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>

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>

Common prefrontal cortical gene expression profiles between adolescent SHR/NCrl and WKY/NCrl rats which showed inattention behavior

dela Peñ,a, Ike,Bang, Minji,Lee, Jinhee,de la Peñ,a, June Bryan,Kim, Bung-Nyun,Han, Doug Hyun,Noh, Minsoo,Shin, Chan Young,Cheong, Jae Hoon Elsevier 2015 Behavioural brain research Vol.291 No.-

<P><B>Abstract</B></P> <P>Factor analyses of attention-deficit/hyperactivity (ADHD) symptoms divide the behavioral symptoms of ADHD into two separate domains, one reflecting inattention and the other, a combination of hyperactivity and impulsivity. Identifying domain-specific genetic risk variants may aid in the discovery of specific biological risk factors for ADHD. In contrast with data available on genes involved in hyperactivity and impulsivity, there is limited information on the genetic influences of inattention. Transcriptional profiling analysis in animal models of disorders may provide an important tool to identify genetic involvement in behavioral phenotypes. To explore some of the potential genetic underpinnings of ADHD inattention, we examined common differentially expressed genes (DEGs) in the prefrontal cortex of SHR/NCrl, the most validated animal model of ADHD and WKY/NCrl, animal model of ADHD-inattentive type. In contrast with Wistar rats, strain representing the “normal” heterogeneous population, SHR/NCrl and WKY/NCrl showed inattention behavior in the Y-maze task. The common DEGs in the PFC of SHR/NCrl and WKY/NCrl vs. Wistar rats are those involved in transcription (e.g. <I>Creg1</I>, <I>Thrsp</I>, <I>Zeb2</I>), synaptic transmission (e.g. <I>Atp2b2</I>, <I>Syt12</I>, <I>Chrna5</I>), neurological system process (e.g. <I>Atg7</I>, <I>Cacnb4</I>, <I>Grin3a</I>), and immune response (e.g. <I>Atg7</I>, <I>Ip6k2</I>, <I>Mx2</I>). qRT-PCR analyses validated expression patterns of genes representing the major functional gene families among the DEGs (<I>Grin3a</I>, <I>Thrsp</I>, <I>Vof-16</I> and <I>Zeb2</I>). Although further studies are warranted, the present findings indicate novel genes associated with known functional pathways of relevance to ADHD which are assumed to play important roles in the etiology of ADHD-inattentive subtype.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We describe novel genes associated with inattention in SHR/NCrl and WKY/NCrl. </LI> <LI> These are genes involved in transcription, synapse transmission, immune system, etc. </LI> <LI> qRT-PCR validated expression patterns of <I>Grin3a, Zeb2, Vof-16</I> and <I>Thrsp</I>. </LI> <LI> Further studies are needed to determine their roles in ADHD inattentive subtype. </LI> </UL> </P>

Transcriptional profiling of SHR/NCrl prefrontal cortex shows hyperactivity‐associated genes responsive to amphetamine challenge

dela Peñ,a, I. J. I.,dela Peñ,a, I.,de la Peñ,a, J. B.,Kim, H. J.,Sohn, A.,Shin, C. Y.,Han, D. H.,Kim, B.‐,N.,Ryu, J. H.,Cheong, J. H. Blackwell Publishing Ltd 2017 Genes, brain, and behavior Vol.16 No.7

<P>Several studies suggest a strong genetic component of attention‐deficit/hyperactivity disorder (ADHD), a complex neurodevelopmental disorder characterized by inappropriate levels of hyperactivity, impulsivity and inattention. Determining specific genetic risk variants for each symptom dimension of ADHD may aid in the identification of the biological risk factors of the disorder. In this study, we explored the potential genetic underpinnings of the hyperactive phenotype of ADHD. To this end, we examined differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of SHR/NCrl, an animal model of ADHD, compared with its genetic control, the Wistar Kyoto (WKY/NCrl) rat and the Wistar rat, strain used to represent the ‘normal’ heterogeneous population. Relative to WKY/NCrl and Wistar controls, SHR/NCrl showed hyperactivity in the open‐field test. Treatment with the ADHD drug, amphetamine (AMPH) reduced hyperactivity in SHR/NCrl. Meanwhile, AMPH increased locomotor activity in WKY/NCrl and Wistar rats. Gene expression analysis found 21 common upregulated and 36 downregulated genes in the PFC of drug‐naive SHR/NCrl when compared with WKY/NCrl and Wistar rats. Of these DEGs, expression levels of two genes, <I>Atxn7</I> and <I>Per2,</I> which are involved in transcription and circadian rhythm, respectively, were downregulated following AMPH treatment in SHR/NCrl. Quantitative real‐time‐polymerase chain reaction analyses verified expression patterns of these genes in the PFC of drug‐naïve and AMPH‐treated SHR/NCrl. The present findings indicate genetic risk variants that may be associated with the hyperactive phenotype in ADHD. Further studies are warranted to establish the roles of <I>Atxn7</I> and <I>Per2</I> in mediating hyperactivity.</P>

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.-

Methoxetamine: A foe or friend?

Botanas, Chrislean Jun,de la Peñ,a, June Bryan,Kim, Hee Jin,Lee, Yong Sup,Cheong, Jae Hoon Elsevier 2019 Neurochemistry International Vol.122 No.-

<P><B>Abstract</B></P> <P>Methoxetamine (MXE) is an <I>N</I>-methyl-D-aspartate (NMDA) receptor antagonist that is chemically and pharmacologically similar to other dissociative substances, such as ketamine and phencyclidine. There are reports on the misuse of MXE, which sometimes resulted in adverse consequences and death. Studies have also shown that MXE has abuse liability and stimulates dopamine neurotransmission in the mesolimbic reward pathway in the brain. These findings have contributed to the negative impression on MXE. However, recent preclinical studies have identified the antidepressant properties of MXE, which are attributed to its ability to affect the glutamatergic and serotonergic systems. MXE is also reported to have analgesic effects. These findings show some of the “redeeming qualities” of MXE and indicate its possible therapeutic uses. In this paper, we have reviewed the findings that provide insights into the adverse and potential therapeutic effects of MXE. We compiled studies on the toxicity, psychotomimetic effects, and abuse liability of MXE, as well as its promising antidepressant and analgesic properties. We also have discussed the mechanism of action that might mediate the somewhat paradoxical effects observed. Importantly, this review provides valuable information on MXE for future research and will enable a better understanding of its psychopharmacological properties and the mechanisms responsible for its unique effects.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We review the adverse and potential therapeutic effects of methoxetamine (MXE). </LI> <LI> MXE, a structural analogue of ketamine, is an NMDA receptor antagonist. </LI> <LI> MXE produces toxic and dissociative effects and has abuse liability. </LI> <LI> MXE also has antidepressant and analgesic properties like ketamine. </LI> <LI> MXE can affect the dopaminergic, glutamatergic, and serotonergic system. </LI> </UL> </P>

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

Botanas, Chrislean Jun,Bryan de la Peñ,a, June,Custodio, Raly James,Joy dela Peñ,a, Irene,Kim, Mikyung,Woo, Taeseon,Kim, Hee Jin,Kim, Hye In,Chang Cho, Min,Lee, Yong Sup,Cheong, Jae Hoon Pergamon Press 2017 Neuropharmacology Vol.126 No.-

<P><B>Abstract</B></P> <P>Depression afflicts around 16% of the world's 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 α-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.</P> <P><B>Highlights</B></P> <P> <UL> <LI> MXE produced rapid and sustained antidepressant effects. </LI> <LI> Antidepressant effects MXE were blocked by NBQX, an AMPA receptor antagonist. </LI> <LI> Ketanserin, a 5HT2 receptor antagonist, attenuated antidepressant effects of MXE. </LI> <LI> MXE altered hippocampal glutamatergic and serotonergic-related gene expression. </LI> <LI> MXE's effects likely mediated by glutamertergic and serotonergic systems. </LI> </UL> </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>