ABSTRACT
Tobacco smoking is a serious health problem in society. While smoking rates are declining, smoking remains a serious risk to national health. Currently, there are several medications available to aid in smoking cessation. However, these medications have the disadvantages of low success rates in smoking cessation and various side effects. Therefore, natural-based smoking cessation aids are being suggested as a good alternative due to their accessibility and minimal side effects. The roots and stems of Acanthopanax koreanum (AK) Nakai, a plant that is native to Jeju Island, South Korea, have traditionally been used as tonic and sedatives. Moreover, eleutheroside B and chlorogenic acid are the main components of AK stem extract. In the present study, we investigated the effect of 70% ethanol AK extract and its components on ameliorating nicotine dependence and withdrawal symptoms by using behavioural tests in mice. In addition, alterations in the dopaminergic and DRD1-EPAC-ERK-CREB pathways were observed using dopamine ELISA and western blotting using mouse brains. Our findings demonstrate that the AK extract and its components effectively mitigated the effects of nicotine treatment in behavioural tests. Furthermore, it normalized the dopamine concentration and the expression level of nicotine acetylcholine receptor α7. Additionally, it was observed that AK extract and its components led to the normalization of DRD1, ERK and CREB expression levels. These results indicate that AK extract exhibits effects in ameliorating nicotine dependence behaviour and alleviating withdrawal symptoms. Moreover, EB and CGA are considered potential marker components of AK extract.
Subject(s)
Eleutherococcus , Substance Withdrawal Syndrome , Tobacco Use Disorder , Animals , Mice , Tobacco Use Disorder/drug therapy , Nicotine/adverse effects , Dopamine , Substance Withdrawal Syndrome/drug therapy , EthanolABSTRACT
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.
Subject(s)
Conditioning, Operant/drug effects , Dopamine Antagonists/pharmacology , Dopamine/metabolism , Illicit Drugs/metabolism , Synthetic Drugs/metabolism , Animals , Mice , Neuronal Plasticity/drug effects , Nucleus Accumbens/drug effects , Rats , Reinforcement, Psychology , Reward , Self Administration , Ventral Tegmental Area/drug effectsABSTRACT
RATIONALE: Circulating CTRP1 (C1q/TNF-α [tumor necrosis factor-α]-related protein 1) levels are increased in hypertensive patients compared with those in healthy subjects. Nonetheless, little is known about the molecular and physiological function of CTRP1 in blood pressure (BP) regulation. OBJECTIVE: To investigate the physiological/pathophysiological role of CTRP1 in BP regulation. METHODS AND RESULTS: CTRP1 production was increased to maintain normotension under dehydration conditions, and this function was impaired in inducible CTRP1 KO (knockout) mice (CTRP1 ΔCAG). The increase in CTRP1 under dehydration conditions was mediated by glucocorticoids, and the antagonist mifepristone prevented the increase in CTRP1 and attenuated BP recovery. Treatment with a synthetic glucocorticoid increased the transcription, translation, and secretion of CTRP1 from skeletal muscle cells. Functionally, CTRP1 increases BP through the stimulation of the AT1R (Ang II [angiotensin II] receptor 1)-Rho (Ras homolog gene family)/ROCK (Rho kinase)-signaling pathway to induce vasoconstriction. CTRP1 promoted AT1R plasma membrane trafficking through phosphorylation of AKT and AKT substrate of 160 kDa (AS160). In addition, the administration of an AT1R blocker, losartan, recovered the hypertensive phenotype of CTRP1 TG (transgenic) mice. CONCLUSIONS: For the first time, we provide evidence that CTRP1 contributes to the regulation of BP homeostasis by preventing dehydration-induced hypotension.
Subject(s)
Adipokines/metabolism , Blood Pressure , Dehydration/metabolism , Hypotension/metabolism , Adipokines/genetics , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Animals , Cell Line , Cells, Cultured , Dehydration/complications , Dehydration/physiopathology , Female , Glucocorticoids/metabolism , Humans , Hypotension/drug therapy , Hypotension/etiology , Hypotension/physiopathology , Losartan/therapeutic use , Male , Mice , Mice, Inbred C57BL , Muscle, Skeletal/metabolism , Protein Transport , Proto-Oncogene Proteins c-akt/metabolism , Receptor, Angiotensin, Type 1/metabolism , Vasoconstriction , rho-Associated Kinases/metabolismABSTRACT
3-fluoromethamphetamine (3-FMA), a derivative of methamphetamine (METH), produces behavioral impairment and deficits in dopaminergic transmission in the striatum of mice. The abuse potential of 3-FMA has not been fully characterized. The aim of this study was to evaluate the effects of 3-FMA on locomotor activity as well as its rewarding and reinforcing properties in the conditioned place preference (CPP) and self-administration procedures. Intravenous (i.v.) administration of 3-FMA (0.5 and 1.0 mg/kg) significantly increased locomotor activity in a dose-dependent manner in rats. In the CPP procedure, intraperitoneal administration of 3-FMA (10 and 30 mg/kg) produced a significant alteration in place preference in mice. In the self-administration paradigms, 3-FMA showed drug-taking behavior at the dose of 0.1 mg/kg/infusion (i.v.) during 2 hr sessions under fixed ratio schedules and high breakpoints at the dose of 0.3 and 1.0 mg/kg/infusion (i.v.) during 6 hr sessions under progressive ratio schedule of reinforcement in rats. A priming injection of 3-FMA (0.4 mg/kg, i.v.), METH (0.2 mg/kg, i.v.), or cocaine (2.0 mg/kg, i.v.) reinstated 3-FMA-seeking behavior after an extinction period in 3-FMA-trained rats during 2 hr session. Taken together, these findings demonstrate robust psychomotor, rewarding and reinforcing properties of 3-FMA, which may underlie its potential for compulsive use in humans.
Subject(s)
Locomotion/drug effects , Methamphetamine/analogs & derivatives , Methamphetamine/pharmacology , Psychomotor Performance/drug effects , Reward , Animals , Cocaine/metabolism , Male , Methamphetamine/chemistry , Mice , Mice, Inbred C57BL , Rats , Rats, Sprague-Dawley , Reinforcement, Psychology , Self AdministrationABSTRACT
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.
Subject(s)
Anisoles/adverse effects , Anisoles/chemistry , Dopamine/metabolism , Dopaminergic Neurons/drug effects , Phenethylamines/adverse effects , Phenethylamines/chemistry , Reinforcement, Psychology , Reward , Substance-Related Disorders/etiology , Animals , Brain-Derived Neurotrophic Factor/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopaminergic Neurons/metabolism , Male , Mice , Mice, Inbred C57BL , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Sprague-Dawley , Serotonin/metabolism , Substance-Related Disorders/metabolismABSTRACT
The dissociative anesthetic phencyclidine (PCP) and PCP derivatives, including 4'-F-PCP, are illegally sold and abused worldwide for recreational and non-medical uses. The psychopharmacological properties and abuse potential of 4'-F-PCP have not been fully characterized. In this study, we evaluated the psychomotor, rewarding, and reinforcing properties of 4'-F-PCP using the open-field test, conditioned place preference (CPP), and self-administration paradigms in rodents. Using Western immunoblotting, we also investigated the expression of dopamine (DA)-related proteins and DA-receptor-mediated downstream signaling cascades in the nucleus accumbens (NAc) of 4'-F-PCP-self-administering rats. Intraperitoneal administration of 10 mg/kg 4'-F-PCP significantly increased locomotor and rearing activities and increased CPP in mice. Intravenous administration of 1.0 mg/kg/infusion of 4'-F-PCP significantly enhanced self-administration during a 2 h session under fixed ratio schedules, showed a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement, and significantly altered the expression of DA transporter and DA D1 receptor in the NAc of rats self-administering 1.0 mg/kg 4'-F-PCP. Additionally, the expression of phosphorylated (p) ERK, pCREB, c-Fos, and FosB/ΔFosB in the NAc was significantly enhanced by 1.0 mg/kg 4'-F-PCP self-administration. Taken together, these findings suggest that 4'-F-PCP has a high potential for abuse, given its robust psychomotor, rewarding, and reinforcing properties via activation of DAergic neurotransmission and the downstream signaling pathways in the NAc.
Subject(s)
Phencyclidine Abuse/metabolism , Phencyclidine/analogs & derivatives , Phencyclidine/pharmacology , Animals , Behavior, Addictive/physiopathology , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , Nucleus Accumbens/metabolism , Phencyclidine/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Psychomotor Performance/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D1/metabolism , Reinforcement, Psychology , Reward , Self AdministrationABSTRACT
The aim of this study was to investigate whether the glutathione peroxidase-1 gene (GPx-1) affects cocaine-induced conditioned place preference (CPP) using a mouse model. Cocaine-induced CPP was accompanied by an increase in the level of σ-1 receptor in the nucleus accumbens (NAc). This phenomenon was more pronounced in the GPx-1 gene knockout (GPx-1 KO) than in wild type (WT) mice. In contrast, the CPP and expression of σ-1 receptor were much less pronounced in GPx-1-overexpressing transgenic (GPx-1 TG) mice than non-transgenic (non-TG) mice. Treatment of the mice with BD1047, a σ-1 receptor antagonist, significantly attenuated both cocaine-induced CPP and c-Fos-immunoreactivity (c-Fos-IR) in WT and GPx-1 KO mice, although the effects were more evident in the latter group. Despite the protective effects of BD1047 on cocaine-induced CPP and c-Fos in non-TG mice, there were no additional protective effects in cocaine-treated GPx-1 TG mice, indicating that the σ-1 receptor is a critical target for GPx-1-mediated psychoprotective activity. Overall, our results suggest that GPx-1 attenuates cocaine-induced CPP via inhibition of σ-1 receptor expression.
Subject(s)
Behavior, Animal/drug effects , Cocaine/pharmacology , Conditioning, Psychological/drug effects , Gene Expression Regulation/drug effects , Glutathione Peroxidase/genetics , Receptors, sigma/genetics , Animals , Gene Knockout Techniques , Glutathione Peroxidase/deficiency , Mice , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Glutathione Peroxidase GPX1 , Sigma-1 ReceptorABSTRACT
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.
Subject(s)
Amphetamine-Related Disorders/physiopathology , Central Nervous System Stimulants/pharmacology , Methamphetamine/pharmacology , Period Circadian Proteins/physiology , Animals , Conditioning, Psychological/drug effects , Corpus Striatum/drug effects , Dopaminergic Neurons/drug effects , Gene Knockout Techniques , Male , Mice, Inbred C57BL , Motor Activity/drug effects , Period Circadian Proteins/deficiency , Period Circadian Proteins/metabolism , Postural Balance/drug effects , Protease Inhibitors/pharmacology , Reward , Substance Withdrawal Syndrome/physiopathologyABSTRACT
Many works have been performed to understand the mechanisms of the formation and persistence of memory. However, it is not fully understood whether the decay of long-term memory can be modulated by the activation of dopamine D1 receptor. A Barnes maze task was employed to measure long-term spatial memory. We observed that the spatial memory acquired through 3 trials per session for 4â¯days had begun to fade out by the 14th day and had completely disappeared by 21â¯days after the first probe test. The intraperitoneal administration of SKF 38393 (a dopamine D1 receptor agonist) for 7â¯days beginning on the 14th day after the first probe test prevented natural memory forgetting, and the intraperitoneal administration of SCH 23390 (a dopamine D1 receptor antagonist) prevented this memory persistence. In the Western blotting, the administration of SKF 38393 increased the phosphorylation levels of PKA, ERK1/2, CaMKII, and CREB in the hippocampus. In addition, such increased levels were decreased by the corresponding antagonist (SCH 23390). Moreover, the inhibition of PKA could completely reverse the preservation of spatial memory induced by dopamine D1 receptor activation. These results suggest that the activation of the dopamine D1 receptor plays a critical role in the persistence of long-term spatial memory through the PKA signaling pathway.
Subject(s)
Cyclic AMP-Dependent Protein Kinases/metabolism , Hippocampus/metabolism , Memory, Long-Term/physiology , Receptors, Dopamine D1/metabolism , Spatial Memory/physiology , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/administration & dosage , Animals , Dopamine Agonists , Male , Maze Learning/physiology , Mice , Signal TransductionABSTRACT
Impulsivity, the predisposition to act prematurely without foresight, is associated with a number of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Identifying genetic underpinnings of impulsive behavior may help decipher the complex etiology and neurobiological factors of disorders marked by impulsivity. To identify potential genetic factors of impulsivity, we examined common differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of adolescent SHR/NCrl and Wistar rats, which showed marked decrease in preference for the large but delayed reward, compared with WKY/NCrl rats, in the delay discounting task. Of these DEGs, we examined drug-responsive transcripts whose mRNA levels were altered following treatment (in SHR/NCrl and Wistar rats) with drugs that alleviate impulsivity, namely, the ADHD medications methylphenidate and atomoxetine. Prefrontal cortical genetic overlaps between SHR/NCrl and Wistar rats in comparison with WKY/NCrl included genes associated with transcription (e.g., Btg2, Fos, Nr4a2), synaptic plasticity (e.g., Arc, Homer2), and neuron apoptosis (Grik2, Nmnat1). Treatment with methylphenidate and/or atomoxetine increased choice of the large, delayed reward in SHR/NCrl and Wistar rats and changed, in varying degrees, mRNA levels of Nr4a2, Btg2, and Homer2, genes with previously described roles in neuropsychiatric disorders characterized by impulsivity. While further studies are required, we dissected potential genetic factors that may influence impulsivity by identifying genetic overlaps in the PFC of "impulsive" SHR/NCrl and Wistar rats. Notably, these are also drug-responsive transcripts which may be studied further as biomarkers to predict response to ADHD drugs, and as potential targets for the development of treatments to improve impulsivity.
Subject(s)
Impulsive Behavior/drug effects , Impulsive Behavior/physiology , Prefrontal Cortex/drug effects , Animals , Atomoxetine Hydrochloride/metabolism , Attention Deficit Disorder with Hyperactivity/genetics , Choice Behavior , Disease Models, Animal , Male , Methylphenidate/metabolism , Prefrontal Cortex/metabolism , Rats , Rats, Inbred SHR/genetics , Rats, Inbred SHR/metabolism , Rats, Inbred WKY/genetics , Rats, Inbred WKY/metabolism , Rats, Wistar/genetics , Rats, Wistar/metabolismABSTRACT
The large-conductance calcium-activated potassium channel (BKCa channel) plays critical roles in smooth muscle relaxation. In urinary bladder smooth muscle, BKCa channel activity underlies the maintenance of the resting membrane potential and repolarization of the spontaneous action potential triggering the phasic contraction. To identify novel BKCa channel activators, we screened a library of natural compounds using a cell-based fluorescence assay and a hyperactive mutant BKCa channel (Lee et al., 2013). From 794 natural compounds, kurarinone, a flavanone from Sophora flavescens, strongly potentiated BKCa channels. When treated from the extracellular side, this compound progressively shifted the conductance-voltage relationship of BKCa channels to more negative voltages and increased the maximum conductance in a dose-dependent manner. Whereas kurarinone strongly potentiated the homomeric BKCa channel composed of only the α subunit, its effects were much smaller on heteromeric channels coassembled with auxiliary ß subunits. Although the activation kinetics was not altered significantly, the deactivation of BKCa channels was dramatically slowed by kurarinone treatment. At the single-channel level, kurarinone increased the open probability of the BKCa channel without affecting its single-channel conductance. Kurarinone potently relaxed acetylcholine-induced contraction of rat bladder smooth muscle and thus decreased the micturition frequency of rats with overactive bladder symptoms. These results indicate that kurarinone can directly potentiate BKCa channels and demonstrate the therapeutic potentials of kurarinone and its derivatives for developing antioveractive bladder medications and supplements.
Subject(s)
Flavonoids/pharmacology , Large-Conductance Calcium-Activated Potassium Channels/metabolism , Muscle Relaxation/drug effects , Urinary Bladder/physiology , Acetylcholine/pharmacology , Animals , Calcium/metabolism , Cell Line , Flavonoids/chemistry , Fluorescence , Humans , In Vitro Techniques , Intracellular Space/metabolism , Ion Channel Gating/drug effects , Kinetics , Male , Protein Subunits/metabolism , Rats, Inbred SHR , Rats, Sprague-Dawley , Structure-Activity Relationship , Urinary Bladder/drug effects , Urination/drug effects , Xenopus laevisABSTRACT
Typical treatment plans for attention-deficit/hyperactivity disorder (ADHD) utilize nonpharmacological (behavioral/psychosocial) and/or pharmacological interventions. Limited accessibility to behavioral therapies and concerns over adverse effects of pharmacological treatments prompted research for alternative ADHD therapies such as natural product-derived treatments and nutritional supplements. In this study, we reviewed the herbal preparations and nutritional supplements evaluated in clinical studies as potential ADHD treatments and discussed their performance with regard to safety and efficacy in clinical trials. We also discussed some evidence suggesting that adjunct treatment of these agents (with another botanical agent or pharmacological ADHD treatments) may be a promising approach to treat ADHD. The analysis indicated mixed findings with regard to efficacy of natural product-derived ADHD interventions. Nevertheless, these treatments were considered as a "safer" approach than conventional ADHD medications. More comprehensive and appropriately controlled clinical studies are required to fully ascertain efficacy and safety of natural product-derived ADHD treatments. Studies that replicate encouraging findings on the efficacy of combining botanical agents and nutritional supplements with other natural product-derived therapies and widely used ADHD medications are also warranted. In conclusion, the risk-benefit balance of natural product-derived ADHD treatments should be carefully monitored when used as standalone treatment or when combined with other conventional ADHD treatments.
Subject(s)
Attention Deficit Disorder with Hyperactivity/drug therapy , Complementary Therapies/adverse effects , Complementary Therapies/methods , Phytotherapy/adverse effects , Phytotherapy/methods , Clinical Trials as Topic , Drug Therapy, Combination , Humans , Treatment OutcomeABSTRACT
EGb 761(®) , a standardized extract of Ginkgo biloba leaves, has antioxidant and antiinflammatory properties in experimental models of neurodegenerative disorders such as stroke and Alzheimer's disease. Tissue plasminogen activator (tPA) acts a neuromodulator and plays a crucial role in the manifestation of neurotoxicity leading to exaggerated neuronal cell death in neurological insult conditions. In this study, we investigated the effects of EGb 761 on the basal and glutamate-induced activity and expression of tPA in rat primary cortical neurons. Under basal condition, EGb 761 inhibited both secreted and cellular tPA activities, without altering tPA mRNA level, as modulated by the activation of p38. Compared with basal condition, EGb 761 inhibited the glutamate-induced up-regulation of tPA mRNA resulting in the normalization of overt tPA activity and expression. c-Fos is a component of AP-1, which plays a critical role in the modulation of tPA expression. Interestingly, EGb 761 inhibited c-Fos nuclear translocation without affecting c-Fos expression in glutamate-induced rat primary cortical neurons. These results demonstrated that EGb 761 can modulate tPA activity under basal and glutamate-stimulated conditions by both translational and transcriptional mechanisms. Thus, EGb 761 could be a potential and effective therapeutic strategy in tPA-excessive neurotoxic conditions.
Subject(s)
Glutamic Acid/pharmacology , Neurons/drug effects , Plant Extracts/pharmacology , Proto-Oncogene Proteins c-fos/metabolism , Tissue Plasminogen Activator/metabolism , Animals , Cell Death/drug effects , Cells, Cultured , Ginkgo biloba/chemistry , Rats , Rats, Sprague-Dawley , Up-Regulation/drug effectsABSTRACT
Proteinase 3 (PR3) is released from neutrophil granules and is involved in the inflammatory process. PR3 is implicated in antimicrobial defense and cell death, but the exact role of PR3 in the brain is less defined. Microglia is the major immune effector cells in the CNS and is activated by brain injury. In the present study, the effect of PR3 on glial activation was investigated. Microglial activation was assessed by the intracellular level of reactive oxygen species and expression of inflammatory cytokines. The conditioned media from activated microglia by PR3 was used for measuring the neurotoxic effects of PR3-stimulated microglia. The effects of PR3 in vivo were measured by microinjecting PR3 into the rat brain. Herein we show that PR3 increased the inflammatory responses including the intracellular ROS and pro-inflammatory cytokine production in rat primary microglia. Conditioned media from PR3-treated microglia induced neuronal cell death in a concentration dependent manner. Furthermore, microinjected PR3 into the striatum of the rat brain induced microglial activation and neuronal cell death. Interestingly treatment with anti-PR3 monoclonal antibody and protease inhibitors ameliorated microglial activation induced by PR3 in primary microglia and striatum, which also prevented neuronal cell death in both conditions. The data presented here suggest that PR3 is a direct modulator of microglial activation and causes neuronal death through the augmentation of inflammatory responses. We suggest that PR3 could be a new modulator of neuroinflammation, and blocking PR3 would be a promising novel therapeutic target for neuroinflammatory disease such as stroke and Alzheimer's disease.
Subject(s)
Cell Death/drug effects , Macrophage Activation/drug effects , Microglia/drug effects , Myeloblastin/pharmacology , Neurons/drug effects , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/pharmacology , Cerebral Cortex/pathology , Corpus Striatum/pathology , Cytokines/metabolism , Inflammation/chemically induced , Inflammation/metabolism , Inflammation/pathology , Male , Microinjections , Myeloblastin/administration & dosage , Myeloblastin/antagonists & inhibitors , Primary Cell Culture , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolismABSTRACT
Preconception exposure to EtOH through the paternal route may affect neurobehavioral and developmental features of offspring. This study investigates the effects of paternal exposure to EtOH before conception on the hyperactivity, inattention, and impulsivity behavior of male offspring in mice. Sire mice were treated with EtOH in a concentration range approximating human binge drinking (0-4 g/kg/day EtOH) for 7 weeks and mated with untreated females mice to produce offspring. EtOH exposure to sire mice induced attention deficit hyperactivity disorder (ADHD)-like hyperactive, inattentive, and impulsive behaviors in offspring. As a mechanistic link, both protein and mRNA expression of dopamine transporter (DAT), a key determinant of ADHD-like phenotypes in experimental animals and humans, were significantly decreased by paternal EtOH exposure in cerebral cortex and striatum of offspring mice along with increased methylation of a CpG region of the DAT gene promoter. The increase in methylation of DAT gene promoter was also observed in the sperm of sire mice, suggesting germline changes in the epigenetic methylation signature of DAT gene by EtOH exposure. In addition, the expression of two key regulators of methylation-dependent epigenetic regulation of functional gene expression, namely, MeCP2 and DNMT1, was markedly decreased in offspring cortex and striatum sired by EtOH-exposed mice. These results suggest that preconceptional exposure to EtOH through the paternal route induces behavioral changes in offspring, possibly via epigenetic changes in gene expression, which is essential for the regulation of ADHD-like behaviors.
Subject(s)
Attention Deficit Disorder with Hyperactivity/chemically induced , Central Nervous System Depressants/toxicity , Dopamine Plasma Membrane Transport Proteins/metabolism , Epigenesis, Genetic/drug effects , Ethanol/toxicity , Prenatal Exposure Delayed Effects/physiopathology , Animals , Avoidance Learning/physiology , Disease Models, Animal , Dopamine Plasma Membrane Transport Proteins/genetics , Drinking Behavior , Exploratory Behavior/physiology , Female , Gene Expression Regulation/drug effects , Male , Maze Learning/physiology , Methyl-CpG-Binding Protein 2/genetics , Methyl-CpG-Binding Protein 2/metabolism , Mice , Mice, Inbred ICR , Phenotype , Pregnancy , Prenatal Exposure Delayed Effects/chemically inducedABSTRACT
BACKGROUND: Methylphenidate is the most commonly used stimulant drug for the treatment of attention-deficit/hyperactivity disorder (ADHD). Research has found that methylphenidate is a "reinforcer" and that individuals with ADHD also abuse this medication. Nevertheless, the molecular consequences of long-term recreational methylphenidate use or abuse in individuals with ADHD are not yet fully known. METHODS: Spontaneously hypertensive rats (SHR), the most validated and widely used ADHD animal model, were pretreated with methylphenidate (5 mg/kg, i.p.) during their adolescence (post-natal day [PND] 42-48) and tested for subsequent methylphenidate-induced conditioned place preference (CPP) and self-administration. Thereafter, the differentially expressed genes in the prefrontal cortex (PFC) and striatum of representative methylphenidate-treated SHRs, which showed CPP to and self-administration of methylphenidate, were analyzed. RESULTS: Genome-wide transcriptome profiling analyses revealed 30 differentially expressed genes in the PFC, which include transcripts involved in apoptosis (e.g. S100a9, Angptl4, Nfkbia), transcription (Cebpb, Per3), and neuronal plasticity (Homer1, Jam2, Asap1). In contrast, 306 genes were differentially expressed in the striatum and among them, 252 were downregulated. The main functional categories overrepresented among the downregulated genes include those involved in cell adhesion (e.g. Pcdh10, Ctbbd1, Itgb6), positive regulation of apoptosis (Perp, Taf1, Api5), (Notch3, Nsbp1, Sik1), mitochondrion organization (Prps18c, Letm1, Uqcrc2), and ubiquitin-mediated proteolysis (Nedd4, Usp27x, Ube2d2). CONCLUSION: Together, these changes indicate methylphenidate-induced neurotoxicity, altered synaptic and neuronal plasticity, energy metabolism and ubiquitin-dependent protein degradation in the brains of methylphenidate-treated SHRs, which showed methylphenidate CPP and self-administration. In addition, these findings may also reflect cognitive impairment associated with chronic methylphenidate use as demonstrated in preclinical studies. Future studies are warranted to determine the clinical significance of the present findings with regard to long-term recreational methylphenidate use or abuse in individuals with ADHD.
Subject(s)
Attention Deficit Disorder with Hyperactivity/drug therapy , Central Nervous System Stimulants/administration & dosage , Corpus Striatum/drug effects , Methylphenidate/administration & dosage , Prefrontal Cortex/drug effects , Animals , Attention Deficit Disorder with Hyperactivity/genetics , Attention Deficit Disorder with Hyperactivity/metabolism , Behavior, Animal/drug effects , Central Nervous System Stimulants/therapeutic use , Corpus Striatum/metabolism , Disease Models, Animal , Drug Administration Schedule , Gene Expression/drug effects , Gene Expression Profiling , Methylphenidate/therapeutic use , Prefrontal Cortex/metabolism , Rats , Rats, Inbred SHR , Rats, Wistar , Reinforcement, Psychology , Self AdministrationABSTRACT
BACKGROUND: Ethanol (EtOH) is one of the oldest recreational substances known to man, primarily taken because it induces a sense of well-being (euphoric effects) and relaxation (anxiolytic effects). EtOH use entails various negative consequences. Of particular interest are EtOH-induced psychomotor alterations, because of its immediate manifestation and adverse consequences. Rosa roxburghii (RR), a wild plant of Southwest China, has gained attention on account of its numerous beneficial effects on the immune, nervous, and cardiovascular systems. OBJECTIVE: In the present study we assessed the effects of Rosa roxburghii (RR) on EtOH-induced psychomotor alterations in rats. METHODS: Sprague Dawley rats were orally administered distilled water (control group) or ethanol (4 g/kg BW) (EtOH-group) to induce psychomotor alterations. RR extract (25, 50, and 100 mg/kg, p.o.) was administered 30 min before EtOH treatment (RR-group). EtOH-induced psychomotor alterations were evaluated in the open-field, accelerating rotarod, hanging wire, and cold swimming tests. Behavioral evaluation and hematological analysis (EtOH and acetaldehyde concentration) were done at 1, 2, 4 and 8 hours after EtOH administration. RESULTS: The EtOH group showed psychomotor alterations as compared with the control group. These EtOH-induced psychomotor alterations were directly related to the rise in blood ethanol and acetaldehyde concentrations. Pre-treatment of RR significantly improved EtOH-induced psychomotor alterations on open-field, accelerating rotarod, hanging wire, and cold swimming tests. These improvements in psychomotor performance coincided with the decreased blood ethanol and acetaldehyde levels observed in the RR-treated group. CONCLUSION: These results suggest that RR has ameliorating effects against EtOH-induced psychomotor alterations.
Subject(s)
Drugs, Chinese Herbal/pharmacology , Ethanol/antagonists & inhibitors , Ethanol/pharmacology , Motor Skills/drug effects , Physical Endurance/drug effects , Rosa , Acetaldehyde/blood , Animals , Dose-Response Relationship, Drug , Ethanol/blood , Exploratory Behavior/drug effects , Male , Rats , Rotarod Performance TestABSTRACT
BACKGROUND: 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. OBJECTIVE: In the present study we evaluated whether repeated pre-exposure to propofol predisposes to the use/abuse of the tiletamine-zolazepam combination. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Subject(s)
Anesthetics/pharmacology , Association Learning/drug effects , Conditioning, Operant/drug effects , Propofol/pharmacology , Tiletamine/administration & dosage , Zolazepam/administration & dosage , Anesthetics/administration & dosage , Animals , Drug Combinations , Male , Rats , Rats, Sprague-Dawley , Self AdministrationABSTRACT
Even though the number of studies aiming to improve comprehension of ADHD pathology has increased in recent years, there still is an urgent need for more effective studies, particularly in understanding adult ADHD, both at preclinical and clinical levels, due to the increasing evidence that adult ADHD is highly distinct and a different entity from childhood ADHD. This review paper outlines the symptoms, diagnostics, and neurobiological mechanisms of ADHD, with emphasis on how adult ADHD could be different from childhood-onset. Data show a difference in the environmental, genetic, epigenetic, and brain structural changes, when combined, could greatly impact the behavioral presentations and the severity of ADHD in adults. Furthermore, a crucial aspect in the quest to fully understand this disorder could be through longitudinal analysis. In this way, we will determine if and how the pathology and pharmacology of ADHD change with age. This goal could revolutionize our understanding of the disorder and address the weaknesses in the current clinical classification systems, improving the characterization and validity of ADHD diagnosis, specifically those in adults.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Adult , Humans , Child , Attention Deficit Disorder with Hyperactivity/diagnosis , Attention Deficit Disorder with Hyperactivity/pathology , Brain/pathology , MotivationABSTRACT
Over the past decade, new psychoactive substances (NPS) have emerged in the illegal drug market and have continued to attract attention from the international community. Among these, amphetamine-like NPS, classified as stimulants, constitute a significant proportion. However, the pharmacological characteristics and mechanisms underlying addiction to amphetamine-like NPS remain poorly understood. Given that circadian rhythms are linked to the brain stimulation effects of methamphetamine (METH) and amphetamine, we investigated the effects of METH, 1-(4-methoxyphenyl)-N-methylpropan-2-amine (PMMA), and 1-(benzofuran-5-yl)-N-ethylpropan-2-amine (5-EAPB) on intracranial self-stimulation (ICSS) in wild-type (WT) or Period circadian regulator 2 knockout mice. Amphetamine-like drugs increase intracellular Ca2+ levels to provoke dopamine release, so we examined the impact of Per2 knockdown on intracellular Ca2+ levels in PC12 cells to elucidate a potential mechanism underlying NPS-induced ICSS enhancement. Our ICSS results showed that METH and PMMA significantly increased brain stimulation in Per2 knockout mice compared to WT mice. Similarly, METH and PMMA induced higher Ca2+ fluorescence intensity in Per2 knockdown PC12 cells than in control cells. In contrast, 5-EAPB did not produce significant changes in either ICSS or Ca2+ signaling. These findings suggest that Per2 plays a crucial role in the brain stimulation effects of amphetamine-like drugs through the regulation of intracellular Ca2+.