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Psychoactive Substances in Neuronal Development

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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) | Viewed by 41739

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Special Issue Editors

Dr. João Pedro Silva

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UCIBIO, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Interests: molecular toxicology; developmental neurotoxicology; new psychoactive substances; cannabinoids; oxidative stress
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Prof. Helena Carmo

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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

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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

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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

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Keywords

psychoactive substances
developmental neurotoxicology
drug abuse
neurodevelopment disorders
intracellular signalling mechanisms

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Published Papers (8 papers)

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Research

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18 pages, 2350 KiB

Open AccessArticle

Prenatal THC Does Not Affect Female Mesolimbic Dopaminergic System in Preadolescent Rats

by Francesco Traccis, Valeria Serra, Claudia Sagheddu, Mauro Congiu, Pierluigi Saba, Gabriele Giua, Paola Devoto, Roberto Frau, Joseph Francois Cheer and Miriam Melis

Int. J. Mol. Sci. 2021, 22(4), 1666; https://doi.org/10.3390/ijms22041666 - 7 Feb 2021

Cited by 17 | Viewed by 3208

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 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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22 pages, 5415 KiB

Open AccessArticle

The Synthetic Cannabinoids THJ-2201 and 5F-PB22 Enhance In Vitro CB₁ Receptor-Mediated Neuronal Differentiation at Biologically Relevant Concentrations

by João Alexandre, Rui Malheiro, Diana Dias da Silva, Helena Carmo, Félix Carvalho and João Pedro Silva

Int. J. Mol. Sci. 2020, 21(17), 6277; https://doi.org/10.3390/ijms21176277 - 30 Aug 2020

Cited by 16 | Viewed by 3816

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 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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14 pages, 2366 KiB

Open AccessArticle

Early Transcriptomic Changes upon Thalidomide Exposure Influence the Later Neuronal Development in Human Embryonic Stem Cell-Derived Spheres

by Mami Kikegawa, Xian-Yang Qin, Tomohiro Ito, Hiromi Nishikawa, Hiroko Nansai and Hideko Sone

Int. J. Mol. Sci. 2020, 21(15), 5564; https://doi.org/10.3390/ijms21155564 - 3 Aug 2020

Cited by 2 | Viewed by 3262

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 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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20 pages, 5394 KiB

Open AccessArticle

Neonatal Clonazepam Administration Induced Long-Lasting Changes in GABA_A and GABA_B Receptors

by Hana Kubová, Zdeňka Bendová, Simona Moravcová, Dominika Pačesová, Luisa Rocha and Pavel Mareš

Int. J. Mol. Sci. 2020, 21(9), 3184; https://doi.org/10.3390/ijms21093184 - 30 Apr 2020

Cited by 7 | Viewed by 3390

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 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 GABA_A receptor subunits (α1, α2, α4, γ2, and δ) and the GABA_B B2 subunit, and GABA_A, benzodiazepine, and GABA_B 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. GABA_A 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 GABA_B 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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24 pages, 1975 KiB

Open AccessReview

Ketamine and Calcium Signaling—A Crosstalk for Neuronal Physiology and Pathology

by Malwina Lisek, Ludmila Zylinska and Tomasz Boczek

Int. J. Mol. Sci. 2020, 21(21), 8410; https://doi.org/10.3390/ijms21218410 - 9 Nov 2020

Cited by 20 | Viewed by 8739

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 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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18 pages, 1626 KiB

Open AccessReview

Molecular Pharmacology of Synthetic Cannabinoids: Delineating CB1 Receptor-Mediated Cell Signaling

by Kenneth B. Walsh and Haley K. Andersen

Int. J. Mol. Sci. 2020, 21(17), 6115; https://doi.org/10.3390/ijms21176115 - 25 Aug 2020

Cited by 50 | Viewed by 8988

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 (-)-trans-Δ⁹-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 (G_i/G_o) 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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21 pages, 657 KiB

Open AccessReview

S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy

by Asher Ornoy, Maria Becker, Liza Weinstein-Fudim and Zivanit Ergaz

Int. J. Mol. Sci. 2020, 21(10), 3721; https://doi.org/10.3390/ijms21103721 - 25 May 2020

Cited by 20 | Viewed by 5661

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 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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12 pages, 288 KiB

Open AccessReview

Changes in TRPV1-Mediated Physiological Function in Rats Systemically Treated With Capsaicin on the Neonate

by Keun-Yeong Jeong

Int. J. Mol. Sci. 2020, 21(9), 3143; https://doi.org/10.3390/ijms21093143 - 29 Apr 2020

Cited by 10 | Viewed by 3555

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 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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