Taeseon Woo

Rearing in an enriched environment attenuated hyperactivity and inattention in the Spontaneously Hypertensive Rats, an animal model of Attention-Deficit Hyperactivity Disorder

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder, characterized by symptoms of hyperactivity, inattention, and impulsivity. It is commonly treated with psychostimulants that typically begins during childhood and lasts for an extended period of time. However, there are concerns regarding the consequences of chronic psychostimulant treatment; thus, there is a growing search for an alternative management for ADHD. One non-pharmacological management that is gaining much interest is environmental enrichment. Here, we investigated the effects of rearing in an enriched environment (EE) on the expression of ADHD-like symptoms in the Spontaneously Hypertensive Rats (SHRs), an animal model of ADHD. SHRs were reared in EE or standard environment (SE) from post-natal day (PND) 21 until PND 49. Thereafter, behavioral tests that measure hyperactivity (open field test [OFT]), inattention (Y-maze task), and impulsivity (delay discounting task) were conducted. Additionally, electroencephalography (EEG) was employed to assess the effects of EE on rats brain activity. Wistar-Kyoto (WKY) rats, the normotensive counterpart of the SHRs, were used to determine whether the effects of EE were specific to a particular genetic background. EE improved the performance of the SHRs and WKY rats in the OFT and Y-maze task, but not the delay discounting task. Interestingly, EE induced significant EEG changes in WKY rats, but not in the SHRs. These findings show that rearing environment may play a role in the expression of ADHD-like symptoms in the SHRs and that EE may be considered as a putative complementary approach in managing ADHD symptoms.

A novel synthetic cathinone, 2-(methylamino)-1-(naphthalen-2-yl) propan-1-one (BMAPN), produced rewarding effects and altered striatal dopamine-related gene expression in mice

HighlightsWe designed and synthesized a new synthetic cathinone BMAPN.BMAPN is a synthetic cathinone with naphthalene substituent on the aromatic ring.BMAPN produced rewarding and reinforcing effects.BMPAN has the ability to alter dopamine‐related gene expression. ABSTRACT The recreational use of synthetic cathinones has grown rapidly which prompted concerns from legal authorities and health care providers. However, in response to legislative regulations, synthesis of novel synthetic cathinones by introducing substituents in cathinone molecule has dramatically increased the diversity of these substances. Based on current trends, the aromatic ring is one of the popular sites in cathinone molecule being explored by designer‐type modifications. In this study, we designed and synthesized a novel synthetic cathinone, 2‐(methylamino)‐1‐(naphthalen‐2‐yl) propan‐1‐one (BMAPN), which has a naphthalene substituent on the aromatic ring. Thereafter, we determined whether BMAPN has rewarding and reinforcing effects through the conditioned place preference (CPP) test in mice and self‐administration (SA) paradigm in rats. Locomotor sensitization was also assessed in mice during daily BMAPN treatment for 7 days and drug challenge. Furthermore, we investigated the effects on BMAPN on dopamine‐related genes in the striatum of mice using quantitative real‐time polymerase chain reaction (qRT‐PCR). BMAPN induced CPP at 10 and 30 mg/kg and was modestly self‐administered at 0.3 mg/kg/infusion. Repeated BMAPN (30 mg/kg) administration also produced locomotor sensitization. qRT‐PCR analyses revealed decreased dopamine transporter and increased dopamine receptor D2 gene expression in the striatum of the BMAPN‐treated mice. These data indicate that BMAPN has rewarding and reinforcing properties, which might be due to its effects on dopamine‐related genes. The present study suggests that these findings may be useful in predicting abuse potential of future cathinone entities with aromatic ring substitutions.

The abuse potential of two novel synthetic cathinones with modification on the alpha-carbon position, 2-cyclohexyl-2-(methylamino)-1-phenylethanone (MACHP) and 2-(methylamino)-1-phenyloctan-1-one (MAOP), and their effects on dopaminergic activity

ABSTRACT The recreational use of synthetic cathinones has dramatically increased in recent years, which is partly due to easy accessibility and ability of synthetic cathinones to exert rewarding effects similar to cocaine and methamphetamine. Many synthetic cathinones have already been scheduled in several countries; however, novel and diverse synthetic cathinones are emerging at an unprecedented rate, often outpacing regulatory processes. Recently, designer modifications of the basic cathinone molecule are usually performed on the alpha‐carbon position. In this study, we designed and synthesized two novel synthetic cathinones with substituents on alpha‐carbon position, [1] 2‐cyclohexyl‐2‐(methylamino)‐1‐phenylethanone (MACHP), and [2] 2‐(methylamino)‐1‐phenyloctan‐1‐one (MAOP). Then, we evaluated their rewarding and reinforcing effects through the conditioned place preference (CPP) in mice and self‐administration (SA) test in rats. Locomotor activity was also assessed in mice during daily MACHP or MAOP treatment for 7 days and drug challenge. qRT‐PCR analyses were conducted to determine their effects on dopamine‐related genes in the striatum. MACHP and MAOP produced CPP at 10 and 30 mg/kg. In the SA test, MACHP (1 mg/kg/infusion), but not MAOP, was self‐administered. Both MACHP and MAOP induced locomotor sensitization in mice. qRT‐PCR analyses showed that MACHP and MAOP reduced dopamine transporter gene expression in the striatum. These data indicate that MACHP and MAOP may have rewarding properties, which might be attributed to their ability to affect the dopaminergic activity. These findings may be useful in predicting the abuse potential and hasten the regulation of future cathinone entities with similar modifications. HighlightsWe synthesized two new synthetic cathinones MACHP and MAOP.MACHP and MAOP are synthetic cathinones with alpha‐carbon modification.MACHP and MAOP can produce rewarding effects.MACHP, but not MAOP, supports self‐administration.MACHP and MAOP have the ability to decrease DAT gene expression.

The Abuse Potential of α-Piperidinopropiophenone (PIPP) and α-Piperidinopentiothiophenone (PIVT), Two New Synthetic Cathinones with Piperidine Ring Substituent

A diversity of synthetic cathinones has flooded the recreational drug marketplace worldwide. This variety is often a response to legal control actions for one specific compound (e.g. methcathinone) which has resulted in the emergence of closely related replacement. Based on recent trends, the nitrogen atom is one of the sites in the cathinone molecule being explored by designer type modifications. In this study, we designed and synthesized two new synthetic cathinones, (1) α-piperidinopropiophenone (PIPP) and (2) α-piperidinopentiothiophenone (PIVT), which have piperidine ring substituent on their nitrogen atom. Thereafter, we evaluated whether these two compounds have an abuse potential through the conditioned place preference (CPP) in mice and self-administration (SA) in rats. We also investigated whether the substances can induce locomotor sensitization in mice following 7 days daily injection and challenge. qRT-PCR analyses were conducted to determine their effects on dopamine-related genes in the striatum. PIPP (10 and 30 mg/kg) induced CPP in mice, but not PIVT. However, both synthetic cathinones were not self-administered by the rats and did not induce locomotor sensitization in mice. qRT-PCR analyses showed that PIPP, but not PIVT, reduced dopamine transporter gene expression in the striatum. These data indicate that PIPP, but not PIVT, has rewarding effects, which may be attributed to its ability to affect dopamine transporter gene expression. Altogether, this study suggests that PIPP may have abuse potential. Careful monitoring of this type of cathinone and related drugs are advocated.

A tryptic hydrolysate from bovine milk αs1-casein enhances pentobarbital-induced sleep in mice via the GABAA receptor.

Studies have shown that enzymatic hydrolysis of casein, the primary protein component of cows milk, produces peptides with various biological activities, and some of these peptides may have sleep-promoting effects. In the present study, we evaluated the sedative and sleep-promoting effects of bovine αS1-casein tryptic hydrolysate (CH), containing a decapeptide αS1-casein known as alpha-casozepine. CH was orally administered to ICR mice at various concentrations (75, 150, 300, or 500mg/kg). An hour after administration, assessment of its sedative (open-field and rota-rod tests) and sleep-potentiating effects (pentobarbital-induced sleeping test and EEG monitoring) were conducted. Although a trend can be observed, CH treatment did not significantly alter the spontaneous locomotor activity and motor function of mice in the open-field and rota-rod tests. On the other hand, CH (150mg/kg, respectively) enhanced the sleep induced by pentobarbital sodium in mice. It also promoted slow-wave (delta) EEG activity in rats; a pattern indicative of sleep or relaxation. These behavioral results indicate that CH has sleep-promoting effects, but no or has minimal sedative effects. To elucidate the probable mechanism behind the effects of CH, we examined its action on intracellular chloride ion influx in cultured human neuroblastoma cells. CH dose-dependently increased chloride ion influx, which was blocked by co-administration of bicuculline, a competitive GABAA receptor antagonist. Taken together, the results of the present study suggest that CH has sleep-promoting properties which are probably mediated through the GABAA receptor-chloride ion channel complex.

Evaluation of the Abuse Potential of Novel Amphetamine Derivatives with Modifications on the Amine (NBNA) and Phenyl (EDA, PMEA, 2-APN) Sites

Recently, there has been a rise in the number of amphetamine derivatives that serve as substitutes for controlled substances (e.g. amphetamine and methamphetamine) on the global illegal drug market. These substances are capable of producing rewarding effects similar to their parent drug. In anticipation of the future rise of new and similar psychoactive substances, we designed and synthesized four novel amphetamine derivatives with N-benzyl, N-benzylamphetamine HCl (NBNA) substituent on the amine region, 1,4-dioxane ring, ethylenedioxy-amphetamine HCl (EDA), methyl, para-methylamphetamine HCl (PMEA), and naphthalene, 2-(aminopropyl) naphthalene HCl (2-APN) substituents on the phenyl site. Then, we evaluated their abuse potential in the conditioned place preference (CPP) test in mice and self-administration (SA) test in rats. We also investigated the psychostimulant properties of the novel drugs using the locomotor sensitization test in mice. Moreover, we performed qRT-PCR analyses to explore the effects of the novel drugs on the expression of D1 and D2 dopamine receptor genes in the striatum. NBNA, but not EDA, PMEA, and 2-APN, induced CPP and SA in rodents. None of the test drugs have produced locomotor sensitization. qRT-PCR analyses demonstrated that NBNA increased the expression of striatal D1 dopamine receptor genes. These data indicate that NBNA yields rewarding effects, suggesting potential for abuse. Continual observation for the rise of related substances is thus strongly encouraged.

Cigarette smoke exposure during adolescence but not adulthood induces anxiety-like behavior and locomotor stimulation in rats during withdrawal

Adolescence is a critical period for cigarette smoking. Studies have shown that adolescent smokers are more likely to become addicted, are less likely to quit, and are more prone to relapse. In the present study, we examined the affective symptoms experienced by adolescents during withdrawal from cigarette smoke exposure. Towards this goal, adolescent male rats were repeatedly exposed to cigarette smoke, through an automated smoking machine, for 14 days. Then, cigarette smoke exposure was discontinued to induce spontaneous withdrawal. During the withdrawal period, anxiety‐like behavior (elevated plus‐maze test), locomotor activity (open‐field test), and learning and memory (passive‐avoidance test) were evaluated. These behavioral evaluations were conducted during the first, third, seventh, and fourteenth day of withdrawal. For comparison, parallel experiments were performed in adult rats. We found that adolescent rats exposed to cigarette smoke experiences increased anxiety‐like behavior and locomotor activity during withdrawal relative to control rats. Learning and memory processes were undisturbed. On the other hand, adult rats exposed to cigarette smoke did not show any statistically significant behavioral alteration during withdrawal. These results are consistent with the notion that adolescents are differentially sensitive to the withdrawal effects of cigarette smoking. This sensitivity might be a factor why adolescent smokers have difficulty quitting and are more prone to relapse.

Methoxetamine produces rapid and sustained antidepressant effects probably via glutamatergic and serotonergic mechanisms

&NA; Depression afflicts around 16% of the worlds population, making it one of the leading causes of disease burden worldwide. Despite a number of antidepressants available today, the delayed onset time and low remission rate of these treatments are still a major challenge. The N‐methyl‐D‐aspartate (NMDA) receptor antagonist ketamine has shown to produce rapid and sustained antidepressant effects and has paved the way for a new generation of glutamate‐based antidepressants. Methoxetamine (MXE) is a ketamine analogue that acts as an NMDA receptor antagonist and a serotonin reuptake inhibitor. However, no studies have evaluated the antidepressant effects of MXE. Here, we assessed whether MXE produces antidepressant effects and explored possible mechanisms underlying its effects. Mice were treated with MXE (2.5, 5, or 10 mg/kg) and their behavior was evaluated 30 min and 24 h later in an array of behavioral experiments used for screening antidepressant drugs. A separate group of mice were treated with NBQX, an &agr;‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonist, or ketanserin, a 5HT2 receptor antagonist, before MXE (5 mg/kg) administration in the forced swimming test (FST). We also investigated the effect of MXE on glutamatergic‐ and serotonergic‐related genes in the mouse hippocampus using quantitative real‐time PCR. MXE produced antidepressant effects 30 min after treatment that persisted for 24 h. Both NBQX and ketanserin blocked the antidepressant effects of MXE in the FST. MXE also altered hippocampal glutamatergic‐ and serotonergic gene expressions. These results suggest that MXE has rapid and sustained antidepressant effects, possibly mediated by the glutamatergic and serotonergic system. HighlightsMXE produced rapid and sustained antidepressant effects.Antidepressant effects MXE were blocked by NBQX, an AMPA receptor antagonist.Ketanserin, a 5HT2 receptor antagonist, attenuated antidepressant effects of MXE.MXE altered hippocampal glutamatergic and serotonergic‐related gene expression.MXEs effects likely mediated by glutamertergic and serotonergic systems.

A new synthetic drug 5-(2-aminopropyl)indole (5-IT) induces rewarding effects and increases dopamine D1 receptor and dopamine transporter mRNA levels

Highlights5‐IT is an indole and phenethylamine derivative.5‐IT induced conditioned place preference.5‐IT elicited locomotor sensitization in mice.Dopamine D1 receptor in mice striatum and PFC was increased by 5‐IT.5‐IT has rewarding properties. Abstract In recent years, there has been a marked increase in the use of recreational synthetic psychoactive substances, which is a cause of concern among healthcare providers and legal authorities. In particular, there have been reports on the misuse of 5‐(2‐aminopropyl)indole (5‐API; 5‐IT), a new synthetic drug, and of fatal and non‐fatal intoxication. Despite these reports, little is known about its psychopharmacological effects and abuse potential. Here, we investigated the abuse potential of 5‐IT by evaluating its rewarding and reinforcing effects through conditioned place preference (CPP) (1, 10, and 30 mg/kg, i.p.) in mice and self‐administration test (0.1, 0.3, 1, and 3 mg/kg/inf., i.v.) in rats. We also examined whether 5‐IT (1, 3, and 10 mg/kg, i.p.) induces locomotor sensitization in mice following a 7‐day treatment and drug challenge. Then, we explored the effects of 5‐IT (10 mg/kg, i.p.) on dopamine‐related genes in the striatum, prefrontal cortex (PFC), and substantia nigra pars compacta (SNc)/ventral tegmental (VTA) of mice by quantitative real‐time polymerase chain reaction. 5‐IT produced CPP in mice but was not reliably self‐administered by rats. 5‐IT also induced locomotor sensitization following repeated administration and drug challenge. Moreover, 5‐IT increased mRNA levels of dopamine D1 receptor in the striatum and PFC and dopamine transporter in the SNc/VTA of mice. These results indicate that 5‐IT has psychostimulant and rewarding properties, which may be attributed to its ability to affect the dopaminergic system in the brain. These findings suggest that 5‐IT poses a substantial risk for abuse and addiction in humans.