ABSTRACT
Methamphetamine (MA) is a psychostimulant and addictive substance. Long-term uses and toxic high doses of MA can induce neurotoxicity. The present study aimed to investigate the protective role of melatonin against MA toxicity-induced dysregulation of the neurotransmission related to cognitive function in rats. The adult male Sprague Dawley rats were intraperitoneally injected with 5 mg/kg MA for 7 consecutive days with or without subcutaneously injected with 10 mg/kg melatonin before MA injection. Some rats were injected with saline solution (control) or 10 mg/kg melatonin. MA administration induced reduction in total weight gain, neurotoxic features of stereotyped behaviors, deficits in cognitive flexibility, and significantly increased lipid peroxidation in the brain which diminished in melatonin pretreatment. The neurotoxic effect of MA on glutamate, dopamine and GABA transmitters was represented by the alteration of the GluR1, DARPP-32 and parvalbumin (PV) levels, respectively. A significant decrease in the GluR1 was observed in the prefrontal cortex of MA administration in rats. MA administration significantly increased the DARPP-32 but decreased PV in the striatum. Pretreatment of melatonin can abolish the neurotoxic effect of MA on neurotransmission dysregulation. These findings might reveal the antioxidative role of melatonin to restore neurotransmission dysregulation related to cognitive deficits in MA-induced neurotoxicity.
Subject(s)
Cognition Disorders/chemically induced , Melatonin/pharmacology , Methamphetamine/toxicity , Neuroprotective Agents/pharmacology , Synaptic Transmission/drug effects , Animals , Attention/drug effects , Blotting, Western , Cognition/drug effects , Cognition Disorders/prevention & control , Corpus Striatum/drug effects , Hippocampus/drug effects , Male , Methamphetamine/antagonists & inhibitors , Prefrontal Cortex/drug effects , Rats , Rats, Sprague-Dawley , Stereotyped Behavior/drug effectsABSTRACT
Norepinephrine (NE) neurons and extracellular NE exert some protective effects against a variety of insults, including methamphetamine (Meth)-induced cell damage. The intimate mechanism of protection remains difficult to be analyzed in vivo. In fact, this may occur directly on target neurons or as the indirect consequence of NE-induced alterations in the activity of trans-synaptic loops. Therefore, to elude neuronal networks, which may contribute to these effects in vivo, the present study investigates whether NE still protects when directly applied to Meth-treated PC12 cells. Meth was selected based on its detrimental effects along various specific brain areas. The study shows that NE directly protects in vitro against Meth-induced cell damage. The present study indicates that such an effect fully depends on the activation of plasma membrane ß2-adrenergic receptors (ARs). Evidence indicates that ß2-ARs activation restores autophagy, which is impaired by Meth administration. This occurs via restoration of the autophagy flux and, as assessed by ultrastructural morphometry, by preventing the dissipation of microtubule-associated protein 1 light chain 3 (LC3) from autophagy vacuoles to the cytosol, which is produced instead during Meth toxicity. These findings may have an impact in a variety of degenerative conditions characterized by NE deficiency along with autophagy impairment.
Subject(s)
Methamphetamine/antagonists & inhibitors , Methamphetamine/toxicity , Microtubule-Associated Proteins/metabolism , Neurons/drug effects , Neurons/metabolism , Norepinephrine/pharmacology , Receptors, Adrenergic, beta-2/metabolism , Adrenergic Agents/pharmacology , Animals , Autophagy/drug effects , Cell Compartmentation/drug effects , Central Nervous System Stimulants/administration & dosage , Central Nervous System Stimulants/antagonists & inhibitors , Central Nervous System Stimulants/toxicity , Desipramine/pharmacology , Dose-Response Relationship, Drug , Methamphetamine/administration & dosage , Microscopy, Electron, Transmission , Models, Neurological , Neurons/ultrastructure , Neuroprotective Agents/pharmacology , Norepinephrine/metabolism , PC12 Cells , Rats , Vacuoles/drug effects , Vacuoles/metabolism , Vacuoles/ultrastructureABSTRACT
Methamphetamine (MET) is one of the most prevalently abused psychostimulants in the world with drastic repercussions. Several studies emphasized the inhibitory effect of Cannabidiol (CBD) on the reward properties of psychostimulants. The current investigation utilized conditioned place preference (CPP) to assay CBD's impact on MET's reward characteristic, including acquisition and expression phases of MET-induced CPP. Like our prior researches, animals received MET (1 mg/kg; sc) in a five-day schedule to induce CPP. The rats were given intracerebroventricular (ICV) microinjection of CBD (2, 10, and 50 µg/5 µL DMSO) during the 5-day conditioning phase in the CPP paradigm to highlight the CBD's impact on the development (acquisition) of MET-induced place preference. Furthermore, animals were treated with CBD (2, 10 and 50 µg/5 µL) in the lateral ventricle on the post-conditioning day to elucidate the effect of ICV injection of CBD on the expression of MET-induced CPP. It was revealed that CBD (10 and 50 µg/5 µL) microinjection profoundly inhibited both phases of MET-induced CPP without any side effect on the locomotion in animals were treated by MET injection over conditioning phase. Also, CBD's inhibitory impact was more potent in the acquisition phase than the expression phase of MET-induced CPP. Ultimately, the current research reported that CBD could be a beneficial compound to treat drug abuse however more investigations are needed.
Subject(s)
Cannabidiol/pharmacology , Conditioning, Classical/drug effects , Methamphetamine/pharmacology , Animals , Dose-Response Relationship, Drug , Locomotion/drug effects , Male , Methamphetamine/antagonists & inhibitors , Rats , Rats, Wistar , RewardABSTRACT
Dopamine D2 receptors (D2Rs) are densely expressed in the striatum and have been linked to neuropsychiatric disorders such as schizophrenia1,2. High-affinity binding of dopamine suggests that D2Rs detect transient reductions in dopamine concentration (the dopamine dip) during punishment learning3-5. However, the nature and cellular basis of D2R-dependent behaviour are unclear. Here we show that tone reward conditioning induces marked stimulus generalization in a manner that depends on dopamine D1 receptors (D1Rs) in the nucleus accumbens (NAc) of mice, and that discrimination learning refines the conditioning using a dopamine dip. In NAc slices, a narrow dopamine dip (as short as 0.4 s) was detected by D2Rs to disinhibit adenosine A2A receptor (A2AR)-mediated enlargement of dendritic spines in D2R-expressing spiny projection neurons (D2-SPNs). Plasticity-related signalling by Ca2+/calmodulin-dependent protein kinase II and A2ARs in the NAc was required for discrimination learning. By contrast, extinction learning did not involve dopamine dips or D2-SPNs. Treatment with methamphetamine, which dysregulates dopamine signalling, impaired discrimination learning and spine enlargement, and these impairments were reversed by a D2R antagonist. Our data show that D2Rs refine the generalized reward learning mediated by D1Rs.
Subject(s)
Dendritic Spines/physiology , Discrimination Learning/physiology , Receptors, Dopamine D2/metabolism , Animals , Calcium/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Conditioning, Classical/drug effects , Dendritic Spines/drug effects , Discrimination Learning/drug effects , Dopamine/metabolism , Dopamine D2 Receptor Antagonists/pharmacology , Extinction, Psychological/drug effects , Male , Methamphetamine/antagonists & inhibitors , Methamphetamine/pharmacology , Mice , Neuronal Plasticity , Neurons/drug effects , Neurons/metabolism , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Optogenetics , Receptor, Adenosine A2A/metabolism , Receptors, Dopamine D1/metabolism , Reward , Signal Transduction/drug effects , Synapses/metabolismABSTRACT
Levo-tetrahydropalmatine (L-THP) is the main active ingredient of traditional Chinese herbal medicine Corydalis and Stephania, which have been used for sedative, neuroleptic, and analgesic purposes. Previous studies have demonstrated that L-THP has antagonistic activation on dopamine receptors. Despite its effectiveness on treating drug addiction, L-THP's underlying molecular mechanisms in modulating methamphetamine (METH) reward behavior remain unclear. In order to clarify the mechanisms behind, we designed an experiment of conditioned place preference (CPP) to investigate the effects of L-THP on METH-induced CPP in mice. We then dissected the underlying molecular mechanisms of L-THP in modulating METH-induced CPP by evaluating accompanying changes in expression of phosphorylated extracellular signal-regulated kinase (p-ERK) in reward-relevant brain regions, including nucleus accumbens (NAc), prefrontal cortex (PFc), caudate putamen (CPu), and hippocampus (Hip), which may mediate the effects of L-THP on METH-induced CPP. The results showed that 1.0â¯mg/kg METH could induce obvious CPP in mice; 10.0â¯mg/kg L-THP could significantly attenuate METH-induced CPP in mice, though it could not induce CPP or conditioned place aversion by itself. Moreover, the levels of p-ERK in NAc and PFc of the METH group were significantly higher than that of the saline group. Although there was no evident difference between the levels of p-ERK of the L-THP group with that of the saline group, the levels of p-ERK in NAc and PFc of the Mâ¯+â¯T group were significantly lower than that of the METH group. There was no striking difference among the levels of p-ERK in CPu and Hip of all experimental groups. Our research suggested that NAc and PFc function as circuits contributing to METH addiction, and the activation of the ERK phosphorylation plays an important role in the mechanisms of METH addiction. Besides, L-THP significantly decreased ERK phosphorylation's high expression induced by METH, which suggested that the inhibitory effect of L-THP on modulating METH reward behavior may be related to the suppression of ERK phosphorylation in NAc and PFc of mice. In conclusion, L-THP could suppress the reward properties of METH, therefore, it may be a promising candidate for the treatment of METH addiction.
Subject(s)
Berberine Alkaloids/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , Methamphetamine/antagonists & inhibitors , Reward , Animals , Conditioning, Psychological/drug effects , Male , Methamphetamine/pharmacology , Mice , Nucleus Accumbens/metabolism , Phosphorylation/drug effects , Prefrontal Cortex/metabolism , Up-Regulation/drug effectsABSTRACT
Methamphetamine (METH) is one of the most prevalently used illegal psychostimulants in many countries. Continuous exposure to METH leads to behavioral sensitization in animals, which can be used as a behavioral model with many mechanisms in common with relapse in humans. Molecular hydrogen has recently gained attention for its potential as a novel healthcare product with preventive and therapeutic applicability to a wide range of pathological conditions. However, it remains unclear whether and, if so, how hydrogen regulates METH-induced behavioral abnormalities. In the present study, we investigated the roles of molecular hydrogen on the acquisition and transfer of METH-induced behavioral sensitization and the accompanying changes in ERK phosphorylation and ΔFosB activation in the nucleus accumbens (NAc) of mice. To this end, male C57BL/6 mice received METH (0.1, 0.5 and 1.0â¯mg/kg, i.p.) injections for 7â¯days followed by a METH challenge (0.1, 0.5 and 1.0â¯mg/kg, i.p.) after a 7-day transfer period. Molecular hydrogen, delivered through a hydrogen-rich saline (HRS) injection (10â¯mL/kg, i.p., 3-h interval), was administered during the acquisition and transfer periods. We found that HRS administration was able to inhibit the acquisition and transfer of 0.1 and 0.5â¯mg/kg METH-induced behavioral sensitization to a certain extent, thereby attenuating the expression of behavioral sensitization. The HRS injections alone did not induce any obvious changes in locomotor activity in mice. Intriguingly, the increases in pERK and ΔFosB in the NAc, which accompanied the METH-induced behavioral sensitization, were also attenuated by the HRS treatments. Due to the anti-oxidative function of molecular hydrogen, the HRS injections reduced METH-induced reactive oxygen species and malondialdehyde generation in the NAc. These results suggest that molecular hydrogen serves as an anti-oxidative agent with potentially therapeutic applicability to the treatment of METH addicts.
Subject(s)
Central Nervous System Sensitization/drug effects , Hydrogen/pharmacology , MAP Kinase Signaling System/drug effects , Methamphetamine/antagonists & inhibitors , Nucleus Accumbens/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Animals , Dose-Response Relationship, Drug , Locomotion/drug effects , Male , Malondialdehyde , Methamphetamine/pharmacology , Mice , Phosphorylation/drug effects , Reactive Oxygen Species/metabolismABSTRACT
There are no Food and Drug Administration approved pharmacotherapies for methamphetamine (METH) overdose, thus identifying novel drug targets to prevent this devastating adverse event is a public-health imperative. Previous research suggests that serotonin and sigma receptors may contribute to the adverse effects of METH. The present study assessed whether pretreatment with the 5-HT2A receptor antagonist M100907 or the sigma 1 (σ1) receptor antagonist BD 1047 attenuated METH-induced lethality, hyperthermia, convulsions, and seizures. Male, Swiss-Webster mice received intraperitoneal injections of M100907 (1 and 10â¯mg/kg), BD 1047 (10â¯mg/kg), or a combination of M100907 (1â¯mg/kg) and BD 1047 (10â¯mg/kg) prior to treatment with METH (78â¯mg/kg). Convulsions and lethality were assessed by observation, core body temperature was assessed by surgically implanted telemetric probes, and seizures were assessed by electroencephalography. M100907 reduced METH-elicited lethality from 67% to 33%, BD1047 reduced METH-elicited lethality from 67% to 50%, and combined administration of both agents eliminated lethality in all mice tested. Similarly, both agents and their combination reduced METH-elicited seizures and convulsions. None of the treatments decreased METH-induced hyperthermia. This research suggests that reducing METH-induced seizures is an important factor in reducing lethality associated with METH overdose. However, future studies should examine whether M100907 and BD 1047 modulate METH-induced hypertension and other adverse effects that may also contribute to METH overdose. Our data support the continued investigation of compounds that target 5-HT2A and σ1 receptors in METH-induced overdose, including their potential to yield emergency reversal agents.
Subject(s)
Central Nervous System Stimulants/antagonists & inhibitors , Central Nervous System Stimulants/toxicity , Ethylenediamines/pharmacology , Fluorobenzenes/pharmacology , Methamphetamine/antagonists & inhibitors , Methamphetamine/toxicity , Piperidines/pharmacology , Receptors, sigma/antagonists & inhibitors , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Animals , Body Temperature/drug effects , Electroencephalography/drug effects , Fever/chemically induced , Fever/prevention & control , Lethal Dose 50 , Male , Mice , Seizures/chemically induced , Seizures/prevention & control , Sigma-1 ReceptorABSTRACT
The molecular mechanism and treatment of methamphetamine (METH) use disorder remain unclear. The current study aimed to investigate the role of central angiotensin II receptor (ATR) in drug taking and seeking behavior associated with METH use disorder. The effect of an ATR type 1 (AT1R) antagonist, candesartan cilexetil, on the reinforcing and motivational effects of METH was first assessed using the animal model of METH self-administration (SA) and reinstatement. The levels of dopamine D2 receptor (D2R) and AT1R were subsequently examined. Furthermore, the present study determined the expression of microRNAs (miRNAs) by comparing METH SA, METH-yoked, and Saline-yoked groups. The target miRNAs were further overexpressed in the nucleus accumbens (NAc) via a lentivirus vector to investigate the effects of target miRNAs on METH SA maintained under a fixed ratio 1, progressive ratio, and cue/drug reinstatement of METH SA. The potential role of the AT1R-PLCß-CREB signaling pathway was finally investigated. The results suggest that AT1R blockade effectively reduced METH SA and reinstatement, in conjunction with the counter-regulation of D2R and AT1R. A total of 17 miRNAs targeting Ang II in NAc were found to be associated with the voluntary intake of METH. Furthermore, overexpression of specific miR-219a-5p targeting AT1R-regulated METH SA and reinstatement. The AT1R-PLCß-CREB signaling pathway was found to be associated with the effect of AT1R on the drug-taking and drug-seeking behavior involving METH use disorder.
Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Methamphetamine/antagonists & inhibitors , Receptors, Angiotensin/metabolism , Reinforcement, Psychology , Animals , Benzimidazoles/pharmacology , Biphenyl Compounds/pharmacology , Brain/drug effects , Brain/metabolism , Brain/physiology , Cues , Cyclic AMP Response Element-Binding Protein/metabolism , Gene Expression Regulation/drug effects , Male , Methamphetamine/pharmacology , MicroRNAs/genetics , PC12 Cells , Phospholipase C beta/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Angiotensin, Type 1/metabolism , Receptors, Dopamine D2/metabolism , Self Administration , Tetrazoles/pharmacologyABSTRACT
BACKGROUND AND OBJECTIVE: Methamphetamine (MA) substance use disorder (SUD) does not have an efficacious pharmacotherapy. We developed a MA vaccine and investigated its potential to attenuate MA induced responses. METHODS: We examined a novel adjuvant, E6020, a Toll-like receptor-4 (TLR-4) agonist combined with tetanus-toxoid conjugated to succinyl-methamphetamine (TT-SMA) adsorbed on aluminum hydroxide (alum). Adult BALB/c female mice received the vaccine and booster injections at weeks 0, 3, and 6. The efficacy of the vaccine was assessed by the level and affinity of anti-MA antibodies elicited, its ability to attenuate MA induced locomotor activation and its reduction in the amount of MA entering the brains of vaccinated mice. RESULTS: The TT-SMA vaccine containing alum and E6020 adjuvant produced anti-MA antibodies with nanomolar affinities and showed threefold greater peak titer levels than without E6020 (700 vs 250 µg/ml). These antibodies significantly decreased MA-induced locomotor activation (p < .05), and reduced the brain (p < .005) MA levels following MA administration in actively immunized mice. CONCLUSIONS: Thus, this anti-MA vaccine formulated with E6020 demonstrated effective functional protection against behavioral disruptions induced by MA. SCIENTIFIC SIGNIFICANCE: Together, anti-MA vaccine showing a promising improvement in the efficacy of the vaccine that could be an effective candidate vaccine for methamphetamine use disorder (MUD). Furthermore, combinations of adjuvants may be a tool to design vaccines for MA dependence in humans. (Am J Addict 2019;XX:1-8).
Subject(s)
Aluminum Hydroxide/pharmacology , Amphetamine-Related Disorders/therapy , Methamphetamine/antagonists & inhibitors , Phospholipids/pharmacology , Tetanus Toxoid/pharmacology , Adjuvants, Immunologic/pharmacology , Animals , Biological Availability , Drug Combinations , Drug Monitoring/methods , Mice , Models, Animal , Toll-Like Receptor 4/agonists , Treatment OutcomeABSTRACT
Methamphetamine (METH) abuse is one the most worldwide problems with wide-ranging effects on the central nervous system (CNS). Chronic METH abuse can associate with cognitive abnormalities and neurodegenerative changes in the brain. Agmatine, a cationic polyamine, has been proposed as a neuromodulator that modulates many effects of abused drugs. The aim of this study was to determine if agmatine can decrease the impairment effect of METH on memory and hippocampal CaMKII-α gene expression, a gene that plays a major role in memory. Male wistar rats (200-220â¯g) were allocated into 7 groups, including 5 groups of saline, METH (1, 2â¯mg/kg), Agmatine (5, 10â¯mg/kg) and 2 groups of agmatine (5, 10â¯mg/kg) with higher doses of METH (2â¯mg/kg) for 5 consecutive days (nâ¯=â¯8 in each group). All injections were done intraperitoneally and agmatine was administrated 10â¯min before METH treatment. Furthermore, Passive avoidance learning (PAL) test was assessed on the 5th day. Retention test was done 24â¯h after training and the rats were sacrificed immediately. Hippocampi were removed and stored at -80⯰C. Finally, hippocampal CaMKII-α gene expression was measured using Quantitative Real-time PCR. Our data showed that chronic METH dose-dependently impaired PAL retrieval, as it decreased step-through latency (STL) and increased time spent in the dark compartment (TDC). While Agmatine with a higher dose (10â¯mg/kg) significantly decreased impairment effect of METH (2â¯mg/kg) on PAL and memory. Also, molecular results revealed that METH (2â¯mg/kg) markedly decreased hippocampal CaMKII-α gene expression while agmatine (10â¯mg/kg) co-adminstration prevented it. Taken together, the results propose that agmatine may provide a potential therapy for learning and memory deficits induced by METH.
Subject(s)
Agmatine/pharmacology , Avoidance Learning/drug effects , Calcium-Calmodulin-Dependent Protein Kinase Type 2/biosynthesis , Hippocampus/metabolism , Memory/drug effects , Methamphetamine/antagonists & inhibitors , Animals , Dose-Response Relationship, Drug , Male , Mental Recall/drug effects , Methamphetamine/pharmacology , RatsABSTRACT
Methamphetamine (METH) is a commonly abused psychostimulant that can induce severe neurotoxicity. Cardiovascular injury caused by METH has recently gained increasing attention; however, the underlying mechanisms remain unclear. As autophagy has been shown to be associated with cell injury, the association between autophagy and METH-mediated cell apoptosis was investigated in the present study. METH treatment significantly increased the expression of two key autophagy proteins, i.e., Beclin-1 and LC3-II, in the cardiomyocyte cell line H9C2. Furthermore, according to western blot and flow cytometry analyses, METH contributed to cell injury and markedly enhanced cleaved-caspase 3 and PARP expression. In addition, the corresponding AKT-mTOR survival pathway axis was appeared deactivated. The autophagic activity was closely associated with METH-mediated cell injury because rapamycin, which is an autophagy inducer, markedly attenuated METH-induced cell injury, while 3-Methyladenine (3-MA), which is an autophagy inhibitor, and bafilomycinA1 (Baf-A1), which is a blocker of autophagosome-lysosome fusion, markedly exacerbated METH-induced cell injury. Notably, defective autophagosome-lysosome fusion might be partially involved in the METH-induced enhancement of LC3-II expression and cell injury. However, the underlying mechanisms require further investigation.
Subject(s)
Apoptosis/drug effects , Autophagy/drug effects , Central Nervous System Stimulants/toxicity , Gene Expression Regulation/drug effects , Methamphetamine/toxicity , Myocytes, Cardiac/drug effects , Animals , Antibiotics, Antineoplastic/pharmacology , Autophagosomes/drug effects , Autophagosomes/enzymology , Autophagosomes/metabolism , Beclin-1/agonists , Beclin-1/genetics , Beclin-1/metabolism , Caspase 3/chemistry , Caspase 3/genetics , Caspase 3/metabolism , Cell Survival/drug effects , Central Nervous System Stimulants/agonists , Central Nervous System Stimulants/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Green Fluorescent Proteins/chemistry , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Lysosomes/drug effects , Lysosomes/enzymology , Lysosomes/metabolism , Macrolides/pharmacology , Membrane Fusion/drug effects , Methamphetamine/agonists , Methamphetamine/antagonists & inhibitors , Microtubule-Associated Proteins/agonists , Microtubule-Associated Proteins/chemistry , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , Poly (ADP-Ribose) Polymerase-1/chemistry , Poly (ADP-Ribose) Polymerase-1/genetics , Poly (ADP-Ribose) Polymerase-1/metabolism , Rats , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/metabolism , Sirolimus/pharmacologyABSTRACT
The use of the synthetic cathinones ("bath salts"), methylone and mephedrone, has been associated with the development of life-threatening hyperthermia. To date, no direct pharmacological intervention to mitigate the hyperthermia induced by synthetic cathinones has been identified. Here, we investigated the effects of the non-selective α1 and ß adrenergic receptor antagonist carvedilol (5mg/kg ip) on established hyperthermia mediated by methylone and mephedrone (30mg/kg sc) in Sprague-Dawley rats. Methylone and mephedrone induced a hyperthermic response that peaked 60min post treatment. The administration of carvedilol 30min after methylone or mephedrone significantly attenuated these hyperthermic responses. Analysis of the Temperature Area Under the Curve (TAUC) demonstrated carvedilol significantly reduced the TAUC associated with methylone or mephedrone alone. The present study provides the first direct pharmacological intervention for the treatment of synthetic cathinone induced hyperthermia.
Subject(s)
Adrenergic beta-Antagonists/pharmacology , Carbazoles/pharmacology , Central Nervous System Stimulants/toxicity , Designer Drugs/chemistry , Fever/chemically induced , Fever/prevention & control , Methamphetamine/analogs & derivatives , Propanolamines/pharmacology , Animals , Body Temperature/drug effects , Carvedilol , Central Nervous System Stimulants/antagonists & inhibitors , Male , Methamphetamine/antagonists & inhibitors , Methamphetamine/toxicity , Rats , Rats, Sprague-DawleyABSTRACT
Melatonin is a hormone that mostly produced from the pineal gland, and it performs as a strong neuroprotectant to both neuron and glial cells against methamphetamine (METH)-induced neurotoxicity. Recently, it has been found that METH also damages the blood brain barrier (BBB) structure and function. However, the protective mechanism of melatonin on the BBB impairment caused by METH has not been investigated. In this study, the primary rat brain microvascular endothelium cells (BMVECs) isolated from neonatal rats was used to investigate the protective effect of melatonin on METH-induced BBB impairment and the underlying mechanism. The results demonstrated that melatonin decreased the level of reactive oxygen species (ROS), reactive nitrogen species (RNS), and apoptosis induced by METH via NADPH oxidase (NOX)-2 since apocynin, a NOX-2 inhibitor abolished those changes. In addition, melatonin was found to improve cell integrity by increasing the transendothelial electric resistance (TEER) values, and up-regulate the tight junction proteins ZO-1, occludin, and claudin-5, thereby decreasing the paracellular permeability caused by METH mediated by NOX-2. Our data suggest that METH induces BBB impairment by mediating NOX-2 activity, and then induces oxidative and nitrative stress, as well as apoptosis, which causes the impairment of cell integrity, and that melatonin reduces these negative effects of METH by mediating via MT1/2 receptors.
Subject(s)
Melatonin/metabolism , Melatonin/therapeutic use , Methamphetamine/antagonists & inhibitors , NADPH Oxidases/metabolism , Animals , Apoptosis/drug effects , Blood-Brain Barrier/metabolism , Brain/metabolism , Brain Diseases/metabolism , Central Nervous System Stimulants/pharmacology , Cerebellum , Claudin-5/metabolism , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Melatonin/pharmacology , Methamphetamine/adverse effects , Methamphetamine/metabolism , NADP , NADPH Oxidases/drug effects , Neuroprotective Agents/pharmacology , Occludin/metabolism , Permeability/drug effects , Rats , Rats, Wistar , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , Tight Junctions/metabolism , Zonula Occludens-1 Protein/metabolismABSTRACT
BACKGROUND: Our pilot study suggested that the angiotensin-converting enzyme inhibitor perindopril might reduce some subjective effects produced by i.v. methamphetamine. We characterized the impact of a wider range of perindopril doses on methamphetamine-induced effects in a larger group of non-treatment-seeking, methamphetamine-using volunteers. METHODS: Before treatment, participants received 30mg methamphetamine. After 5 to 7 days of perindopril treatment (0, 4, 8, or 16mg/d), participants received 15 and 30mg of methamphetamine on alternate days. Before and after treatment, participants rated subjective effects and cardiovascular measures were collected. RESULTS: Prior to treatment with perindopril, there were no significant differences between treatment groups on maximum or peak subjective ratings or on peak cardiovascular effects. Following perindopril treatment, there were significant main effects of treatment on peak subjective ratings of "anxious" and "stimulated"; compared to placebo treatment, treatment with 8mg perindopril significantly reduced peak ratings of both anxious (P=.0009) and stimulated (P=.0070). There were no significant posttreatment differences between groups on peak cardiovascular effects. CONCLUSIONS: Moderate doses of perindopril (8mg) significantly reduced peak subjective ratings of anxious and stimulated as well as attenuated many other subjective effects produced by methamphetamine, likely by inhibiting angiotensin II synthesis. Angiotensin II is known to facilitate the effects of norepinephrine, which contributes to methamphetamine's subjective effects. The lack of a classic dose-response function likely results from either nonspecific effects of perindopril or from between-group differences that were not accounted for in the current study (i.e., genetic variations and/or caffeine use). The current findings suggest that while angiotensin-converting enzyme inhibitors can reduce some effects produced by methamphetamine, more consistent treatment effects might be achieved by targeting components of the renin-angiotensin system that are downstream of angiotensin-converting enzyme.
Subject(s)
Anxiety/drug therapy , Blood Pressure/drug effects , Heart Rate/drug effects , Methamphetamine/administration & dosage , Methamphetamine/pharmacology , Perindopril/pharmacology , Administration, Intravenous , Adolescent , Adult , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Anxiety/chemically induced , Central Nervous System Stimulants/administration & dosage , Central Nervous System Stimulants/antagonists & inhibitors , Central Nervous System Stimulants/pharmacology , Dose-Response Relationship, Drug , Double-Blind Method , Drug Users/psychology , Female , Healthy Volunteers/psychology , Humans , Male , Methamphetamine/antagonists & inhibitors , Middle Aged , Perindopril/antagonists & inhibitors , Young AdultABSTRACT
BACKGROUND: Despite numerous clinical trials no efficacious medications for methamphetamine (MA) have been identified. Neuroinflammation, which has a role in MA-related reward and neurodegeneration, is a novel MA pharmacotherapy target. Ibudilast inhibits activation of microglia and pro-inflammatory cytokines and has reduced MA self-administration in preclinical research. This study examined whether ibudilast would reduce subjective effects of MA in humans. METHODS: Adult, non-treatment seeking, MA-dependent volunteers (N=11) received oral placebo, moderate ibudilast (40 mg), and high-dose ibudilast (100mg) via twice-daily dosing for 7 days each in an inpatient setting. Following infusions of saline, MA 15 mg, and MA 30 mg participants rated 12 subjective drug effects on a visual analog scale (VAS). RESULTS: As demonstrated by statistically-significant ibudilast × MA condition interactions (p<.05), ibudilast reduced several MA-related subjective effects including High, Effect (i.e., any drug effect), Good, Stimulated and Like. The ibudilast-related reductions were most pronounced in the MA 30 mg infusions, with ibudilast 100mg significantly reducing Effect (97.5% CI [-12.54, -2.27]), High (97.5% CI [-12.01, -1.65]), and Good (97.5% CI [-11.20, -0.21]), compared to placebo. CONCLUSIONS: Ibudilast appeared to reduce reward-related subjective effects of MA in this early-stage study, possibly due to altering the processes of neuroinflammation involved in MA reward. Given this novel mechanism of action and the absence of an efficacious medication for MA dependence, ibudilast warrants further study to evaluate its clinical efficacy.
Subject(s)
Amphetamine-Related Disorders/drug therapy , Methamphetamine/antagonists & inhibitors , Pyridines/pharmacology , Reward , Adult , Amphetamine-Related Disorders/psychology , Cross-Over Studies , Double-Blind Method , Female , Humans , Inpatients , Male , Middle Aged , Self Administration , Vasodilator Agents/pharmacologyABSTRACT
BACKGROUND: The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a nontoxic peptide with demonstrated in vitro and in vivo neuroprotective effects against striatal dopaminergic damage induced by 1-methyl-4-phenylpyridinium and 6-hydoxydopamine, suggesting its possible therapeutic potential in Parkinson's disease. Methamphetamine, a widely abused psychostimulant, has selective dopaminergic neurotoxicity in rodents, monkeys, and humans. This study was undertaken to determine whether Hc-TeTx might also protect against methamphetamine-induced dopaminergic neurotoxicity and the consequent motor impairment. METHODS: For this purpose, we treated mice with a toxic regimen of methamphetamine (4mg/kg, 3 consecutive i.p. injections, 3 hours apart) followed by 3 injections of 40 ug/kg of Hc-TeTx into grastrocnemius muscle at 1, 24, and 48 hours post methamphetamine treatment. RESULTS: We found that Hc-TeTx significantly reduced the loss of dopaminergic markers tyrosine hydroxylase and dopamine transporter and the increases in silver staining (a well stablished degeneration marker) induced by methamphetamine in the striatum. Moreover, Hc-TeTx prevented the increase of neuronal nitric oxide synthase but did not affect microglia activation induced by methamphetamine. Stereological neuronal count in the substantia nigra indicated loss of tyrosine hydroxylase-positive neurons after methamphetamine that was partially prevented by Hc-TeTx. Importantly, impairment in motor behaviors post methamphetamine treatment were significantly reduced by Hc-TeTx. CONCLUSIONS: Here we demonstrate that Hc-TeTx can provide significant protection against acute methamphetamine-induced neurotoxicity and motor impairment, suggesting its therapeutic potential in methamphetamine abusers.
Subject(s)
Locomotion/drug effects , Methamphetamine/antagonists & inhibitors , Methamphetamine/toxicity , Neuroprotective Agents/pharmacology , Neurotoxicity Syndromes/prevention & control , Peptide Fragments/pharmacology , Tetanus Toxin/pharmacology , Animals , Body Temperature/drug effects , Cell Count , Corpus Striatum/metabolism , Dopaminergic Neurons/drug effects , Male , Mice , Nerve Degeneration/chemically induced , Nerve Degeneration/prevention & control , Rotarod Performance Test , Tyrosine 3-Monooxygenase/metabolismABSTRACT
RATIONALE: Although dependence to methamphetamine (METH) is associated with serious psychiatric symptoms and is a global health and social problem, no effective therapeutic approaches have been identified. Pseudoginsenoside-F11 (PF11) is an ocotillol-type saponin that is isolated from Panax quinquefolius (American ginseng) and was shown to have neuroprotective effects to promote learning and memory and to antagonize the pharmacological effects of morphine. Furthermore, PF11 also shows protective effects against METH-induced neurotoxicity in mice. However, the effects of PF11 on METH-induced preference and dopamine (DA) release have not been defined. OBJECTIVES: We investigated the effects of PF11 administration on METH-induced hyperlocomotion and conditioned place preference (CPP) in mice. Subsequently, extracellular DA and gamma-aminobutyric acid (GABA) levels were determined in the nucleus accumbens (NAc) of mice after co-administration of PF11 and METH using in vivo microdialysis analyses. Moreover, the effects of PF11 administration on the µ-opioid neuronal responses, DAMGO (µ-opioid receptor agonist; [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin)-induced hyperlocomotion and accumbal extracellular DA increase were investigated to elucidate how PF11 inhibits METH-induced dependence by dopaminergic neuronal hyperfunction. RESULTS: Co-administration of PF11 and METH for 6 days attenuated METH-induced locomotor sensitization compared with treatment with METH alone. In the CPP test, PF11 administration also inhibited METH-induced place preference. In vivo microdialysis analyses indicated that co-administration of PF11 and METH for 7 days prevented METH-induced extracellular DA increase in the NAc and repeated PF11 administration with or without METH for 7 days increased extracellular GABA levels in the NAc, whereas single administration of PF11 did not. Furthermore, DAMGO-induced hyperlocomotion and accumbal extracellular DA increase were significantly inhibited by acute PF11 administration. CONCLUSIONS: The present data suggest that PF11 inhibits METH-induced hyperlocomotion, preference, and accumbal extracellular DA increase by regulating GABAergic neurons and µ-opioid receptors.
Subject(s)
Behavior, Animal/drug effects , Central Nervous System Stimulants/antagonists & inhibitors , Dopamine Uptake Inhibitors/antagonists & inhibitors , Dopaminergic Neurons/drug effects , Ginsenosides/pharmacology , Methamphetamine/antagonists & inhibitors , Neurons/drug effects , Nucleus Accumbens/drug effects , gamma-Aminobutyric Acid/physiology , Analgesics, Opioid/pharmacology , Animals , Conditioning, Operant/drug effects , Dopamine/metabolism , Dopamine Uptake Inhibitors/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Male , Methamphetamine/pharmacology , Mice , Mice, Inbred ICR , Nucleus Accumbens/cytology , Receptors, Opioid, mu/drug effectsABSTRACT
Resveratrol is originally extracted from huzhang, a Chinese herbal medicine. Recently, resveratrol has attracted a great of attention due to its antioxidant and antiapoptotic properties. Although the neuroprotection of resveratrol on neural damages in various models has been well characterized, little is known about the role of resveratrol in methamphetamine (MA) induced neurotoxicity in mesencephalic dopaminergic neurons. Dopaminergic neurons were isolated from midbrain of mouse embryos at embryonic day 15 and cultured in the presence of MA and resveratrol. Cell viability was examined by MTT assay and the apoptosis was assessed using Hoechst33342/PI double staining. To evaluate the Oxidative damage, ROS assay was performed. Moreover, the changes of time course of intracellular free calcium concentration ([Ca(2+) ]i) were analyzed with Fluo-3/AM tracing. The data showed that MA induced the neurotoxicity of cultured cells in a dose-dependent manner. Resveratrol significantly increased cellular viability and retarded cell apoptosis. Furthermore, resveratrol also attenuated MA induced ROS production and intracellular free calcium overload. Our results suggest that resveratrol protects dopaminergic neurons from MA-induced neuronal cytotoxicity, which, at least partly, is mediated by inhibition of [Ca(2+) ]i and oxidative stress. © 2015 BioFactors 41(4):252-260, 2015.
Subject(s)
Antioxidants/pharmacology , Dopamine Uptake Inhibitors/antagonists & inhibitors , Dopaminergic Neurons/drug effects , Methamphetamine/antagonists & inhibitors , Neuroprotective Agents/pharmacology , Stilbenes/pharmacology , Aniline Compounds , Animals , Apoptosis/drug effects , Calcium/metabolism , Cell Survival/drug effects , Dopamine/metabolism , Dopamine Uptake Inhibitors/toxicity , Dopaminergic Neurons/cytology , Dopaminergic Neurons/metabolism , Embryo, Mammalian , Fluorescent Dyes , Mesencephalon/cytology , Mesencephalon/drug effects , Mesencephalon/metabolism , Methamphetamine/toxicity , Mice , Oxidative Stress , Primary Cell Culture , Reactive Oxygen Species/agonists , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Resveratrol , XanthenesABSTRACT
Valproate (VPA) has recently been shown to influence the behavioral effects of psycho-stimulants. Although glycogen synthase kinase 3ß (GSK3ß) signaling in the nucleus accumbens (NAc) plays a key role in mediating dopamine (DA)-dependent behaviors, there is less direct evidence that how VPA acts on the GSK3ß signaling in the functionally distinct sub-regions of the NAc, the NAc core (NAcC) and the NAc shell (NAcSh), during psycho-stimulant-induced hyperactivity. In the present study, we applied locomotion test after acute methamphetamine (MA) (2 mg/kg) injection to identify the locomotor activity of rats received repeated VPA (300 mg/kg) pretreatment. We next measured phosphor-GSK3ß at serine 9 and total GSK3ß levels in NAcC and NAcSh respectively to determine the relationship between the effect of VPA on MA-induced hyperlocomotor and changes in GSK3ß activity. We further investigated whether microinjection of VPA (300 µg/0.5 µl/side, once daily for 7 consecutive days) into NAcC or NAcSh could affect hyperactivity induced by MA. Our data indicated that repeated VPA treatment attenuated MA-induced hyperlocomotor, and the effect was associated with decreased levels of phosphorylated GSK3ß at Ser 9 in the NAcC. Moreover, repeated bilateral intra-NAcC, but not intra-NAcSh VPA treatment, significantly attenuated MA-induced hyperactivity. Our results suggested that GSK3ß activity in NAcC contributes to the inhibitory effects of VPA on MA-induced hyperactivity.
Subject(s)
Glycogen Synthase Kinase 3/metabolism , Hyperkinesis/chemically induced , Hyperkinesis/pathology , Methamphetamine/adverse effects , Nucleus Accumbens/drug effects , Signal Transduction/drug effects , Valproic Acid/pharmacology , Animals , Behavior, Animal/drug effects , Central Nervous System Stimulants/adverse effects , Central Nervous System Stimulants/antagonists & inhibitors , Glycogen Synthase Kinase 3/chemistry , Glycogen Synthase Kinase 3 beta , Hyperkinesis/drug therapy , Hyperkinesis/physiopathology , Male , Methamphetamine/antagonists & inhibitors , Microinjections , Motor Activity/drug effects , Nucleus Accumbens/metabolism , Nucleus Accumbens/pathology , Phosphorylation/drug effects , Rats , Rats, Sprague-Dawley , Serine/metabolism , Valproic Acid/administration & dosage , Valproic Acid/therapeutic useABSTRACT
BACKGROUND: d-Methamphetamine (METH) addiction is a serious public health concern for which successful treatment remains elusive. Immunopharmacotherapy has been shown to attenuate locomotor and thermoregulatory effects of METH. The current study investigated whether active vaccination against METH could alter intravenous METH self-administration in rats. METHODS: Male Sprague-Dawley rats (Experiment 1: N=24; Experiment 2: N=18) were vaccinated with either a control keyhole-limpet hemocyanin conjugate vaccine (KLH) or a candidate anti-METH vaccine (MH6-KLH) or. Effects of vaccination on the acquisition of METH self-administration under two dose conditions (0.05, 0.1mg/kg/inf) and post-acquisition dose-substitution (0, 0.01, 0.05, 0.20mg/kg/inf, Experiment 1; 0.01, 0.05, 0.10, 0.15mg/kg/inf, Experiment 2) during steady-state responding were investigated. Plasma METH concentrations were determined 30min after an acute challenge dose of 3.2mg/kg METH. RESULTS: Active vaccination inhibited the acquisition of METH self-administration under the 0.1mg/kg/inf dose condition, with 66% of the MH6-KLH-vaccinated rats compared to 100% of the controls reaching criteria, and produced transient and dose-dependent effects on self-administration during the maintenance phase. Under the 0.05mg/kg/inf dose condition, MH6-KLH-vaccinated rats initially self-administered more METH than controls, but then self-administration decreased across the acquisition phase relative to controls; a subsequent dose-response assessment confirmed that MH6-KLH-vaccinated rats failed to acquire METH self-administration. Finally, plasma METH concentrations were higher in MH6-KLH-vaccinated rats compared to controls after an acute METH challenge, and these were positively correlated with antibody titers. CONCLUSIONS: These data demonstrate that active immunopharmacotherapy for METH attenuates the acquisition of METH self-administration.