4-F-PCP, a Novel PCP Analog Ameliorates the Depressive-Like Behavior of Chronic Social Defeat Stress Mice via NMDA Receptor Antagonism.

Major depressive disorder is a leading cause of disability in more than 280 million people worldwide. Monoamine-based antidepressants are currently used to treat depression, but delays in treatment effects and lack of responses are major reasons for the need to develop faster and more efficient antidepressants. Studies show that ketamine (KET), a PCP analog, produces antidepressant effects within a few hours of administration that lasts up to a week. However, the use of KET has raised concerns about side effects, as well as the risk of abuse. 4 -F-PCP analog is a novel PCP analog that is also an NMDA receptor antagonist, structurally similar to KET, and might potentially elicit similar antidepressant effects, however, there has been no study on this subject yet. Herein, we investigate whether 4-F-PCP displays antidepressant effects and explored their potential therapeutic mechanisms. 4-F-PCP at 3 and 10 mg/kg doses showed antidepressant-like effects and repeated treatments maintained its effects. Furthermore, treatment with 4-F-PCP rescued the decreased expression of proteins most likely involved in depression and synaptic plasticity. Changes in the excitatory amino acid transporters (EAAT2, EAAT3, EAAT4) were also seen following drug treatment. Lastly, we assessed the possible side effects of 4-F-PCP after long-term treatment (up to 21 days). Results show that 4-F-PCP at 3 mg/kg dose did not alter the cognitive function of mice. Overall, current findings provide significant implications for future research not only with PCP analogs but also on the next generation of different types of antidepressants.

R (-)-methoxetamine exerts rapid and sustained antidepressant effects and fewer behavioral side effects relative to S (+)-methoxetamine.

The newfound antidepressant efficacy of ketamine has provided opportunities for the development of new-generation, rapid-acting, glutamate-based antidepressants. We previously identified that methoxetamine (MXE), a ketamine analog, and an N-Methyl-d-aspartate (NMDA) receptor antagonist, produced rapid and sustained antidepressant effects in mice. MXE (R, S (±)-MXE) is a racemic mixture containing equal parts of S (+)-MXE and R (-)-MXE. However, studies have yet to investigate the antidepressant effects of its enantiomers. Here, we examined the potential antidepressant properties and behavioral side effects of S- and R-MXE in mice. Both S- and R-MXE showed significant NMDA receptor affinity and appreciable inhibitory activity on serotonin transporter. Also, S- and R-MXE (10 mg kg-1) exerted antidepressant effects and increased gamma waves (electroencephalography) but were inhibited by NBQX (an AMPA receptor antagonist). Subsequently, they increased mammalian target of rapamycin phosphorylation and AMPA receptor subunits GluA1 and GluA2 protein levels in the hippocampus or prefrontal cortex. Furthermore, they increased 5HT2a and 5HT2c receptor mRNA levels in the prefrontal cortex, with their antidepressant effects inhibited by ketanserin (a 5HT2a/c receptor antagonist). Taken together, S-MXE and R-MXE elicit antidepressant effects that are probably mediated via glutamatergic and serotonergic mechanisms. Unlike S-MXE, R-MXE did not induce prepulse inhibition deficits, hyperlocomotion, conditioned place preference, and locomotor sensitization, although it acutely altered motor coordination. This suggests that R-MXE induces fewer behavioral side effects and is a safer antidepressant than S-MXE. Overall, this study provides significant implications for future research on the next generation of rapid-acting, glutamate-based antidepressant drugs.

1-Phenylcyclohexan-1-amine hydrochloride (PCA HCl) alters mesolimbic dopamine system accompanied by neuroplastic changes: A neuropsychopharmacological evaluation in rodents.

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 SCH 2 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. SCH 23390 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 SCH 2 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.

The dopaminergic alterations induced by 4-F-PCP and 4-Keto-PCP may enhance their drug-induced rewarding and reinforcing effects: Implications for abuse.

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 tegmental area (VTA) was measured. Additionally, phosphorylated cyclic-adenosine monophosphate-activated protein (AMP) response element-binding (p-CREB) protein, deltaFosB (∆FosB), 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, ∆FosB, 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.

Two newly-emerging substituted phenethylamines MAL and BOD induce differential psychopharmacological effects in rodents.

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 investigate the abuse potential of MAL and BOD. METHODS: The psychostimulant, reinforcing, and rewarding properties of MAL and BOD were analyzed using locomotor sensitization, self-administration, and conditioned place preference tests. Dopamine antagonists (i.e. SCH23390, haloperidol) were administered during conditioned place preference to evaluate the involvement of the mesolimbic dopamine system. Furthermore, dopamine-related protein expression in the nucleus accumbens and the ventral tegmental area was measured along with dopamine concentrations in the nucleus accumbens. Electroencephalography was conducted to determine effects of MAL and BOD on brain wave activity. RESULTS: MAL induced psychostimulant effects and sensitization, while BOD induced locomotor depression in mice. Only MAL was self-administered by rats. Both drugs induced conditioned place preference in mice at different doses; dopamine receptor antagonists blocked MAL- and BOD-induced conditioned place preference. Both the compounds altered the expression of dopamine receptor D1 and D2 proteins in the nucleus accumbens and tyrosine hydroxylase (TH) and dopamine transporter in the ventral tegmental area, enhanced dopamine levels in the nucleus accumbens, and increased delta and gamma wave activities in the brain. CONCLUSIONS: MAL may induce abuse potential via the mesolimbic dopaminergic system and possibly accompanied by alterations in brain wave activity. Moreover, the lack of rewarding and reinforcing effects in BOD suggest that this drug may have little to no capability to engender compulsive behavior, though having found to induce alterations in dopaminergic system and brain wave activities.

Four Novel Synthetic Tryptamine Analogs Induce Head-Twitch Responses and Increase 5-HTR2a in the Prefrontal Cortex in Mice.

Tryptamines are monoamine alkaloids with hallucinogenic properties and are widely abused worldwide. To hasten the regulations of novel substances and predict their abuse potential, we designed and synthesized four novel synthetic tryptamine analogs: Pyrrolidino tryptamine hydrochloride (PYT HCl), Piperidino tryptamine hydrochloride (PIT HCl), N,N-dibutyl tryptamine hydrochloride (DBT HCl), and 2-Methyl tryptamine hydrochloride (2-MT HCl). Then, we evaluated their rewarding and reinforcing effects using the conditioned place preference (CPP) and self-administration (SA) paradigms. We conducted an open field test (OFT) to determine the effects of the novel compounds on locomotor activity. A head-twitch response (HTR) was also performed to characterize their hallucinogenic properties. Lastly, we examined the effects of the compounds on 5-HTR1a and 5-HTR2a in the prefrontal cortex using a quantitative real-time polymerase chain reaction (qRT-PCR) assay. None of the compounds induced CPP in mice or initiated SA in rats. PYT HCl and PIT HCl reduced the locomotor activity and elevated the 5-HTR1a mRNA levels in mice. Acute and repeated treatment with the novel tryptamines elicited HTR in mice. Furthermore, a drug challenge involving a 7-day abstinence from drug use produced higher HTR than acute and repeated treatments. Both the acute treatment and drug challenge increased the 5-HTR2a mRNA levels. Ketanserin blocked the induced HTR. Taken together, the findings suggest that PYT HCl, PIT HCl, DBT HCl, and 2-MT HCl produce hallucinogenic effects via 5-HTR2a stimulation, but may have low abuse potential.

4-MeO-PCP and 3-MeO-PCMo, new dissociative drugs, produce rewarding and reinforcing effects through activation of mesolimbic dopamine pathway and alteration of accumbal CREB, deltaFosB, and BDNF levels.

RATIONALE: A high number of synthetic dissociative drugs continue to be available through online stores, leading to their misuse. Recent inclusions in this category are 4-MeO-PCP and 3-MeO-PCMo, analogs of phencyclidine. Although the dissociative effects of these drugs and their recreational use have been reported, no studies have investigated their abuse potential. OBJECTIVES: To examine their rewarding and reinforcing effects and explore the mechanistic correlations. METHODS: We used conditioned place preference (CPP), self-administration, and locomotor sensitization tests to assess the rewarding and reinforcing effects of the drugs. We explored their mechanism of action by pretreating dopamine receptor (DR) D1 antagonist SCH23390 and DRD2 antagonist haloperidol during CPP test and investigated the effects of 4-MeO-PCP and 3-MeO-PCMo on dopamine-related proteins in the ventral tegmental area and nucleus accumbens. We also measured the levels of dopamine, phosphorylated cyclic-AMP response element-binding (p-CREB) protein, deltaFosB, and brain-derived neurotrophic factor (BDNF) in the nucleus accumbens. Additionally, we examined the effects of both drugs on brain wave activity using electroencephalography. RESULTS: While both 4-MeO-PCP and 3-MeO-PCMo induced CPP and self-administration, only 4-MeO-PCP elicited locomotor sensitization. SCH23390 and haloperidol inhibited the acquisition of drug CPP. 4-MeO-PCP and 3-MeO-PCMo altered the levels of tyrosine hydroxylase, DRD1, DRD2, and dopamine, as well as that of p-CREB, deltaFosB, and BDNF. All drugs increased the delta and gamma wave activity, whereas pretreatment with SCH23390 and haloperidol inhibited it. CONCLUSION: Our results indicate that 4-MeO-PCP and 3-MeO-PCMo induce rewarding and reinforcing effects that are probably mediated by the mesolimbic dopamine system, suggesting an abuse liability in humans.

25B-NBOMe, a novel N-2-methoxybenzyl-phenethylamine (NBOMe) derivative, may induce rewarding and reinforcing effects via a dopaminergic mechanism: Evidence of abuse potential.

An increasing number of N-2-methoxybenzyl-phenethylamine (NBOMe) derivatives are being misused worldwide, including the potent hallucinogen 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25B-NBOMe). However, the number of studies characterizing the abuse potential and psychopharmacological properties of 25B-NBOMe is limited; thus, we examined its rewarding and reinforcing effects using conditioned place preference (CPP) and self-administration (SA) tests. Pretreatment with SCH23390 (SCH), Haloperidol (HAL), and ketanserin (KS), antagonists of dopamine D1 (DRD1 ), dopamine D2 (DRD2 ), and serotonin 2A (5-HT2A receptor) receptors, respectively, was utilized during a CPP test to investigate the involvement of the dopaminergic and serotonergic systems in 25B-NBOMe-mediated effects. We also examined the effects of 25B-NBOMe on the expression of dopamine-related proteins in the nucleus accumbens (NAcc) and ventral tegmental area (VTA). Then, we measured the dopamine level, phosphorylated CREB (p-CREB), deltaFosB (ΔFosB), and brain-derived neurotrophic factor (BDNF) in the NAcc. In addition, we explored the involvement of 5-HT2A receptors in the 25B-NBOMe-induced head twitch response (HTR). We also examined the effects of 25B-NBOMe on brain wave activity using electroencephalography. 25B-NBOMe elicited CPP and SA. SCH and HAL blocked 25B-NBOMe-induced CPP, whereas KS did not. Moreover, 25B-NBOMe altered the DRD1 , DRD2 , and dopamine transporter expression and increased dopamine levels. It also induced changes in p-CREB, ΔFosB, and BDNF expression. 25B-NBOMe induced HTR and increased 5-HT2A receptor mRNA levels, effects inhibited by KS. Furthermore, 25B-NBOMe altered delta and gamma wave activity, which was normalized by SCH and HAL. These findings show that 25B-NBOMe may induce rewarding and reinforcing effects via a dopaminergic mechanism, suggesting its abuse potential.

Catalpol and Mannitol, Two Components of Rehmannia glutinosa, Exhibit Anticonvulsant Effects Probably via GABAA Receptor Regulation.

Epilepsy is a brain disorder that affects millions of people worldwide and is usually managed using currently available antiepileptic drugs, which result in adverse effects and are ineffective in approximately 20-25% of patients. Thus, there is growing interest in the development of new antiepileptic drugs with fewer side effects. In a previous study, we showed that a Rehmannia glutinosa (RG) water extract has protective effects against electroshock- and pentylenetetrazol (PTZ)-induced seizures, with fewer side effects. In this study, the objective was to identify the RG components that are responsible for its anticonvulsant effects. Initially, a number of RG components (aucubin, acteoside, catalpol, and mannitol) were screened, and the anticonvulsant effects of different doses of catalpol, mannitol, and their combination on electroshock- and chemically (PTZ or strychnine)-induced seizures in mice, were further assessed. Gamma-aminobutyric acid (GABA) receptor binding assay and electroencephalography (EEG) analysis were conducted to identify the potential underlying drug mechanism. Additionally, treated mice were tested using open-field and rotarod tests. Catalpol, mannitol, and their combination increased threshold against electroshock-induced seizures, and decreased the percentage of seizure responses induced by PTZ, a GABA antagonist. GABA receptor binding assay results revealed that catalpol and mannitol are associated with GABA receptor activity, and EEG analysis provided evidence that catalpol and mannitol have anticonvulsant effects against PTZ-induced seizures. In summary, our results indicate that catalpol and mannitol have anticonvulsant properties, and may mediate the protective effects of RG against seizures.

The novel methoxetamine analogs N-ethylnorketamine hydrochloride (NENK), 2-MeO-N-ethylketamine hydrochloride (2-MeO-NEK), and 4-MeO-N-ethylketamine hydrochloride (4-MeO-NEK) elicit rapid antidepressant effects via activation of AMPA and 5-HT2 receptors.

RATIONALE: Depressive syndrome or depression is a debilitating brain disorder affecting numerous people worldwide. Although readily available, current antidepressants have low remission rates and late onset times. Recently, N-methyl-D-aspartate (NMDA) receptor antagonists, like ketamine and methoxetamine (MXE), were found to elicit rapid antidepressant effects. As the search for glutamatergic-based antidepressants is increasing, we synthesized three novel MXE analogs, N-ethylnorketamine hydrochloride (NENK), 2-MeO-N-ethylketamine hydrochloride (2-MeO-NEK), and 4-MeO-N-ethylketamine hydrochloride (4-MeO-NEK). OBJECTIVES: To determine whether the three novel MXE analogs induce antidepressant effects and explore their mechanistic correlation. METHODS: We examined their affinity for NMDA receptors through a radioligand binding assay. Mice were treated with each drug (2.5, 5, and 10 mg/kg), and their behavior was assessed 30 min later in the forced swimming test (FST), tail suspension test (TST), elevated plus-maze (EPM) test, and open-field test (OFT). Another group of mice were pretreated with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione (NBQX), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, or ketanserin (KS), a 5-HT2 receptor antagonist, during the FST. We also measured mRNA levels of the AMPA receptor subunits GluA1 and GluA2, brain-derived neurotrophic factor (BDNF), and mammalian target of rapamycin (mTOR) in the hippocampus and prefrontal cortex. RESULTS: The MXE analogs showed affinity to NMDA receptors and decreased immobility time during the FST and TST. NBQX and KS blocked their effects in the FST. The compounds did not induce behavioral alteration during the EPM and OFT. The compounds altered GluA1, GluA2, and BDNF mRNA levels. CONCLUSION: These results suggest that the novel MXE analogs induce antidepressant effects, which is likely via AMPA and 5-HT2 receptor activation.

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.

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 (Atxn7) 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.

The circadian gene, Per2, influences methamphetamine sensitization and reward through the dopaminergic system in the striatum of mice.

Drug addiction is a chronic and relapsing brain disorder, influenced by complex interactions between endogenous and exogenous factors. Per2, a circadian gene, plays a role in drug addiction. Previous studies using Per2-knockout mice have shown a role for Per2 in cocaine, morphine and alcohol addiction. In the present study, we investigated the role of Per2 in methamphetamine (METH) addiction using Per2-overexpression and knockout mice. We observed locomotor sensitization responses to METH administration, and rewarding effects using a conditioned place preference test. In addition, we measured expression levels of dopamine and dopamine-related genes (monoamine oxidase A, DA receptor 1, DA receptor 2, DA active transporter, tyrosine hydroxylase and cAMP response element-binding protein 1) in the striatum of the mice after repeated METH treatments, using qRT-PCR. Per2-overexpressed mice showed decreased locomotor sensitization and rewarding effects of METH compared to the wildtype mice, whereas the opposite was observed in Per2 knockout mice. Both types of transgenic mice showed altered expression levels of dopamine-related genes after repeated METH administration. Specifically, we observed lower dopamine levels in Per2-overexpressed mice and higher levels in Per2-knockout mice. Taken together, Per2 expression levels may influence the addictive effects of METH through the dopaminergic system in the striatum of mice.

5-Methoxy-α-methyltryptamine (5-MeO-AMT), a tryptamine derivative, induces head-twitch responses in mice through the activation of serotonin receptor 2a in the prefrontal cortex.

5-Methoxy-α-methyltryptamine (5-MeO-AMT) is a tryptamine derivative that is used recreationally because of its reported hallucinogenic and mood elevating effects. Studies suggest that the psychopharmacological effects of tryptamines involve serotonin receptor 2a (5-HTR2a) activation in the brain. The head-twitch response (HTR) is widely used as a behavioral correlate for assessing 5-HTR2a agonist activity of a drug. Thus, we investigated whether 5-MeO-AMT induces HTR in mice and explored its mechanism of action. 5-MeO-AMT (0.3, 1, 3, 10 mg/kg) was administered once a day for 7 days, and the HTR was measured after 1 day (acute) and 7 days (repeated) of administration. Another cohort of mice was treated with 5-HTR2a antagonist ketanserin (KS) before 5-MeO-AMT administration. We measured 5-HTR2a and 5-HTR2c mRNA levels in the prefrontal cortex of the mice treated acutely or repeatedly with 5-MeO-AMT. We performed western blotting to determine the effects of the drug on the expression of G protein (Gq/11), protein kinase C gamma (PKC-γ), and extracellular signal-regulated kinases 1/2 (ERK1/2), in addition to PKC-γ and ERK1/2 phosphorylation. Additionally, we evaluated potential rewarding and reinforcing effects of 5-MeO-AMT using locomotor sensitization, conditioned place preference (CPP), and self-administration (SA) paradigms. Acute 5-MeO-AMT administration elicited the HTR, while repeated administration resulted in tolerance. KS blocked the 5-MeO-AMT-induced HTR. 5-MeO-AMT increased 5-HTR2a mRNA levels and induced PKC-γ phosphorylation in the prefrontal cortex. 5-MeO-AMT did not induce locomotor sensitization, CPP, or SA. This study shows that 5-MeO-AMT induces HTR through 5-HTR2a activation in the prefrontal cortex, and may have low potential for abuse.

Methoxetamine: A foe or friend?

Methoxetamine (MXE) is an N-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.

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

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.

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

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.

Exploring the Validity of Proposed Transgenic Animal Models of Attention-Deficit Hyperactivity Disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a common, behavioral, and heterogeneous neurodevelopmental condition characterized by hyperactivity, impulsivity, and inattention. Symptoms of this disorder are managed by treatment with methylphenidate, amphetamine, and/or atomoxetine. The cause of ADHD is unknown, but substantial evidence indicates that this disorder has a significant genetic component. Transgenic animals have become an essential tool in uncovering the genetic factors underlying ADHD. Although they cannot accurately reflect the human condition, they can provide insights into the disorder that cannot be obtained from human studies due to various limitations. An ideal animal model of ADHD must have face (similarity in symptoms), predictive (similarity in response to treatment or medications), and construct (similarity in etiology or underlying pathophysiological mechanism) validity. As the exact etiology of ADHD remains unclear, the construct validity of animal models of ADHD would always be limited. The proposed transgenic animal models of ADHD have substantially increased and diversified over the years. In this paper, we compiled and explored the validity of proposed transgenic animal models of ADHD. Each of the reviewed transgenic animal models has strengths and limitations. Some fulfill most of the validity criteria of an animal model of ADHD and have been extensively used, while there are others that require further validation. Nevertheless, these transgenic animal models of ADHD have provided and will continue to provide valuable insights into the genetic underpinnings of this complex disorder.

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.

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

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.