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The novel substituted phenethylamines (a) phenethylamine (PEA) base structure with marked substitution points, (b) methamphetamine (METH), (c) 2-(3,5-dimethoxy-4-((2-methylallyl)oxy)phenyl)ethanamine (MAL), and (d) 2-(2,5-dimethoxy-4-methylphenyl)-2-methoxyethan-1-amine (BOD).
Source publication
Background
Recently, the recreational use of substituted phenethylamines has grown rapidly. Among these are 2-(3,5-dimethoxy-4-((2-methylallyl)oxy)phenyl)ethanamine (MAL) and 2-(2,5-dimethoxy-4-methylphenyl)-2-methoxyethan-1-amine (BOD). However, studies characterizing their abuse potential are still lacking.
Aim
The purpose of this study was to i...
Contexts in source publication
Context 1
... an enhanced psychostimulant effect was observed upon substitution of a 3,4,5-methoxy group on the phenyl ring (Halberstadt et al., 2013). Interestingly, similar structural moieties were found in two novel substituted PEAs, 2-(3,5-dimethoxy-4-((2-methylallyl)oxy)phenyl) ethanamine (MAL) and 2-(2,5-dimethoxy-4-methylphenyl)-2-methoxyethan-1-amine (BOD) (Figure 1). ...
Context 2
... reduced TH protein expressions. For DAT protein expressions, a one-way ANOVA revealed a significant difference between treatment groups (F(3,16)=8.49, p<0.01). ...
Context 3
... an enhanced psychostimulant effect was observed upon substitution of a 3,4,5-methoxy group on the phenyl ring (Halberstadt et al., 2013). Interestingly, similar structural moieties were found in two novel substituted PEAs, 2-(3,5-dimethoxy-4-((2-methylallyl)oxy)phenyl) ethanamine (MAL) and 2-(2,5-dimethoxy-4-methylphenyl)-2-methoxyethan-1-amine (BOD) (Figure 1). ...
Citations
... All drugs used were in the hydrochloride salt form, dissolved in 0.9% saline solution (vehicle; VEH), and administered intraperitoneally. All drug dosages used were based on previously published findings evaluating the HTR and neurotoxic Custodio et al. 2020a;Hur et al. 2020) properties of similar compounds. ...
Rationale: Serotonergic psychedelics exert their effects via their high affinity for serotonin (5-HT) receptors, particularly through activating 5-HT2A receptors (5-HT2AR), employing the frontal cortex-dependent head-twitch response (HTR). Although universally believed to be so, studies have not yet fully ascertained whether 5-HT2AR activation is the sole initiator of these psychedelic effects. This is because not all 5-HT2AR agonists exhibit similar pharmacologic properties. Objective: This study aims to identify and discriminate the roles of 5-HT2AR and 5-HT2CR in the HTR induced by Methal-lylescaline (MAL) and 4-Methyl-2,5,β-trimethoxyphenethylamine (BOD) in male mice. Also, an analysis of their potential neurotoxic properties was evaluated.
Methods: Male mice treated with MAL and BOD were evaluated in different behavioral paradigms targeting HTR and neurotoxicity effects. Drug affinity, pharmacological blocking, and molecular analysis were also conducted to support the behavioral findings. The HTR induced by DOI has been extensively characterized in male mice, making it a good positive control for this study, specifically for comparing the pharmacological effects of our test compounds.
Results: The activation of 5-HT2CR, alone or in concert with 5-HT2AR, produces a comparable degree of HTRs (at a dose of 1 mg·kg −1), with divergent 5-HT2CR-and 5-HT2AR-Gqα11-mediated signaling and enhanced neurotoxic properties (at a dose of 30 mg·kg −1) coupled with activated pro-inflammatory cytokines. These findings show these compounds' potential psychedelic and neurotoxic effects in male mice.
Conclusion: These findings showed that while 5-HT2AR is the main initiator of HTR, the 5-HT2CR also has a distinct property that renders it effective in inducing HTR in male mice.
... In the past, it has been proposed that anhedonia might result from reduced dopamine release in the brain reward system [57]. In support of this model, several animal studies have revealed that the administration of dopamine D 2 receptor antagonists in the striatum attenuates the reinforcing effects of various psychoactive substances [58]. In humans, several functional neuroimaging studies have shown that striatal activity is reduced in MDD subjects when they anticipate or receive a reward [59]. ...
Background:
Fibromyalgia (FM) and major depression disorder (MDD) frequently co-occur. Both disorders may share common serotonergic alterations, although there is less evidence of such alterations in FM. It is also unclear as to whether these alterations are persistent over time or transient. The objectives of this study were to (i) examine the changes in mRNA expression of serotonin transporter (SERT) on the surface of peripheral blood mononuclear cells (PBMCs) in FM, MDD, and the FM + MDD subjects compared to healthy controls, and to (ii) evaluate the effect of drug treatment on SERT expression.
Methods:
PBMCs were isolated from FM, MDD, FM + MDD, and control subjects. SERT expression was analyzed at the mRNA level via quantitative real-time polymerase chain reaction. Statistical analyses were performed using analyses of variance and linear mixed-effects models.
Results:
SERT mRNA expression was significantly reduced in MDD subjects compared to controls (p < 0.001), but not in FM nor in FM + MDD subjects. Although the drug treatments improved symptoms in FM, MDD, and FM + MDD subjects, they had no significant effect on SERT mRNA expression.
Conclusions:
These results corroborate the role of the SERT in the pathophysiology of MDD, but not in FM, and show that the decreased mRNA expression of SERT is a persistent, rather than transient, phenomenon.
... Our results revealed that the butanol fraction (BuF) with non-polar components, including β-sitosterol, significantly prolonged sleep duration and decreased sleep latency. In addition, our results showed that β-sitosterol also has an effect on sleep improvement, consistent with previous studies that showed that β-sitosterol has sedative and sleep-promoting effects [31,33]. All of these results suggest that MS extracts can be a novel therapeutic candidate for sleep disorders such as insomnia, as well as other neurological disorders related to sleep disorders. ...
... Neuroactive steroids such as BS modulate GABAA receptors, which have potential anticonvulsant, anxiolytic, neuroprotective, and sedativehypnotic effects [63,64]. It has been reported that BS improves sleep via GABAergic systems [31], and BS and its derivatives showed antidepressive effects by modifying 5-HT, DA, and GABAergic systems in mice [33]. Our results demonstrate that BS, a major component of MSE, has a sleep-promoting effect, which increases the expression of melatonin receptors 1 and 2. Therefore, our results suggest a novel mechanism of BS on sleep improvement targeting melatonin receptors. ...
Sleep is a restorative period that plays a crucial role in the physiological functioning of the body, including that of the immune system, memory processing, and cognition. Sleep disturbances can be caused by various physical, mental, and social problems. Recently, there has been growing interest in sleep. Maydis stigma (MS, corn silk) is a female maize flower that is traditionally used as a medicinal plant to treat many diseases, including hypertension, edema, and diabetes. It is also used as a functional food in tea and other supplements. β-Sitosterol (BS) is a phytosterol and a natural micronutrient in higher plants, and it has a similar structure to cholesterol. It is a major component of MS and has anti-inflammatory, antidepressive, and sedative effects. However, the potential effects of MS on sleep regulation remain unclear. Here, we investigated the effects of MS on sleep in mice. The effects of MS on sleep induction were determined using pentobarbital-induced sleep and caffeine-induced sleep disruption mouse models. MS extracts decreased sleep latency and increased sleep duration in both the pentobarbital-induced sleep induction and caffeine-induced sleep disruption models compared to the positive control, valerian root extract. The butanol fraction of MS extracts decreased sleep latency time and increased sleep duration. In addition, β-sitosterol enhances sleep latency and sleep duration. Both MS extract and β-sitosterol increased alpha activity in the EEG analysis. We measured the mRNA expression of melatonin receptors 1 and 2 (MT1/2) using qRT-PCR. The mRNA expression of melatonin receptors 1 and 2 was increased by MS extract and β-sitosterol treatment in rat primary cultured neurons and the brain. In addition, MS extract increased the expression of clock genes including per1/2, cry1/2, and Bmal1 in the brain. MS extract and β-sitosterol increased the phosphorylation of ERK1/2 and αCaMKII. Our results demonstrate for the first time that MS has a sleep-promoting effect via melatonin receptor expression, which may provide new scientific evidence for its use as a potential therapeutic agent for the treatment and prevention of sleep disturbance.
... Likewise, MDPV, i.e., the powerful stimulant structurally similar to 3,4-MDPHP, was shown to be consistently self-administered by rats at rates comparable with or higher than those observed during self-administration of methamphetamine [48,49]. In line with this observation, other substituted phenethylamines and synthetic cathinones, such as methylone, are robustly self-administered by rats [50][51][52], although failure to acquire self-administration behavior was recently reported for a newly emerging substituted phenethylamine, i.e., 2-(2,5-dimethoxy-4-methylphenyl)-2-methoxyethan-1-amine (BOD) [53]. All this evidence supported the hypothesis that 2-Cl-4,5-MDMA and 3,4-MDPHP could also be able to sustain reliable operant behavior in rats. ...
The illicit drug market of novel psychoactive substances (NPSs) is expanding, becoming an alarming threat due to increasing intoxication cases and insufficient (if any) knowledge of their effects. Phenethylamine 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) and synthetic cathinone 3,4-methylenedioxy-α-pyrrolidinohexanophenone (3,4-MDPHP) are new, emerging NPSs suggested to be particularly dangerous. This study verified whether these two new drugs (i) possess abuse liability, (ii) alter plasma corticosterone levels, and (iii) interfere with dopaminergic transmission; male and female adolescent rats were included to evaluate potential sex differences in the drug-induced effects. Findings show that the two NPSs are not able to sustain reliable self-administration behavior in rats, with cumulatively earned injections of drugs being not significantly different from cumulatively earned injections of saline in control groups. Yet, at the end of the self-administration training, females (but not males) exhibited higher plasma corticosterone levels after chronic exposure to low levels of 3,4-MDPHP (but not of 2-Cl-4,5-MDMA). Finally, electrophysiological patch-clamp recordings in the rostral ventral tegmental area (rVTA) showed that both drugs are able to increase the firing rate of rVTA dopaminergic neurons in males but not in females, confirming the sex dimorphic effects of these two NPSs. Altogether, this study demonstrates that 3,4-MDPHP and 2-Cl-4,5-MDMA are unlikely to induce dependence in occasional users but can induce other effects at both central and peripheral levels that may significantly differ between males and females.
... Procedure: This method was based on previous studies with some modifications (Kim et al., 2019;Custodio et al., 2020;Sayson et al., 2020). The test consisted of three phases: (A) habituation (days 1-3) and pre-conditioning (day 4; 15 min), (B) conditioning (days 5-12; 30 min), and (C) post-conditioning (day 13; 15 min). ...
Previous reports have demonstrated that genetic mechanisms greatly mediate responses to drugs of abuse, including methamphetamine (METH). The circadian gene Period 2 (Per2) has been previously associated with differential responses towards METH in mice. While the behavioral consequences of eliminating Per2 have been illustrated previously, Per2 overexpression has not yet been comprehensively described; although, Per2-overexpressing (Per2 OE) mice previously showed reduced sensitivity towards METH-induced addiction-like behaviors. To further elucidate this distinct behavior of Per2 OE mice to METH, we identified possible candidate biomarkers by determining striatal differentially expressed genes (DEGs) in both drug-naïve and METH-treated Per2 OE mice relative to wild-type (WT), through RNA sequencing. Of the several DEGs in drug naïve Per2 OE mice, we identified six genes that were altered after repeated METH treatment in WT mice, but not in Per2 OE mice. These results, validated by quantitative real-time polymerase chain reaction, could suggest that the identified DEGs might underlie the previously reported weaker METH-induced responses of Per2 OE mice compared to WT. Gene network analysis also revealed that Asic3, Hba-a1, and Rnf17 are possibly associated with Per2 through physical interactions and predicted correlations, and might potentially participate in addiction. Inhibiting the functional protein of Asic3 prior to METH administration resulted in the partial reduction of METH-induced conditioned place preference in WT mice, supporting a possible involvement of Asic3 in METH-induced reward. Although encouraging further investigations, our findings suggest that these DEGs, including Asic3, may play significant roles in the lower sensitivity of Per2 OE mice to METH.
... SA test was conducted following a previously described procedure (Custodio et al., 2020a), with modifications for mouse experimentation. Briefly, training for drug-paired lever pressing was conducted for 3 days consecutively (30 min; 2×/day), contingent on food pellet reward under continuous reinforcement. ...
... Subsequently, the mice were given a 7 day recovery period prior to the EEG recording. Data analyses were conducted in accordance with previous studies (Custodio et al., 2020a(Custodio et al., , 2020bKim et al., 2022). ...
Background:
Morphine abuse is a devastating disorder that affects millions of people worldwide, and literature evidence indicates a relationship between opioid abuse and the circadian clock.
Aim:
We explored morphine reward and reinforcement using mouse models with Per2 gene modifications (knockout (KO); overexpression (OE)).
Methods:
Mice were exposed to various behavioral, electroencephalographic, pharmacological, and molecular tests to assess the effects of morphine and identify the underlying mechanisms with a focus on reward and reinforcement and the corresponding involvement of circadian and clock-controlled gene regulation.
Results:
Per2 deletion enhances morphine-induced analgesia, locomotor sensitization, conditioned place preference (CPP), and self-administration (SA) in mice, whereas its overexpression attenuated these effects. In addition, reduced withdrawal was observed in Per2 KO mice, whereas an augmented withdrawal response was observed in Per2 OE mice. Moreover, naloxone and SCH 23390 blocked morphine CPP in Per2 KO and wild-type (WT) mice. The rewarding (CPP) and reinforcing effects (SA) observed in morphine-conditioned and morphine self-administered Per2 KO and WT mice were accompanied by activated μ-opioid and dopamine D1 receptors and TH in the mesolimbic (VTA/NAcc) system. Furthermore, genetic modifications of Per2 in mice innately altered some clock genes in response to morphine.
Conclusion:
These findings improve our understanding of the role of Per2 in morphine-induced psychoactive effects. Our data and those obtained in previous studies indicate that targeting Per2 may have applicability in the treatment of substance abuse.
... Electroencephalography (EEG). EEG was performed to assess theta waves in mice according to our previous study 80,81 . Briefly, a tethered, three-channel system head-mount (8200-K3-iS/iSE; Pinnacle Technology, Inc., Lawrence, KS) was implanted, secured with two stainless steel screws positioned frontally (A/P: −1.0 mm; M/L, −1.5 mm) and posteriorly (A/P: −1.0 mm; M/L, ±1.5 mm), and fixed with cement. ...
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, potentially with a biological basis; however, its exact cause remains unknown. Thyroid hormone (TH) abnormalities are more prevalent in patients with ADHD than in the general population, indicating a shared pathogenetic mechanism for these conditions. Previously, we identified that overexpression of thyroid hormone-responsive protein (THRSP), a gene highly responsive to TH status, induced inattention in male mice. Herein, we sought to explore whether TH function in THRSP-overexpressing (THRSP OE) mice influences ADHD-like (inattention) behavior. We now confirm that THRSP overexpression in male mice reproduces behavioral features of ADHD, including sustained inattention and memory impairment, accompanied by excessive theta waves that were found normal in both the THRSP-knockout and hetero groups. Physiological characterization revealed low striatal T3 levels in the THRSP OE mice due to reduced striatal T3-specific monocarboxylate transporter 8 (MCT8), indicating brain-specific hypothyroidism in this transgenic mouse strain. TH replacement for seven days rescued inattention and memory impairment and the normalization of theta waves. This study further supports the involvement of the upregulated THRSP gene in ADHD pathology and indicates that THRSP OE mice can serve as an animal model for the predominantly inattentive subtype of ADHD. Custodio et al. characterise a mouse model of ADHD in which thyroid hormone-responsive protein is overexpressed. They demonstrate that reduced levels of striatal triiodothyronine (T3) play a role in inattention and memory impairment in this model and that the model could be used in future studies examining the predominantly inattentive subtype of ADHD.
... Another class of NPS, properly of the dissociative type, is represented by derivative of phencyclidine (PCP) and ketamine, which are N-methyl D-aspartate (NMDA) receptor antagonists. Subjective effects associated with the intake of these drugs include dissociativelike effects, with alteration of the mood and thought, and schizophrenia-like effects [163]. ...
... Diphenidine further inhibits NET and DAT, while it is a less potent DAT inhibitor, but both do not mediate an efflux of monoamines [137]. N-Ethyl-1,2-diphenylethanamine (ephenidine) also acts selectively by blocking NMDA receptors with a higher potency than ketamine, though also interacting with NET and DAT, which might contribute to the behavioral profile of the drug [163]. ...
Novel psychoactive substances (NPS) represent a severe health risk for drug users. Even though the phenomenon has been growing since the early 2000s, the mechanisms of action of NPS at the receptors and beyond them are still scarcely understood. The aim of the present study was to provide a systematic review of the updated knowledge regarding the molecular mechanisms underlying the toxicity of synthetic opioids, cannabinoids, cathinones, and stimulants. The study was conducted on the PubMed database. Study eligibility criteria included relevance to the topic, English language, and time of publication (2010–2020). A combined Mesh and free-text protocols search was performed. Study selection was performed on the title/abstract and, in doubtful cases, on the full texts of papers. Of the 580 records identified through PubMed searching and reference checking, 307 were excluded by title/abstract and 78 additional papers were excluded after full-text reading, leaving a total of 155 included papers. Molecular mechanisms of synthetic opioids, synthetic cannabinoids, stimulants, psychedelics, and hallucinogens were reviewed and mostly involved both a receptor-mediated and non-receptor mediated cellular modulation with multiple neurotransmitters interactions. The molecular mechanisms underlying the action of NPS are more complex than expected, with a wide range of overlap among activated receptors and neurotransmitter systems. The peculiar action profile of single compounds does not necessarily reflect that of the structural class to which they belong, accounting for possible unexpected toxic reactions.
... The locomotor sensitization test was patterned as described in our previous studies Custodio et al., 2020;Sayson et al., 2020). Briefly, under normal light conditions (100 lx) and between 1000 and 1700 h, locomotor activity was assessed in a square Plexiglas container with an open field arena measuring 42 cm × 42 cm × 42 cm on a white surface. ...
The recreational use of N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP) and ketamine have grown rapidly due to their psychotomimetic properties. These compounds induce both non-fatal and fatal adverse effects and despite the enhanced regulation, they are continuously synthesized and are being sold in the illegal drug market, including 1-phenylcyclohexan-1-amine hydrochloride (PCA). Therefore, we evaluated its abuse potential through the conditioned-place preference (CPP), self-administration, and locomotor sensitization paradigms. Pretreatment with SCH2 3390 and haloperidol was also performed during a CPP test. We used ELISA to measure dopamine (DA) levels and western blotting to determine effects on the DA-related proteins as well as on phosphorylated CREB, deltaFosB, and brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA) and nucleus accumbens (NAc). Finally, we examined the effects on brain wave activity using electroencephalography (EEG). PCA induced CPP in mice and was self-administered by rats, suggesting that PCA has rewarding and reinforcing properties. PCA increased locomotor of mice on the first treatment and challenge days. SCH2 3390 and haloperidol blocked the CPP. PCA altered the DA, tyrosine hydroxylase, dopamine D1 and D2 receptors as well as p-CREB and deltaFosB. Also, PCA altered the delta and gamma waves in the brain, which were then normalized by SCH2 3390 and haloperidol. The present findings indicate that PCA may induce abuse potential through the dopaminergic system and probably accompanied with alterations in brain wave activity which is similar to that of other psychotomimetic NMDA antagonists. We advocate thorough monitoring of PCP analogs as they pose potential harm to public health.
... Intrajugular surgeries were performed, according to a previously described procedure. 15,16 Rats were allowed to recover for at least 5 days and then the SA testing commenced and was performed for 2 h/day. Rats ...
... The effects of SCH and HAL pretreatment on the acquisition of 4-F-PCP, 4-Keto-PCP, and KET CPP in mice are shown in Figure 3B. 15,16 The SA test assesses the reinforcing efficacy of substances by counting the number of times a subject elicits the lever response that results in drug infusion. 16 Of note, CPP studies with PCP analogs have produced differential results. ...
... 15,16 The SA test assesses the reinforcing efficacy of substances by counting the number of times a subject elicits the lever response that results in drug infusion. 16 Of note, CPP studies with PCP analogs have produced differential results. Some show place preference or place aversion even at a same dose. ...
Novel psychoactive substances remain the popular recreational drugs of use over the years. They continue to bypass government restrictions due to their synthesis and modifications. Recent additions to the lists are the 4-F-PCP and 4-Keto-PCP, analogs of the drug phencyclidine (PCP) known to induce adverse effects and abuse potential. However, studies on the abuse potential of 4-F-PCP and 4-Keto-PCP remain scarce. The rewarding and reinforcing effects of the drugs were assessed using conditioned place preference (CPP), self-administration, and locomotor sensitization tests. Dopamine (DA) receptor antagonists (SCH23390 and haloperidol) were administered during CPP to evaluate the involvement of the mesolimbic dopaminergic system. DA-related protein expression in the nucleus accumbens (NAcc) and ventral tegmen-tal area (VTA) was measured. Additionally, phosphorylated cyclic-adenosine monophosphate-activated protein (AMP) response element-binding (p-CREB) protein , deltaFosB (ΔFosB), and brain-derived neurotrophic factor (BDNF) protein levels in the NAcc were measured to assess the addiction neural plasticity effect of the drugs. Both 4-F-PCP and 4-Keto-PCP-induced CPP and self-administration; however, only 4-F-PCP elicited locomotor sensitization. Treatment with DA receptor antagonists (SH23390 and haloperidol) inhibited the 4-F-and 4-Keto-induced CPP. Both substances altered the levels of DA receptor D1 (DRD1), thyroxine hydroxylase (TH), DA receptor D2 (DRD2), p-CREB, ΔFosB, and BDNF. The results suggest that 4-F-PCP and 4-Keto-PCP may induce abuse potential in rodents via alterations in dopaminergic system accompanied by addiction neural plasticity.
