere with neuronal processes. Recently, the fast emergence of new psychoactive substances—designer drugs with stronger effects than their original counterparts—has become especially alarming due to the accumulating reports of acute intoxications and deaths. However, the role of psychoactive substances during neurodevelopment remains poorly understood.

This Special Issue welcomes up-to-date review and research papers focused on providing a better understanding of the role of psychoactive substances in neurodevelopment-related processes, both in vivo and in vitro (at cellular, subcellular and molecular levels).

Dr. João Pedro Silva
Prof. Helena Carmo
Dr. Diana Dias da Silva
Prof. Félix Carvalho
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • psychoactive substances
  • developmental neurotoxicology
  • drug abuse
  • neurodevelopment disorders
  • intracellular signalling mechanisms

Published Papers (8 papers)

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Research

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Article
Prenatal THC Does Not Affect Female Mesolimbic Dopaminergic System in Preadolescent Rats
Int. J. Mol. Sci. 2021, 22(4), 1666; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041666 - 07 Feb 2021
Viewed by 809
Abstract
Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring [...] Read more.
Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular, and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase in dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure. Full article
(This article belongs to the Special Issue Psychoactive Substances in Neuronal Development)
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Article
The Synthetic Cannabinoids THJ-2201 and 5F-PB22 Enhance In Vitro CB1 Receptor-Mediated Neuronal Differentiation at Biologically Relevant Concentrations
Int. J. Mol. Sci. 2020, 21(17), 6277; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176277 - 30 Aug 2020
Cited by 3 | Viewed by 911
Abstract
Recreational use of synthetic cannabinoids (SCs) before and during pregnancy poses a major public health risk, due to the potential onset of neurodevelopmental disorders in the offspring. Herein, we report the assessment of the neurotoxic potential of two commonly abused SCs, THJ-2201 and [...] Read more.
Recreational use of synthetic cannabinoids (SCs) before and during pregnancy poses a major public health risk, due to the potential onset of neurodevelopmental disorders in the offspring. Herein, we report the assessment of the neurotoxic potential of two commonly abused SCs, THJ-2201 and 5F-PB22, particularly focusing on how they affect neuronal differentiation in vitro. Differentiation ratios, total neurite length, and neuronal marker expression were assessed in NG108-15 neuroblastoma x glioma cells exposed to the SCs at non-toxic, biologically relevant concentrations (≤1 μM), either in acute or repeated exposure settings. Both SCs enhanced differentiation ratios and total neurite length of NG108-15 cells near two-fold compared to vehicle-treated cells, in a CB1R activation-dependent way, as the CB1R blockade with a specific antagonist (SR141718) abrogated SC-induced effects. Interestingly, repeated 5F-PB22 exposure was required to reach effects similar to a single THJ-2201 dose. Cell viability and proliferation, mitochondrial membrane potential, and intracellular ATP levels were also determined. The tested SCs increased mitochondrial tetramethyl rhodamine ethyl ester (TMRE) accumulation after 24 h at biologically relevant concentrations but did not affect any of the other toxicological parameters. Overall, we report firsthand the CB1R-mediated enhancement of neurodifferentiation by 5F-PB22 and THJ-2201 at biologically relevant concentrations. Full article
(This article belongs to the Special Issue Psychoactive Substances in Neuronal Development)
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Article
Early Transcriptomic Changes upon Thalidomide Exposure Influence the Later Neuronal Development in Human Embryonic Stem Cell-Derived Spheres
Int. J. Mol. Sci. 2020, 21(15), 5564; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155564 - 03 Aug 2020
Cited by 1 | Viewed by 967
Abstract
Stress in early life has been linked with the development of late-life neurological disorders. Early developmental age is potentially sensitive to several environmental chemicals such as alcohol, drugs, food contaminants, or air pollutants. The recent advances using three-dimensional neural sphere cultures derived from [...] Read more.
Stress in early life has been linked with the development of late-life neurological disorders. Early developmental age is potentially sensitive to several environmental chemicals such as alcohol, drugs, food contaminants, or air pollutants. The recent advances using three-dimensional neural sphere cultures derived from pluripotent stem cells have provided insights into the etiology of neurological diseases and new therapeutic strategies for assessing chemical safety. In this study, we investigated the neurodevelopmental effects of exposure to thalidomide (TMD); 2,2′,4,4′-tetrabromodiphenyl ether; bisphenol A; and 4-hydroxy-2,2′,3,4′,5,5′,6-heptachlorobiphenyl using a human embryonic stem cell (hESC)-derived sphere model. We exposed each chemical to the spheres and conducted a combinational analysis of global gene expression profiling using microarray at the early stage and morphological examination of neural differentiation at the later stage to understand the molecular events underlying the development of hESC-derived spheres. Among the four chemicals, TMD exposure especially influenced the differentiation of spheres into neuronal cells. Transcriptomic analysis and functional annotation identified specific genes that are TMD-induced and associated with ERK and synaptic signaling pathways. Computational network analysis predicted that TMD induced the expression of DNA-binding protein inhibitor ID2, which plays an important role in neuronal development. These findings provide direct evidence that early transcriptomic changes during differentiation of hESCs upon exposure to TMD influence neuronal development in the later stages. Full article
(This article belongs to the Special Issue Psychoactive Substances in Neuronal Development)
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Article
Neonatal Clonazepam Administration Induced Long-Lasting Changes in GABAA and GABAB Receptors
Int. J. Mol. Sci. 2020, 21(9), 3184; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093184 - 30 Apr 2020
Viewed by 785
Abstract
Benzodiazepines (BZDs) are widely used in patients of all ages. Unlike adults, neonatal animals treated with BZDs exhibit a variety of behavioral deficits later in life; however, the mechanisms underlying these deficits are poorly understood. This study aims to examine whether administration of [...] Read more.
Benzodiazepines (BZDs) are widely used in patients of all ages. Unlike adults, neonatal animals treated with BZDs exhibit a variety of behavioral deficits later in life; however, the mechanisms underlying these deficits are poorly understood. This study aims to examine whether administration of clonazepam (CZP; 1 mg/kg/day) in 7–11-day-old rats affects Gama aminobutyric acid (GABA)ergic receptors in both the short and long terms. Using RT-PCR and quantitative autoradiography, we examined the expression of the selected GABAA receptor subunits (α1, α2, α4, γ2, and δ) and the GABAB B2 subunit, and GABAA, benzodiazepine, and GABAB receptor binding 48 h, 1 week, and 2 months after treatment discontinuation. Within one week after CZP cessation, the expression of the α2 subunit was upregulated, whereas that of the δ subunit was downregulated in both the hippocampus and cortex. In the hippocampus, the α4 subunit was downregulated after the 2-month interval. Changes in receptor binding were highly dependent on the receptor type, the interval after treatment cessation, and the brain structure. GABAA receptor binding was increased in almost all of the brain structures after the 48-h interval. BZD-binding was decreased in many brain structures involved in the neuronal networks associated with emotional behavior, anxiety, and cognitive functions after the 2-month interval. Binding of the GABAB receptors changed depending on the interval and brain structure. Overall, the described changes may affect both synaptic development and functioning and may potentially cause behavioral impairment. Full article
(This article belongs to the Special Issue Psychoactive Substances in Neuronal Development)
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Review

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Review
Ketamine and Calcium Signaling—A Crosstalk for Neuronal Physiology and Pathology
Int. J. Mol. Sci. 2020, 21(21), 8410; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218410 - 09 Nov 2020
Cited by 3 | Viewed by 820
Abstract
Ketamine is a non-competitive antagonist of NMDA (N-methyl-D-aspartate) receptor, which has been in clinical practice for over a half century. Despite recent data suggesting its harmful side effects, such as neuronal loss, synapse dysfunction or disturbed neural network formation, the drug is still [...] Read more.
Ketamine is a non-competitive antagonist of NMDA (N-methyl-D-aspartate) receptor, which has been in clinical practice for over a half century. Despite recent data suggesting its harmful side effects, such as neuronal loss, synapse dysfunction or disturbed neural network formation, the drug is still applied in veterinary medicine and specialist anesthesia. Several lines of evidence indicate that structural and functional abnormalities in the nervous system caused by ketamine are crosslinked with the imbalanced activity of multiple Ca2+-regulated signaling pathways. Due to its ubiquitous nature, Ca2+ is also frequently located in the center of ketamine action, although the precise mechanisms underlying drug’s negative or therapeutic properties remain mysterious for the large part. This review seeks to delineate the relationship between ketamine-triggered imbalance in Ca2+ homeostasis and functional consequences for downstream processes regulating key aspects of neuronal function. Full article
(This article belongs to the Special Issue Psychoactive Substances in Neuronal Development)
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Review
Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling
Int. J. Mol. Sci. 2020, 21(17), 6115; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176115 - 25 Aug 2020
Cited by 12 | Viewed by 1545
Abstract
Synthetic cannabinoids (SCs) are a class of new psychoactive substances (NPSs) that exhibit high affinity binding to the cannabinoid CB1 and CB2 receptors and display a pharmacological profile similar to the phytocannabinoid (-)-trans9-tetrahydrocannabinol (THC). SCs are marketed under brand [...] Read more.
Synthetic cannabinoids (SCs) are a class of new psychoactive substances (NPSs) that exhibit high affinity binding to the cannabinoid CB1 and CB2 receptors and display a pharmacological profile similar to the phytocannabinoid (-)-trans9-tetrahydrocannabinol (THC). SCs are marketed under brand names such as K2 and Spice and are popular drugs of abuse among male teenagers and young adults. Since their introduction in the early 2000s, SCs have grown in number and evolved in structural diversity to evade forensic detection and drug scheduling. In addition to their desirable euphoric and antinociceptive effects, SCs can cause severe toxicity including seizures, respiratory depression, cardiac arrhythmias, stroke and psychosis. Binding of SCs to the CB1 receptor, expressed in the central and peripheral nervous systems, stimulates pertussis toxin-sensitive G proteins (Gi/Go) resulting in the inhibition of adenylyl cyclase, a decreased opening of N-type Ca2+ channels and the activation of G protein-gated inward rectifier (GIRK) channels. This combination of signaling effects dampens neuronal activity in both CNS excitatory and inhibitory pathways by decreasing action potential formation and neurotransmitter release. Despite this knowledge, the relationship between the chemical structure of the SCs and their CB1 receptor-mediated molecular actions is not well understood. In addition, the potency and efficacy of newer SC structural groups has not been determined. To address these limitations, various cell-based assay technologies are being utilized to develop structure versus activity relationships (SAR) for the SCs and to explore the effects of these compounds on noncannabinoid receptor targets. This review focuses on describing and evaluating these assays and summarizes our current knowledge of SC molecular pharmacology. Full article
(This article belongs to the Special Issue Psychoactive Substances in Neuronal Development)
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Review
S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy
Int. J. Mol. Sci. 2020, 21(10), 3721; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103721 - 25 May 2020
Cited by 3 | Viewed by 1400
Abstract
S-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss [...] Read more.
S-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss in some length the process of DNA methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. We also discuss the effects of SAMe deficiency and the attempts to use SAMe for therapeutic purposes such as the treatment of major depressive disorder, Alzheimer disease, and other neuropsychiatric disorders. SAMe is an approved food additive and as such is also used during pregnancy. Yet, there seems to scanty data on the possible effects of SAMe on the developing embryo and fetus. Valproic acid (VPA) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. Due to its high teratogenicity, it is contraindicated in pregnancy. A major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. This prompted clinical trials using VPA for additional indications i.e., treating degenerative brain disease such as Alzheimer disease, dementia, HIV, and even cancer. Therefore, we discuss the possible effects of VPA and SAMe on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. VPA is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. In contrast, SAMe modified gene expression when administered on day 12 of pregnancy but not postnatally. If administered together, VPA prevented the changes in gene expression induced by prenatal SAMe administration, and SAMe prevented the gene expression changes and autistic-like behavior induced by early postnatal VPA. It is concluded that both VPA and SAMe are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system. Full article
(This article belongs to the Special Issue Psychoactive Substances in Neuronal Development)
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Review
Changes in TRPV1-Mediated Physiological Function in Rats Systemically Treated With Capsaicin on the Neonate
Int. J. Mol. Sci. 2020, 21(9), 3143; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093143 - 29 Apr 2020
Cited by 3 | Viewed by 960
Abstract
Capsaicin is the active component of chili peppers and is a hydrophobic, colorless, odorless, and crystalline to waxy compound. The transient receptor potential vanilloid 1 (TRPV1) is the capsaicin receptor channels that are involved in a variety of functions like transduction and transmission [...] Read more.
Capsaicin is the active component of chili peppers and is a hydrophobic, colorless, odorless, and crystalline to waxy compound. The transient receptor potential vanilloid 1 (TRPV1) is the capsaicin receptor channels that are involved in a variety of functions like transduction and transmission of the physiological stimulus. Subcutaneous injection of capsaicin to a newborn rat leads to involuntary lifelong TRPV1 desensitization. Various physiological changes including sensory and homeostatic actions in the body associated with neonatal capsaicin treatment are induced by direct TRPV1 channel targeting. Interesting changes include unique phenomena such as the reduction in pain perception, abnormal body temperature, increase in infection, infectious or neuropathological itching, and irregular circadian core body temperature rhythm. These symptoms are associated with relatively higher fever or loss of sensory c-fiber related to TRPV1 desensitization. The aforementioned outcomes not only provide a warning about the risk of capsaicin exposure in newborns but also indicate the possible occurrence of relatively rare diseases that are difficult to diagnose. Therefore, Therefore, the present review aims to summarize the unique phenomena caused by systemic capsaicin administration in neonatal rats. Full article
(This article belongs to the Special Issue Psychoactive Substances in Neuronal Development)
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