Milk Collected at Night Induces Sedative and Anxiolytic-Like Effects and Augments Pentobarbital-Induced Sleeping Behavior in Mice

Irene Joy I. dela Peña,홍은영,DELAPENAJUNEBRYAN,김희진,Chrislean Jun Botanas,홍예슬,황예슬,문병석,정재훈 한국식품영양과학회 2015 Journal of medicinal food Vol.18 No.11

Milk has long been known and used to promote sleep. The sleep-promoting effect of milk has been attributed to its psychological associations (i.e., the memory of a mother giving milk at bedtime) and its rich store of sleep-promoting constituents (e.g., tryptophan). Studies have shown that milk harvested at night (Night milk) contains exceptionally high amounts of tryptophan and melatonin. In the present study, we evaluated the psychopharmacological properties of Night milk, particularly its probable sleep-promoting/enhancing, and anxiolytic effects. Night milk was orally administered to ICR mice at various concentrations (100, 200, or 300mg/kg). An hour after administration, assessment of its sedative (open-field and rotarod tests) and sedative sleep-potentiating effects (pentobarbital-induced sleeping test) was conducted. For comparison, the effects of Day milk (daytime milking) were also assessed. In addition, the effects of Night milk on anxiety behavior (elevated plus maze [EPM] test) and electroencephalographic (EEG) waves were evaluated. Night milk-treated animals exhibited decreased spontaneous locomotion (open-field test) and impaired motor balance and coordination (rotarod test). Furthermore, Night milk shortened the sleep onset and prolonged the sleep duration induced by pentobarbital sodium. These effects were comparable to that of diazepam. In addition, Night milk significantly increased the percentage of time spent and entries into the open arms of the EPM, indicating that it also has anxiolytic effects. No significant changes in EEG waves were observed. Altogether, these findings suggest that Night milk is a promising natural aid for sleep- and anxiety-related disturbances.

The psychopharmacological activities of Vietnamese ginseng in mice: characterization of its psychomotor, sedativeehypnotic, antistress, anxiolytic, and cognitive effects

Irene Joy I. dela Peña,김희진,Chrislean Jun Botanas,June Bryan de la Peña,Thi Hong Van Le,Minh Duc Nguyen,박정힐,정재훈 고려인삼학회 2017 Journal of Ginseng Research Vol.41 No.2

Background: Panax vietnamensis Ha et Grushv. or Vietnamese ginseng (VG) is a recently discovered ginseng species. Studies on its chemical constituents have shown that VG is remarkably rich in ginseng saponins, particularly ocotillol saponins. However, the psychopharmacological effects of VG have not been characterized. Thus, in the present study we screened the psychopharmacological activities of VG in mice. Methods: VG extract (VGE) was orally administered to mice at various dosages to evaluate its psychomotor (open-field and rota-rod tests), sedativeehypnotic (pentobarbital-induced sleeping test), antistress (cold swimming test), anxiolytic (elevated plus-maze test), and cognitive (Y-maze and passiveavoidance tests) effects. Results: VGE treatment increased the spontaneous locomotor activity, enhanced the endurance to stress, reduced the anxiety-like behavior, and ameliorated the scopolamine-induced memory impairments in mice. In addition, VGE treatment did not alter the motor balance and coordination of mice and did not potentiate pentobarbital-induced sleep, indicating that VGE has no sedative-hypnotic effects. The effects of VGE were comparable to those of the Korean Red Ginseng extract. Conclusion: VG, like other ginseng products, has significant and potentially useful psychopharmacological effects. This includes, but is not limited to, psychomotor stimulation, anxiolytic, antistress, and memory enhancing effects.

Supplementation of Laurus nobilis Attenuate Ethanol-induced Psychomotor Alterations in Rats

Irene Joy I. dela Peña,June Bryan dela Pen˜a,윤서영,김희진,이진희,백세희,서용기,백석준,문병석,정재훈 한국생약학회 2014 Natural Product Sciences Vol.20 No.1

Laurus nobilis (L. nobilis) is traditionally used as an herbal medicine to treat various diseases. Ethanol (EtOH) consumption entails physiological, mental and psychomotor alterations. The aim of the present study was to assess the effects of L. nobilis in attenuating the EtOH-induced psychomotor alterations. L. nobilis was administered to SD rats, 30 minutes before EtOH administration (4 g/kg), at doses of 25, 50 and 100 mg/kg. Evaluations of psychomotor activity in the open-field, accelerating rota-rod, wire, and swimming ability were done at 1, 2, 4 and 8 hours after EtOH administration. In addition, blood ethanol and acetaldehyde levels were also measured. Pre-treatment of L. nobilis significantly improved EtOH-induced psychomotor alterations and decreased blood ethanol and acetaldehyde levels. These findings suggest that L. nobilis might be an effective substance to attenuate the harmful effects of EtOH, particularly psychomotor alterations, and can potentially be considered as a functional food.

Alleviating Effects of Opuntia ficus indica Extracts on Psychomotor Alterations Induced by Ethanol in Rats

Irene Joy I. dela Peña,윤서영,김희진,심홍,김지형,정나래,백세희,서용기,박석준,문병석,정재훈 한국식품과학회 2014 Food Science and Biotechnology Vol.23 No.6

Effects of Opuntia ficus indica (OFI) extractson ethanol-induced psychomotor alterations were studiedusing Sprague-Dawley rats orally administered 4 g/kg ofethanol (EtOH group) or distilled water (control group). AnOFI-group received OFI extracts (50, 100, and 200 mg/kg)30 min prior to EtOH administration. Behavioral andhematological tests were evaluated 1, 2, 4, and 8 h afterEtOH administration. Electroencephalogram (EEG) assessmentwas also performed. EtOH significantly (p<0.001) inducedpsychomotor alterations (reduced locomotion, balance,coordination, muscle strength, and tolerance to cold),compared with control group rats. Pre-treatment with OFIextracts alleviated alterations and also inhibited elevationof blood ethanol levels. EEG (percent of total power fordelta, theta, alpha, and beta) results for OFI group rats weresimilar to control rats, indicating a countering of EtOHinducedEEG changes. Extracts of OFI can be effective foralleviation of psychomotor alterations induced by EtOHadministration.

Protection Against Electroshock- and Pentylenetetrazol-induced Seizures by the Water Extract of Rehmannia glutinous can be Mediated through GABA Receptor-chloride Channel Complexes

김미경,김희진,김성목,June Bryan de la Peña,Irene Joy dela Peña,Chrislean Jun Botanas,우태선,이용수,류종훈,정재훈 한국생약학회 2017 Natural Product Sciences Vol.23 No.1

Epilepsy is a brain disorder that affects millions of people worldwide. It is characterized by recurrent and unpredictable seizures that are usually controlled with antiepileptic/anticonvulsive drugs. However, most antiepileptic drugs produce various side effects such as tolerance and sedation. Thus, there is a growing interest for alternative anticonvulsive drugs, preferably from natural or herbal sources. In this study, we evaluated the anticonvulsive effects of Rehmannia glutinosa (RG). The anticonvulsive effect of RG extract was evaluated using electroshock- and chemical-induced seizure tests in mice. To identify its probable mechanism of action, the effects of RG extract on Cl- influx was measured in vitro. We found that RG extract has anticonvulsive effects against electroshock-induced seizures, as indicated by an increased seizure threshold in mice. The RG extract also decreased the percentage of seizure responses induced by the GABAergic antagonist, pentylenetetrazole. These results suggest that the anticonvulsive effects of RG extract are mediated through a GABAergic mechanism. In support of this mechanism, our in vitro test showed that RG extract increases intracellular Cl- influx. Furthermore, RG extract did not show sedative and/or muscle relaxant effects in the open-field and rota-rod tests. Altogether, these results confirm that RG extract could be a herbal anticonvulsant and a potential alternative for clinical use.

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

Raly James Perez Custodio,Chrislean Jun Botanas,윤성순,June Bryan de la Peña,Irene Joy dela Peña,김미경,우태선,서정욱,장춘곤,권용호,김남용,이용섭,김희진,정재훈 한국응용약물학회 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.6

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.

A transgenic mouse showing sustained hyperactivity; a possible animal model of ADHD

DE LA PEÑ,A June Bryan,DELA PEÑ,A Irene Joy,KIM Hee Jin,SHIN Chan Young,CHEONG Jae Hoon 한국특수교육학회 2014 한국특수교육학회 학술대회 Vol.2014 No.-

The Atxn7-overexpressing mice showed hyperactivity and impulsivity which were ameliorated by atomoxetine treatment: A possible animal model of the hyperactive-impulsive phenotype of ADHD

dela Peñ,a, Irene Joy I.,Botanas, Chrislean Jun,de la Peñ,a, June Bryan,Custodio, Raly James,dela Peñ,a, Ike,Ryoo, Zae Young,Kim, Bung-Nyun,Ryu, Jong Hoon,Kim, Hee Jin,Cheong, Jae Ho Elsevier 2019 Progress in neuro-psychopharmacology & biological Vol.88 No.-

<P><B>Abstract</B></P> <P>Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder characterized by varying levels of hyperactivity, inattention, and impulsivity. Patients with ADHD are often classified as (1) predominantly hyperactive-impulsive, (2) predominantly inattentive, and (3) combined type. There is a growing interest in developing specific animal models that would recapitulate specific clinical forms of ADHD, with the goal of developing specific therapeutic strategies. In our previous study, we have identified Ataxin-7 (<I>Atxn7</I>) as a hyperactivity-associated gene. Here, we generated Atxn7 overexpressing (Atxn7 OE) mice to investigate whether the increased Atxn7 expression in the brain correlates with ADHD-like behaviors. Quantitative real-time polymerase chain reaction and immunofluorescence confirmed overexpression of the Atxn7 gene and protein in the prefrontal cortex (PFC) and striatum (STR) of the Atxn7 OE mice. The Atxn7 OE mice displayed hyperactivity and impulsivity, but not inattention. Interestingly, treatment with the ADHD drug, atomoxetine (3 mg/kg, intraperitoneal), attenuated ADHD-like behaviors and reduced Atxn7 gene expression in the PFC and STR of these mice. These findings suggest that Atxn7 plays a role in the pathophysiology of ADHD, and that the Atxn7 OE mice can be used as an animal model of the hyperactive-impulsive phenotype of this disorder. Although confirmatory studies are warranted, the present study provides valuable information regarding the potential genetic underpinnings of ADHD.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We previously found that Atxn7 is associated with ADHD-like behaviors. </LI> <LI> We generated mice that overexpresses Atxn7 in the brain (Atxn7 OE). </LI> <LI> The Atxn7 OE mice show hyperactivity and impulsivity, but not inattention. </LI> <LI> Atomoxetine attenuates the hyperactive and impulsive behavior of the Atxn7 OE mice. </LI> <LI> The Atxn7 OE mice may represent the hyperactive-impulsive subtype of ADHD. </LI> </UL> </P>

Propofol pretreatment induced place preference and self-administration of the tiletamine-zolazepam combination: implication on drug of abuse substitution

de la Peñ,a, June Bryan,Ahsan, Hafiz Muhammad,dela Peñ,a, Irene Joy,Park, Hyun Bin,Kim, Hee Jin,Sohn, Aeree,Kim, Yun Tai,Cheong, Jae Hoon Informa Healthcare USA, Inc. 2014 The American journal of drug and alcohol abuse Vol.40 No.4

<P><I>Background</I>: Propofol and the tiletamine-zolazepam combination are anesthetics with both sedative-hypnotic and hallucinogenic effects. In South Korea, propofol is controlled while the tiletamine-zolazepam combination is not. Thus, there is a possibility that this drug combination might be used as a substitute drug by propofol-abusers. <I>Objective</I>: In the present study we evaluated whether repeated pre-exposure to propofol predisposes to the use/abuse of the tiletamine-zolazepam combination. <I>Methods</I>: Rats (8-10 animals/group) were pre-treated with saline (control) or propofol at different dosages (10, 30, 60 mg/kg, i.p.), for 14 days, then conditioned place preference (CPP) and self-administration (SA) for the tiletamine-zolazepam combination were evaluated. <I>Results</I>: Rats pretreated with saline exhibited neither CPP nor SA for the tiletamine-zolazepam combination. On the other hand, rats pretreated with propofol, in all dosages, demonstrated significant CPP and SA for the tiletamine-zolazepam combination. <I>Conclusion</I>: These results suggest that tiletamine-zolazepam combinations might be used as a “substitute drug” by abusers of propofol. The careful use, dispensation, and monitoring of tiletamine-zolazepam combinations are advocated.</P>

Overexpression of the Thyroid Hormone-Responsive (THRSP) Gene in the Striatum Leads to the Development of Inattentive-like Phenotype in Mice

Custodio, Raly James Perez,Botanas, Chrislean Jun,de la Peñ,a, June Bryan,dela Peñ,a, Irene Joy,Kim, Mikyung,Sayson, Leandro Val,Abiero, Arvie,Ryoo, Zae Young,Kim, Bung-Nyun,Kim, Hee Jin,C Elsevier 2018 NEUROSCIENCE Vol.390 No.-

<P><B>Abstract</B></P> <P>Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 8–12% of children globally. Factor analyses have divided ADHD symptoms into two domains: inattention and a combination of hyperactivity and impulsivity. The identification of domain-specific genetic risk variants may help uncover potential genetic mechanisms underlying ADHD. We have previously identified that thyroid hormone-responsive (THRSP) gene expression is upregulated in spontaneously hypertensive rats (SHR/NCrl) and Wistar-Kyoto (WKY/NCrl) rats which exhibited inattention behavior. Thus, we established a line of THRSP overexpressing (OE) mice and assessed their behavior through an array of behavioral tests. The gene and protein overexpression of THRSP in the striatum (STR) was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. The THRSP OE mice exhibited inattention in the novel-object recognition and Y-maze test, but not hyperactivity in the open-field test and impulsivity in the cliff-avoidance and delay-discounting task. We have also found that expression of dopamine-related genes (dopamine transporter, tyrosine hydroxylase, and dopamine D1 and D2 receptors) in the STR increased. Treatment with methylphenidate (5 mg/kg), the most commonly used medication for ADHD, improved attention and normalized expression levels of dopamine-related genes in THRSP OE mice. Our findings suggest that THRSP plays a role in the inattention phenotype of ADHD and that the THRSP OE mice may be used as an animal model to elucidate the genetic mechanisms of the disorder.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Thyroid-hormone responsive (THRSP) overexpressing (OE) mice exhibits inattention, but not hyperactivity and impulsivity. </LI> <LI> THRSP OE mice have elevated striatal dopamine-related gene (DAT, TH, and dopamine D1 and D2 receptors) expression levels. </LI> <LI> Methylphenidate improves attention in THRSP OE mice. </LI> <LI> Methylphenidate normalizes the expression levels of dopaminergic-related genes in the striatum of THRSP OE mice. </LI> <LI> THRSP OE mice can be a potential mouse model for ADHD-inattentive type. </LI> </UL> </P>